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Oxadiazole scaffolds in anti-tuberculosis drug discovery
Bioorganic & Medicinal Chemistry Letters xxx (xxxx) xxx–xxx
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Oxadiazole scaffolds in anti-tuberculosis drug discovery Suparna S. Dea,1, Mihir P. Khambetea,b,1, Mariam S. Degania,
⁎
a b
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N.P Marg, Matunga (East), Mumbai 400019, India SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, Gate No. 1, Mithibai College Campus, V.M. Road, Vile Parle (West), Mumbai 400056, India
ARTICLE INFO
ABSTRACT
Keywords: Tuberculosis Oxadiazole Regioisomer Bioisoster Linker
With the increasing number of cases of latent and drug resistant tuberculosis, there is an urgent need to develop new, potent molecules capable of combating this deadly disease. Molecules containing oxadiazoles are one such class that could be considered to fulfil this need. Oxadiazole regioisomers have been explored in drug discovery programs for their ability to act as effective linkers and also as pharmacophoric features. Oxadiazoles can act as bioisosteric replacements for the hydrazide moiety which can be found in first line anti-TB drugs, and some have been also reported to interact with newer anti-TB targets. In this context, the present review describes the potential of oxadiazoles as antituberculosis agents.
Introduction Latency in tuberculosis (TB) as well as development of drug resistance contribute to TB being the leading cause of death due to infectious diseases. To achieve the United Nations goal of eradicating TB by 2030, several measures are being taken. Amongst the technological breakthroughs, development of newer drugs and vaccines are of prime importance.1 New drugs, which would combat latency and drug resistance require addressing newer, validated molecular targets, as well as designing molecules with better pharmacokinetic and pharmacodynamic properties. Design of new molecules, encompasses understanding of novel pharmacophoric features to address the newer targets. Various approaches to increase the efficacy and decrease the toxicity of existing effective drug molecules, by minor modification in their chemical structure to alter their molecular properties, should also be explored. In this connection, oxadiazoles could be moieties with specific properties worth exploring for design of new chemical entities. Oxadiazoles, are five-membered aromatic heterocycles containing two carbon atoms, two nitrogen atoms, and one oxygen atom. These have recently drawn attention of many research groups, because of their potential to be good bioisosteric replacement options for many carbonyl containing functional groups. Furamizole, an antibiotic and nesapidil (Fig. 1), a class IV antiarrhythmic agent were introduced in the 1970’s. Then after a gap of a few decades, with the US-FDA approval of raltegravir, an antiretroviral drug, and ataluren and zibotentan entering late phases of clinical trials for the treatment of cystic fibrosis and cancer respectively, using oxadiazole containing molecules
in drug discovery has accelerated. The level of interest amongst researchers can be clearly seen from the recent increase in the number of research papers and patent applications with respect to oxadiazole ring containing molecules.2 A wide range of pharmacological activities like antibacterial including anti TB, antifungal, analgesic, anti-inflammatory, antiviral, anticancer, antihypertensive, anticonvulsant have been shown by molecules containing oxadiazole in their backbone.3 The present review describes some key properties of oxadiazoles, followed by an account on various reported oxadiazole containing molecules as antituberculosis agents. Properties of regioisomers of oxadiazole There are three stable regioisomers of oxadiazole, (Fig. 2) a 1,2,3isomer, a 1,3,4-isomer and a 1,2,5-isomer all of which are weakly basic.4 The 1,2,3 regioisomer, being very unstable in the cyclic form, exists mostly in the diazoketone5 tautomeric form and is not considered here. In all the oxadiazoles, two substituents are possible on the two carbon atoms, and their relative positions can lead to differences in the properties of the resultant derivatives. In the 1,2,4-regioisomer, one of the substitutions is between two nitrogen atoms and the other is between the nitrogen and oxygen atom; while in case of 1,3,4-regioisomer, both the substitutions are located between oxygen and nitrogen atoms. Thus, in both these regioisomers, though the substituents are placed in very similar positions with similar bond angles, there is a slight variation in the electronic environment surrounding the side chains. But in the case of the 1,2,5-regioisomer, both the possible
Corresponding author. E-mail address: [email protected] (M.S. Degani). 1 Both authors contributed equally to this manuscript. ⁎
https://doi.org/10.1016/j.bmcl.2019.06.054 Received 11 April 2019; Received in revised form 12 June 2019; Accepted 27 June 2019 0960-894X/ © 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Suparna S. De, Mihir P. Khambete and Mariam S. Degani, Bioorganic & Medicinal Chemistry Letters, https://doi.org/10.1016/j.bmcl.2019.06.054
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Fig. 1. Drugs containing oxadiazole ring.
moiety attached to the oxadiazole ring via a thioether linker at one end and a substituted aromatic ring at the other end. The synthesized compounds were tested for the in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv using the Alamar Blue assay method. Among these, some of the derivatives exhibited more than 90% inhibition at concentration of 12.5 µg/ml. The most active derivative 1 (Fig. 3) showed 98% inhibition. The potent molecules were docked on mycobacterial F420H(2)-dependent reductase Rv1155 (https://www. uniprot.org/uniprot/O06553) and it was observed that the most active compounds dock well in the active site of the enzyme. Inhibitory activity of the most potent compounds was attributed to hydrogen bonding and either electrostatic or pi–pi interactions within the active site of the enzyme. Further, hydrophilic and steric requirements were found to be important factors for SAR. Synthesis of 7-substituted tetrazolo [1,5-a] quinolines incorporating 1,3,4-oxadiazole nucleus was reported by Sapariya et al.9 The in vitro antituberculosis activity was carried out at 100 μg/ml concentration, molecules 2a and 2b (Fig. 3) displayed more than 90% inhibition at this concentration. A series of 5-(4-(1H-pyrrol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl substituted benzothioate derivatives were synthesized by Joshi et al.10 and were evaluated for their in vitro anti-TB activity. Preliminary results indicated that most of the compounds demonstrated moderate to good activity, with compounds 3a-3d (Fig. 3) displaying inhibition at 12.5 µg/ml. The docking studies on the Mycobacterium tuberculosis enoyl reductase (InhA) (PDB ID: 4TZK) showed essential hydrogen bonding interaction between the nitrogen atoms of the oxadiazole ring and the amino acid (Tyr158) and co-factor (NAD+). Additionally, amino acids (Ile21, Phe97, Met98, Pro99, Met103, Ala157, Trp160, Met161, Pro193, Ile194, Trp230) were necessary for hydrophobic contacts. De Souza et al.11 combined the 1,3,4-oxadiazole ring with a protected sugar moiety and tested the derivatives for their antimycobacterial activity. Molecule 4 (Fig. 3) was found to be one of the most active molecules with MIC of 60 µM. This was followed by use of principle component analysis (PCA) to assess the structure activity relationship using various descriptors. Karad et al.12 explored the biological applications of fluoro substituted pyrazole nucleus clubbed with 1,3,4-oxadiazole scaffolds, antituberculosis activity being one of the important potential applications. The molecules were designed by making the hybridization of pyrazole and 1,3,4-oxadiazole moieties. Antituberculosis screening of all the synthesized molecules was conducted and four molecules, 5a-5d (Fig. 3) were found to display more than 90% inhibition at 250 µg/ml. Sajja et al.13 developed a series of molecules which were composed
Fig. 2. Regioisomers of oxadiazole.
substituents are adjacent to each other and are located between two nitrogen atoms, making the orientation of the groups considerably different compared to the other two regioisomers. As a result of this, the matched pairs – 1,2,4-isomer and 1,3,4-isomer, show similar overall molecular shapes and are thus expected to fit receptors with wider pockets and bind in a similar fashion, while the 1,2,5-isomer would fit receptors with narrow active site pockets. All the regioisomers have significantly different hydrogen bond acceptor potential and intrinsically different charge distributions (i.e., dipole moments). In a systematic study, Bostrom et al.6 have compared the matched pairs of 1,2,4- and 1,3,4-oxadiazoles, from the AstraZeneca compound collection, with respect to their lipophilicity, solubility, metabolic stability and hERG inhibition potential. Their results indicated that the 1,3,4oxadiazole isomers show lower lipophilicity (log D), higher aqueous solubility, better metabolic stability and a lower affinity towards the hERG receptor, compared to the 1,2,4-counterparts. The insight into these properties could help in designing oxadiazole containing drug molecules with desirable lipophilicity, solubility and metabolic stability. In the next sections, anti TB compounds containing oxadiazole as a linker or a pharmacophoric feature have been described. The antituberculosis activities have been estimated using various strains of Mycobacteria, most prominent of which is Mycobacterium tuberculosis H37Rv, and have been carried out employing various methods such as Alamar blue assay, BACTEC assay and agar dilution method. 1,3,4-Oxadiazoles Many molecules with 1,3,4-oxadiazole have been designed, some as structural analogues of isoniazid, with the hydrazide group being replaced by the oxadiazole moiety. Macaev et al.7,8 have reported five different structurally diverse series of molecules containing 1,3,4-oxadiazole thioethers, using techniques such as electronic-topological method (ETM) and neural network (NN) methods for design. These molecules have a hydrophobic 2
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Fig. 3. 1,3,4-Oxadiazoles as antituberculosis agents.
by fusion of a pyridine-oxadiazole moiety with a benzocycloheptane ring system. This design was conceived by replacing the pyridine ring of isoniazid with benzo[6,7]cyclohepta[1,2-b]pyridine and replacing the hydrazide fragment with oxadiazole. Molecule 6 (Fig. 3) displayed highest inhibitory activity of 1.56 µg/ml. The presence of methoxy group/s on phenyl ring attached to the oxadiazole moiety was found to be crucial for antituberculosis activity. Gholap et al.14 combined 1,3,4-oxadiazole with trifluoromethylphenyl and benzofuranylamide moieties and tested these compounds for their antimycobacterial potential. These compounds exhibited MIC values in the range of 2–24 µg/ml with the most active compound, 7 (Fig. 3), displaying an IC90 of 5.7 µM against dormant Mtb
H37Ra. The compounds were observed to be non-toxic to host cells when tested against the cell lines THP-1, A549 and PANC-1. A series of novel N-(furan-2-yl)-1-(5-substituted) phenyl-1,3,4-oxadiazol-2-yl) methanimines were synthesized and evaluated by Mathew et al.15 for their activity against Mycobacterium tuberculosis (H37Rv) strain using Alamar Blue assay. The most active compound of this series, 8 (Fig. 3) displayed MIC of 3.125 µg/ml. Molecular modelling studies were also carried out on the designed molecules to assess their binding with Mycobacterium tuberculosis InhA, and were found to display similar interactions as those reported earlier by Joshi et al.10 Desai et al.16,17 reported several 2,3-dihydro-1,3,4-oxadiazole containing molecules with general structure 9 (Fig. 4), where the 3
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Fig. 4. 1,3,4-Oxadiazoles (contd.).
oxadiazole ring-nitrogen was attached to the linker. For the aromatic/ heteroaromatic part of the molecules, phenyl and indole ring were explored while the linker was chalcone or hydrazide. The molecules were evaluated for their in vitro antituberculosis activity against Mtb H37Ra and Mycobacterium bovis BCG strains, both in active and dormant states. The activity for the molecules with hydrazide linker was found to be < 5 µM against the active form of Mtb H37Ra. Additionally, molecular docking was performed against InhA to predict the binding modes and affinity. Karabanovich et al.18 reported the discovery and structure-activity relationships of 5-substituted-2-[(3,5-dinitrobenzyl)-sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as antituberculosis agents, designed on the basis of 5-(3,5-dinitrobenzylsulfanyl)tetrazoles reported by the same research group. These were hypothesized to act on mycobacterial decaprenylphosphoryl-β-D-ribofuranose-2′-oxidase (DprE1), which is involved in the synthesis of decaprenylphosphoryl arabinose, the only
donor of arabinosyl residues for the biosynthesis of arabinan polymers in mycobacteria. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 μM (Molecule 10, Fig. 4). These derivatives also showed high selectivity towards mycobacteria along with no in vitro cytotoxicity. The same research group reported tertiary amine containing derivatives of 3,5-dinitrophenyl oxadiazole as antituberculosis agents,19 where the Nbenzylpiperazine derivatives had MIC values less than 3 µM. Further, by changing the orientation of substituents in compound 10, a new series of molecules was reported. The most active molecule, 11 (Fig. 4) with 4-methoxybenzyl moiety displayed inhibition of 0.03 µM. The presence of electron withdrawing groups, either two nitro groups or one nitro and one trifluoromethyl group, led to high antimycobacterial activity.20 Ahsan et al.21,22 described the antimycobacterial activity of 1,54
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dimethyl-2-phenyl-4-([5-(arylamino)-1,3,4-oxadiazol-2-yl]methylamino)-1,2-dihydro-3H-pyrazol-3-one analogues. Among the synthesized compounds, derivatives 12a and 12b (Fig. 4) were found to be most promising, with MIC of 0.78 µg/ml against Mycobacterium tuberculosis H37Rv. Patel et al.23 synthesized novel quinolinyl-oxadiazoles as antituberculosis agents. The most active compound of the series, 13 (Fig. 4), containing a benzothiazolylacetamide moiety displayed an inhibitory activity of 6.25 µg/ml. Ladani et al.24 further combined chloroquinolines and 1,3,4-oxadiazoles, employing chloro-amine coupling reactions with different catalysts. The synthesized molecules were evaluated for their antituberculosis activity along with their anti-infective potential. However, molecules had low activity, with four molecules 14a-14d (Fig. 4) showing inhibition at the concentration of 250 µg/ml and MIC values ranging from 60 to 200 µM. Vazquez et al.25 synthesized a series of 4-(5-substituted-1,3,4-oxadiazol-2-yl) pyridine derivatives with long aliphatic side chains and evaluated the in vitro antimycobacterial activity. Compounds 15a and 15b (Fig. 4) showed activities comparable to INH and streptomycin against Mycobacterium tuberculosis (Mtb) with MIC values of 0.35 µM and 0.65 µM respectively. Both these molecules have a highly lipophilic chain at the 5 position of the oxadiazole moiety which is possibly an important factor for enhanced permeability of these molecules. Further, these were tested against five clinical isolates (drug-sensitive and -resistant strains). Interestingly these compounds were more than 10 times as active as the first line anti-TB drugs (INH, streptomycin and ethambutol) against the drug-resistant strain CIBIN 112. Armakovic and co-workers26–28 reported molecules containing 1,3,4-oxadiazole moiety attached to a pyrazine ring, 16 (Fig. 4). The molecule with unsubstituted phenyl ring (16a) and the one with furan ring (16b) displayed activity of 1.6 µg/ml, while the most active molecules of the series, 16c, 16d and 16e displayed inhibitory activity of 0.8 µg/ml, which was 4 times more active than the reference, pyrazinamide. Mtb shikimate kinase (MtSK), is an important enzyme of the shikimate pathway, especially for synthesis of metabolites like folic acid, quinones and aromatic amino acids in Mtb. As this pathway is absent in mammals, MtSK inhibitors could be potentially selective and non-toxic antituberculosis agents. Simithy et al.29 synthesized a series of oxadiazole-amides, and tested them for their Mtb shikimate kinase (MtSK) inhibitory activity through a LC-MS based functional assay, where the formation of shikimate-3-phospate (S3P) was quantified. Compounds 17a and 17b (Fig. 5) were found to be the most potent molecules within the oxadiazole series with MIC values < 1 µg/ml against Mtb H37Rv. Additionally, MtSK IC50 values for these 2 compounds were found to be 3.79 µM and 3.43 µM, respectively. The trans-translation process, which is absent in humans, is the only mechanism in Mtb to rescue the stalled ribosomes at 3′end of m-RNA. Alumasa et al.30 exploited this pathway and reported an oxadiazole containing molecule, 17c, as a ribosome rescue inhibitor. The molecule was bactericidal and was found to be active against both, replicating as well as non-replicating bacteria (with 8 µg/ml and 1.6 µg/ml of drug killing > 90% of the replicating and non-replicating cells respectively). The MIC values against Mtb Erdman strain and M. smegmatis were found
to be 1.6 µg/ml and 0.4 µg/ml respectively. The molecule at concentrations more than 20 fold the MIC, showed no cytotoxicity on HepG2 cells. Docking studies were also carried out for 17c on the 50S ribosome region of Mtb (PDB ID: 4ABR). The in-vitro as well as in-silico studies suggested that 17c binds to a pocket adjacent to the polypeptidyl-transfer centre (PTC) at the base of Helix 89 in the ribosome, in such a way that it selectively inhibits the trans-translation process but does not inhibit the process of translation initiation, elongation, or termination. The researchers explain that the polar interactions between the carbonyl oxygen atom and the oxadiazole core of the 17c, with the H89, limits the flexibility of H89, preventing structural changes that are required for ribosome rescue but not for translation. Mtb is capable of adapting to the availability of varying carbon sources within the host environment. To simulate this host environment, Early et al.31 developed and ran a phenotypic screen using butyrate as the sole carbon source. They screened a library of ∼87,000 small compounds and identified potential anti-TB compounds. Interestingly, six out of forty eight potential compounds which were considered for further evaluation studies, contained oxadiazole moiety in the structure. These compounds were found to be selectively active against Mtb grown in medium with butyrate as the source of fatty acids, but were inactive in medium with glucose. The most active compound 18 (Fig. 5), displayed an activity of 0.4 µM against Mtb grown in butyrate containing medium. Thus, it could be assumed that these molecules act on the novel targets which are not expressed in the presence of glucose as the primary carbon source. Further studies can be carried out to identify such unique and novel targets. 1,2,4-Oxadiazoles A few research groups have explored 1,2,4-oxadiazoles as linkers in antituberculosis agents, similar to 1,3,4-oxadiazoles. Sriram and co-workers32 reported the synthesis and biological evaluation of 1,2,4-oxadiazole containing molecules by 1,3-cycloaddition reaction with 4(H)-pyrans, These molecules were screened for their in vitro antimycobacterial activity against Mtb and MDR-TB by agar dilution method and one of the compounds, 19a (Fig. 6) displayed activities of 0.07 µM and 0.14 µM respectively against Mtb and MDR TB. The stereochemistry of the pyran was seen to be important for Mtb activity but unimportant for MDR TB. Further, employing chemoselective cycloaddition reactions, they also reported hybrids of 1,2,4-oxadiazole with pyranopyridine and chromene moieties.33 Among the pyranopyridines hybrids, 4-chlorophenyl and 2,4-dichlorophenyl substituted molecules displayed MICs of 0.3 µM which was comparable with INH. The importance of tertiary nitrogen was established from the observation that the hybrids containing chromene moiety displayed lower activity compared to their pyranopyridine counterparts. Willand et al.34 designed a series of 1,2,4-oxadiazole containing molecules as EthR inhibitors and studied their binding properties with the help of X-ray crystallography. Like many anti-TB drugs, ethionamide is a prodrug activated by flavin monooxygenase, EthA, which is regulated by the transcriptional repressor EthR. Thus, inhibiting EthR can be used to improve the therapeutic index of ethionamide. Taking this into consideration, they studied the ligand binding domain of EthR, and reported the existence of two mobile phenylalanine residues that control the access to a hydrophobic pocket, which if exploited further could lead to development of structurally diverse EthR inhibitors. The study revealed that the oxadiazole ring of the ligand is involved in a Tshape interaction with Trp103. A thorough SAR of these molecules concluded that 1,2,4-oxadiazole ring was essential for the activity. Specifically, the position of the oxygen atom in the heterocyclic ring was found to play a critical role in binding. As a linker to oxadiazole ring, 5 or 6 membered cyclic amide was preferred, which when replaced with cyclic sulphonamide or cyclic urea, led to decrease in activity. Moreover the cyclic amide, when attached to cyclopropyl,
Fig. 5. 1,3,4-Oxadiazoles as inhibitors of Mycobacterial enzymes. 5
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Fig. 6. 1,2,4-Oxadiazoles as antituberculosis agents.
cyclopentyl or cyclohexyl rings, showed better activity compared to their 5/6 membered aromatic counterparts. The most active molecule of the series, 20 (Fig. 6) displayed IC50 of 0.4 µM along with suitable physicochemical properties and microsomal stability. Further, it was able to boost ethionamide activity by 10-fold on Mtb infected macrophages at nanomolar concentration.35,36 Taking into consideration various anti-infective 1,2,4-oxadiazole and benzimidazole derivatives reported in literature, Shruthi et al.37 reported novel hybrids of these two moieties as antimycobacterial agents. Molecules containing chloro substituted phenyl ring or benzyl ring as aromatic substitutions on oxadiazole ring, along with disubstituted phenyl ring attached to the benzimidazole moiety, 21a-21d (Fig. 6), were found to display MIC of 1.6 µg/ml. A series of substituted 2-nitro-1-(4-tolylsulfonyl)-2-(3-methylphenyl-1,2,4-oxadiazol-5-yl)ethanes were synthesized and their antimycobacterial activity was studied by Tyrkov et al.38 The most active compound among the series, 22 (Fig. 6) displayed activity of 3.2 µg/ml along with high LD50 values. Taking into consideration the antituberculosis activity of nicotinamide and pyrazinamide, Gezginci et al.39 reported synthesis and
biological evaluation of pyridines and pyrazines substituted with 1,2,4oxadiazole-5-ones and 1,2,4-oxadiazole-5-thiones. Further, pivaloyloxymethyl (POM) derivatives were also prepared in order to increase their lipophilicity and therefore improve their cellular permeability. All the molecules, 23a,b and c (Fig. 6), displayed MIC of > 50 µg/ml against Mycobacterium tuberculosis H37Rv strain. Jain et al.40 reported a series of novel quinoline-oxadiazole hybrid compounds which were designed based on stepwise rational modifications involving bioisosteric replacement of isoxazole ring with 1,2,4-oxadiazole ring, along with replacement of ester functionality with various hydrophobic moieties. The synthesized compounds were then screened for anti-TB activity against Mtb H37Rv strain and for cytotoxicity in HepG2 cell line. Several molecules (24a-24c, Fig. 6) exhibited good to excellent anti-TB activity and selectivity (minimum inhibitory concentration values < 0.5 μM and selectivity index > 500). The activity data of the series showed that substituted benzyl ring was preferred over 2-furan or pyridyl ring as the “R” group. One of the compounds when tested for microsomal stability using rat microsomes, proved that the quinolone oxadiazole derivatives were 99% metabolically stable for 60 min. 6
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Fig. 7. Molecules containing 1,2,5-oxadiazole moiety.
As can be seen from the above publications, generally 1,2,4-oxadiazole ring is flanked by 2 hydrophobic groups, with or without linker, in most cases of active compounds.
commercially developed for the treatment of TB, but its clinical utility is limited due to toxicity issues arising from lack of target-specificity. Hence, inhibitors which are not substrate analogs and act through different mechanisms of enzyme inhibition could prove useful. With this aim in mind, Karen et al.42 synthesized a series of molecules, where one of the molecules, 26 (Fig. 7) had an oxadiazole ring. Though the derivative was inactive against Mtb, the window for exploring oxadiazoles derivatives against this target has been opened. Though both the studies reported molecules with moderate to poor anti-tuberculosis activity, the targets explored were new and hence can be further explored by researchers for the development of newer oxadiazole containing anti-tuberculosis agents.
1,2,5-Oxdiazoles There have been only a couple of reports where, 1,2,5-oxadiazole containing molecules have been explored for their anti-tuberculosis activity. Nitric Oxide (NO) is an important mediator produced by macrophages during Mycobacterium tuberculosis (Mtb) infection. It has been demonstrated that NO can disrupt bacterial DNA, proteins, signalling mediators, and/or cause induction of macrophage apoptosis. Furoxan (1,2,5-oxadiazole N-oxide) is one such nitric oxide donor with promising antituberculosis activity. Taking this into consideration, Fernandes et al.41 reported the hybrids of furoxan and isonicotinic acid hydrazide derivatives obtained from phenotypic screening of their compound library. The molecules were tested against Mtb H37Rv along with INH and Rifampicin resistant strains of Mtb. Molecule 25 (Fig. 7) displayed MIC90 of 1 µM and 7 µM against the above mentioned strains respectively. Alanine racemase is an essential enzyme of the cell wall synthesis pathway, that racemizes L-alanine into D-alanine, which is a key
Analysis of oxadiazole containing molecules as antituberculosis agents In case of 1,2,4-oxadiazole containing molecules, the substitutions are carried out on 3 and 5 positions of the oxadiazole ring. These substitutions have been summarized in Fig. 8. At position 3, various aromatic and heteroaromatic substitutions such as phenyl, benzyl, pyridyl and thiazolyl are preferred while at 5 position a variety of unique moieties have been explored such as pyranopyridine, substituted piperidine, benzimidazole and thio linked POM.
Fig. 8. Structural analysis of 1,2,4-oxadiazoles as antituberculosis agents.
In case of 1,3,4-oxadiazoles, on the other hand, the substitutions take place at 2 and 5 positions of the ring giving the molecule a different shape. Fig. 9. shows different substitutions at A and B positions.
building block in the biosynthesis of peptidoglycan. This key enzyme of Mtb, could become a very attractive target as the enzyme is absent in humans. Till date cycloserine is the only alanine racemase inhibitor,
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Fig. 9. Structural analysis of 1,3,4-oxadiazoles as antituberculosis agents.
Conclusion
(F.25-1/2014-15(BSR)/No. F.5-63/2007(BSR)) and Mihir Khambete is thankful to DST-INSPIRE, India (IF130396) for financial support.
As seen from the above data, oxadiazole ring has been introduced into drug discovery programs for several different purposes. Very few have been designed to be an essential part of the pharmacophore, favourably contributing to ligand binding. Many may act as flat, aromatic linkers to place substituents in the appropriate orientation. Most oxadiazoles prove to be a good option for bioisosteric replacement of carbonyl containing compounds such as esters, amides, carbamates, and hydroxamic esters. Structural analysis shows that oxadiazole regioisomers have been attached with chemically diverse moieties ranging from simple alkyl groups to various aromatic and heteroaromatic moieties such as phenyl, benzyl, pyridyl, thiazolyl, benzimidazole and pyranopyridine to name a few. It has also recently been shown that two structurally related oxadiazole regioisomers, can be used to achieve significant differences in thermodynamic properties. Most of the research on anti-TB drug development has focused on molecules where the oxadiazole ring is present at the centre part of the molecule, unlike several current oxadiazole containing drugs (Fig. 1), where the ring, with or without small functional groups, is towards the end of the molecule and a key part of the pharmacophore. Moreover, with availability of several probable targets such as EthR, InhA, shikimate kinase, alanine racemase along with ability to act as nitric oxide donor, there is still a wide scope to explore potential of oxadiazoles from these perspectives.
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Acknowledgements Suparna De is thankful to University Grants Commission, India 8
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oxadiazole benzothioate derivatives. Rajiv Gandhi Univ Heal Sci J Pharm Sci. 2015;5:69–80. https://doi.org/10.5530/rjps.2015.2.6. De Souza AO, Pedrosa MT, Alderete JB, et al. Cytotoxicity, antitumoral and antimycobacterial activity of tetrazole and oxadiazole derivatives. Pharmazie. 2005;60:396–397. Karad SC, Purohit VB, Avalani JR, Sapariya NH, Raval DK. Design, synthesis, and characterization of a fluoro substituted novel pyrazole nucleus clubbed with 1,3,4oxadiazole scaffolds and their biological applications. RSC Adv. 2016;6:41532–41541. https://doi.org/10.1039/c6ra01349j. Sajja Y, Vanguru S, Vulupala HR, et al. Design, synthesis, and in vitro antituberculosis activity of benzo[6,7]cyclohepta[1,2-b]pyridine-1,3,4-oxadiazole derivatives. Chem Biol Drug Des. 2017;90:496–500. https://doi.org/10.1111/cbdd. 12969. Gholap S, Tambe M, Nawale L, Sarkar D, Sangshetti J, Damale M. Design, synthesis, and pharmacological evaluation of fluorinated azoles as anti-tubercular agents. Arch Pharm. 2018;351. https://doi.org/10.1002/ardp.201700294. Mathew B, Suresh J, Mathew GE, George S, Krishnan G. Design, synthesis, toxicity estimation and molecular docking studies of N-(furan-2-yl)-1-(5-substituted) phenyl1,3,4-oxadiazol-2-yl) methanimine as antitubercular agents. Indian J Pharm Sci. 2014;76:401–406. Desai NC, Somani H, Trivedi A, et al. Synthesis, biological evaluation and molecular docking study of some novel indole and pyridine based 1,3,4-oxadiazole derivatives as potential antitubercular agents. Bioorg Med Chem Lett. 2016;26:1776–1783. https://doi.org/10.1016/j.bmcl.2016.02.043. Desai NC, Trivedi A, Somani H, et al. Synthesis, biological evaluation, and molecular docking study of pyridine clubbed 1,3,4-oxadiazoles as potential antituberculars. Synth Commun. 2018;48:524–540. https://doi.org/10.1080/00397911.2017. 1410892. Karabanovich G, Zemanova J, Smutny T, et al. Development of 3,5-dinitrobenzylsulfanyl-1,3,4-oxadiazoles and thiadiazoles as selective antitubercular agents active against replicating and nonreplicating Mycobacterium tuberculosis. J Med Chem. 2016;59:2362–2380. https://doi.org/10.1021/acs.jmedchem.5b00608. Roh J, Karabanovich G, Vlčková H, et al. Development of water-soluble 3,5-dinitrophenyl tetrazole and oxadiazole antitubercular agents. Bioorg Med Chem. 2017;25:5468–5476. https://doi.org/10.1016/j.bmc.2017.08.010. Karabanovich G, Nemecek J, Valaskova L, et al. S-substituted 3,5-dinitrophenyl 1,3,4-oxadiazole-2-thiols and tetrazole-5-thiols as highly efficient antitubercular agents. Eur J Med Chem. 2017;126:369–383. https://doi.org/10.1016/j.ejmech. 2016.11.041. Ahsan MJ, Samy JG, Khalilullah H, et al. Molecular properties prediction and synthesis of novel 1,3,4-oxadiazole analogues as potent antimicrobial and antitubercular agents. Bioorg Med Chem Lett. 2011;21:7246–7250. https://doi.org/10. 1016/j.bmcl.2011.10.057. Ahsan MJ, Samy JG, Jain CB, Dutt KR, Khalilullah H, Nomani MS. Discovery of novel antitubercular 1,5-dimethyl-2-phenyl-4-([5-(arylamino)-1,3,4-oxadiazol-2-yl]methylamino)-1,2-dihydro-3H-pyrazol-3-one analogues. Bioorg Med Chem Lett. 2012;22:969–972. https://doi.org/10.1016/j.bmcl.2011.12.014. Rahul VP, Premlata K, Kishor HC. New quinolinyl–1,3,4–oxadiazoles: synthesis, in vitro antibacterial, antifungal and antituberculosis studies. Med Chem (Los Angeles). 2013;9:596–607. https://doi.org/10.2174/1573406411309040014. Ladani GG, Patel MP. Novel 1,3,4-oxadiazole motifs bearing a quinoline nucleus: synthesis, characterization and biological evaluation of their antimicrobial, antitubercular, antimalarial and cytotoxic activities. New J Chem. 2015;39:9848–9857. https://doi.org/10.1039/C5NJ02566D. Navarrete-Vázquez G, Molina-Salinas GM, Duarte-Fajardo ZV, et al. Synthesis and antimycobacterial activity of 4-(5-substituted-1,3,4-oxadiazol-2-yl)pyridines. Bioorg Med Chem. 2007;15:5502–5508. https://doi.org/10.1016/j.bmc.2007.05.053. Al-Tamimi A-MS, Mary YS, Miniyar PB, et al. Synthesis, spectroscopic analyses, chemical reactivity and molecular docking study and anti-tubercular activity of
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Digest
Oxadiazole scaffolds in anti-tuberculosis drug discovery Suparna S. Dea,1, Mihir P. Khambetea,b,1, Mariam S. Degania,
⁎
a b
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, N.P Marg, Matunga (East), Mumbai 400019, India SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, Gate No. 1, Mithibai College Campus, V.M. Road, Vile Parle (West), Mumbai 400056, India
ARTICLE INFO
ABSTRACT
Keywords: Tuberculosis Oxadiazole Regioisomer Bioisoster Linker
With the increasing number of cases of latent and drug resistant tuberculosis, there is an urgent need to develop new, potent molecules capable of combating this deadly disease. Molecules containing oxadiazoles are one such class that could be considered to fulfil this need. Oxadiazole regioisomers have been explored in drug discovery programs for their ability to act as effective linkers and also as pharmacophoric features. Oxadiazoles can act as bioisosteric replacements for the hydrazide moiety which can be found in first line anti-TB drugs, and some have been also reported to interact with newer anti-TB targets. In this context, the present review describes the potential of oxadiazoles as antituberculosis agents.
Introduction Latency in tuberculosis (TB) as well as development of drug resistance contribute to TB being the leading cause of death due to infectious diseases. To achieve the United Nations goal of eradicating TB by 2030, several measures are being taken. Amongst the technological breakthroughs, development of newer drugs and vaccines are of prime importance.1 New drugs, which would combat latency and drug resistance require addressing newer, validated molecular targets, as well as designing molecules with better pharmacokinetic and pharmacodynamic properties. Design of new molecules, encompasses understanding of novel pharmacophoric features to address the newer targets. Various approaches to increase the efficacy and decrease the toxicity of existing effective drug molecules, by minor modification in their chemical structure to alter their molecular properties, should also be explored. In this connection, oxadiazoles could be moieties with specific properties worth exploring for design of new chemical entities. Oxadiazoles, are five-membered aromatic heterocycles containing two carbon atoms, two nitrogen atoms, and one oxygen atom. These have recently drawn attention of many research groups, because of their potential to be good bioisosteric replacement options for many carbonyl containing functional groups. Furamizole, an antibiotic and nesapidil (Fig. 1), a class IV antiarrhythmic agent were introduced in the 1970’s. Then after a gap of a few decades, with the US-FDA approval of raltegravir, an antiretroviral drug, and ataluren and zibotentan entering late phases of clinical trials for the treatment of cystic fibrosis and cancer respectively, using oxadiazole containing molecules
in drug discovery has accelerated. The level of interest amongst researchers can be clearly seen from the recent increase in the number of research papers and patent applications with respect to oxadiazole ring containing molecules.2 A wide range of pharmacological activities like antibacterial including anti TB, antifungal, analgesic, anti-inflammatory, antiviral, anticancer, antihypertensive, anticonvulsant have been shown by molecules containing oxadiazole in their backbone.3 The present review describes some key properties of oxadiazoles, followed by an account on various reported oxadiazole containing molecules as antituberculosis agents. Properties of regioisomers of oxadiazole There are three stable regioisomers of oxadiazole, (Fig. 2) a 1,2,3isomer, a 1,3,4-isomer and a 1,2,5-isomer all of which are weakly basic.4 The 1,2,3 regioisomer, being very unstable in the cyclic form, exists mostly in the diazoketone5 tautomeric form and is not considered here. In all the oxadiazoles, two substituents are possible on the two carbon atoms, and their relative positions can lead to differences in the properties of the resultant derivatives. In the 1,2,4-regioisomer, one of the substitutions is between two nitrogen atoms and the other is between the nitrogen and oxygen atom; while in case of 1,3,4-regioisomer, both the substitutions are located between oxygen and nitrogen atoms. Thus, in both these regioisomers, though the substituents are placed in very similar positions with similar bond angles, there is a slight variation in the electronic environment surrounding the side chains. But in the case of the 1,2,5-regioisomer, both the possible
Corresponding author. E-mail address: [email protected] (M.S. Degani). 1 Both authors contributed equally to this manuscript. ⁎
https://doi.org/10.1016/j.bmcl.2019.06.054 Received 11 April 2019; Received in revised form 12 June 2019; Accepted 27 June 2019 0960-894X/ © 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Suparna S. De, Mihir P. Khambete and Mariam S. Degani, Bioorganic & Medicinal Chemistry Letters, https://doi.org/10.1016/j.bmcl.2019.06.054
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Fig. 1. Drugs containing oxadiazole ring.
moiety attached to the oxadiazole ring via a thioether linker at one end and a substituted aromatic ring at the other end. The synthesized compounds were tested for the in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H37Rv using the Alamar Blue assay method. Among these, some of the derivatives exhibited more than 90% inhibition at concentration of 12.5 µg/ml. The most active derivative 1 (Fig. 3) showed 98% inhibition. The potent molecules were docked on mycobacterial F420H(2)-dependent reductase Rv1155 (https://www. uniprot.org/uniprot/O06553) and it was observed that the most active compounds dock well in the active site of the enzyme. Inhibitory activity of the most potent compounds was attributed to hydrogen bonding and either electrostatic or pi–pi interactions within the active site of the enzyme. Further, hydrophilic and steric requirements were found to be important factors for SAR. Synthesis of 7-substituted tetrazolo [1,5-a] quinolines incorporating 1,3,4-oxadiazole nucleus was reported by Sapariya et al.9 The in vitro antituberculosis activity was carried out at 100 μg/ml concentration, molecules 2a and 2b (Fig. 3) displayed more than 90% inhibition at this concentration. A series of 5-(4-(1H-pyrrol-1-yl)phenyl)-1,3,4-oxadiazol-2-yl substituted benzothioate derivatives were synthesized by Joshi et al.10 and were evaluated for their in vitro anti-TB activity. Preliminary results indicated that most of the compounds demonstrated moderate to good activity, with compounds 3a-3d (Fig. 3) displaying inhibition at 12.5 µg/ml. The docking studies on the Mycobacterium tuberculosis enoyl reductase (InhA) (PDB ID: 4TZK) showed essential hydrogen bonding interaction between the nitrogen atoms of the oxadiazole ring and the amino acid (Tyr158) and co-factor (NAD+). Additionally, amino acids (Ile21, Phe97, Met98, Pro99, Met103, Ala157, Trp160, Met161, Pro193, Ile194, Trp230) were necessary for hydrophobic contacts. De Souza et al.11 combined the 1,3,4-oxadiazole ring with a protected sugar moiety and tested the derivatives for their antimycobacterial activity. Molecule 4 (Fig. 3) was found to be one of the most active molecules with MIC of 60 µM. This was followed by use of principle component analysis (PCA) to assess the structure activity relationship using various descriptors. Karad et al.12 explored the biological applications of fluoro substituted pyrazole nucleus clubbed with 1,3,4-oxadiazole scaffolds, antituberculosis activity being one of the important potential applications. The molecules were designed by making the hybridization of pyrazole and 1,3,4-oxadiazole moieties. Antituberculosis screening of all the synthesized molecules was conducted and four molecules, 5a-5d (Fig. 3) were found to display more than 90% inhibition at 250 µg/ml. Sajja et al.13 developed a series of molecules which were composed
Fig. 2. Regioisomers of oxadiazole.
substituents are adjacent to each other and are located between two nitrogen atoms, making the orientation of the groups considerably different compared to the other two regioisomers. As a result of this, the matched pairs – 1,2,4-isomer and 1,3,4-isomer, show similar overall molecular shapes and are thus expected to fit receptors with wider pockets and bind in a similar fashion, while the 1,2,5-isomer would fit receptors with narrow active site pockets. All the regioisomers have significantly different hydrogen bond acceptor potential and intrinsically different charge distributions (i.e., dipole moments). In a systematic study, Bostrom et al.6 have compared the matched pairs of 1,2,4- and 1,3,4-oxadiazoles, from the AstraZeneca compound collection, with respect to their lipophilicity, solubility, metabolic stability and hERG inhibition potential. Their results indicated that the 1,3,4oxadiazole isomers show lower lipophilicity (log D), higher aqueous solubility, better metabolic stability and a lower affinity towards the hERG receptor, compared to the 1,2,4-counterparts. The insight into these properties could help in designing oxadiazole containing drug molecules with desirable lipophilicity, solubility and metabolic stability. In the next sections, anti TB compounds containing oxadiazole as a linker or a pharmacophoric feature have been described. The antituberculosis activities have been estimated using various strains of Mycobacteria, most prominent of which is Mycobacterium tuberculosis H37Rv, and have been carried out employing various methods such as Alamar blue assay, BACTEC assay and agar dilution method. 1,3,4-Oxadiazoles Many molecules with 1,3,4-oxadiazole have been designed, some as structural analogues of isoniazid, with the hydrazide group being replaced by the oxadiazole moiety. Macaev et al.7,8 have reported five different structurally diverse series of molecules containing 1,3,4-oxadiazole thioethers, using techniques such as electronic-topological method (ETM) and neural network (NN) methods for design. These molecules have a hydrophobic 2
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Fig. 3. 1,3,4-Oxadiazoles as antituberculosis agents.
by fusion of a pyridine-oxadiazole moiety with a benzocycloheptane ring system. This design was conceived by replacing the pyridine ring of isoniazid with benzo[6,7]cyclohepta[1,2-b]pyridine and replacing the hydrazide fragment with oxadiazole. Molecule 6 (Fig. 3) displayed highest inhibitory activity of 1.56 µg/ml. The presence of methoxy group/s on phenyl ring attached to the oxadiazole moiety was found to be crucial for antituberculosis activity. Gholap et al.14 combined 1,3,4-oxadiazole with trifluoromethylphenyl and benzofuranylamide moieties and tested these compounds for their antimycobacterial potential. These compounds exhibited MIC values in the range of 2–24 µg/ml with the most active compound, 7 (Fig. 3), displaying an IC90 of 5.7 µM against dormant Mtb
H37Ra. The compounds were observed to be non-toxic to host cells when tested against the cell lines THP-1, A549 and PANC-1. A series of novel N-(furan-2-yl)-1-(5-substituted) phenyl-1,3,4-oxadiazol-2-yl) methanimines were synthesized and evaluated by Mathew et al.15 for their activity against Mycobacterium tuberculosis (H37Rv) strain using Alamar Blue assay. The most active compound of this series, 8 (Fig. 3) displayed MIC of 3.125 µg/ml. Molecular modelling studies were also carried out on the designed molecules to assess their binding with Mycobacterium tuberculosis InhA, and were found to display similar interactions as those reported earlier by Joshi et al.10 Desai et al.16,17 reported several 2,3-dihydro-1,3,4-oxadiazole containing molecules with general structure 9 (Fig. 4), where the 3
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Fig. 4. 1,3,4-Oxadiazoles (contd.).
oxadiazole ring-nitrogen was attached to the linker. For the aromatic/ heteroaromatic part of the molecules, phenyl and indole ring were explored while the linker was chalcone or hydrazide. The molecules were evaluated for their in vitro antituberculosis activity against Mtb H37Ra and Mycobacterium bovis BCG strains, both in active and dormant states. The activity for the molecules with hydrazide linker was found to be < 5 µM against the active form of Mtb H37Ra. Additionally, molecular docking was performed against InhA to predict the binding modes and affinity. Karabanovich et al.18 reported the discovery and structure-activity relationships of 5-substituted-2-[(3,5-dinitrobenzyl)-sulfanyl]-1,3,4-oxadiazoles and 1,3,4-thiadiazoles as antituberculosis agents, designed on the basis of 5-(3,5-dinitrobenzylsulfanyl)tetrazoles reported by the same research group. These were hypothesized to act on mycobacterial decaprenylphosphoryl-β-D-ribofuranose-2′-oxidase (DprE1), which is involved in the synthesis of decaprenylphosphoryl arabinose, the only
donor of arabinosyl residues for the biosynthesis of arabinan polymers in mycobacteria. The majority of these compounds exhibited outstanding in vitro activity against Mycobacterium tuberculosis CNCTC My 331/88 and six multidrug-resistant clinically isolated strains of M. tuberculosis, with minimum inhibitory concentration values as low as 0.03 μM (Molecule 10, Fig. 4). These derivatives also showed high selectivity towards mycobacteria along with no in vitro cytotoxicity. The same research group reported tertiary amine containing derivatives of 3,5-dinitrophenyl oxadiazole as antituberculosis agents,19 where the Nbenzylpiperazine derivatives had MIC values less than 3 µM. Further, by changing the orientation of substituents in compound 10, a new series of molecules was reported. The most active molecule, 11 (Fig. 4) with 4-methoxybenzyl moiety displayed inhibition of 0.03 µM. The presence of electron withdrawing groups, either two nitro groups or one nitro and one trifluoromethyl group, led to high antimycobacterial activity.20 Ahsan et al.21,22 described the antimycobacterial activity of 1,54
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dimethyl-2-phenyl-4-([5-(arylamino)-1,3,4-oxadiazol-2-yl]methylamino)-1,2-dihydro-3H-pyrazol-3-one analogues. Among the synthesized compounds, derivatives 12a and 12b (Fig. 4) were found to be most promising, with MIC of 0.78 µg/ml against Mycobacterium tuberculosis H37Rv. Patel et al.23 synthesized novel quinolinyl-oxadiazoles as antituberculosis agents. The most active compound of the series, 13 (Fig. 4), containing a benzothiazolylacetamide moiety displayed an inhibitory activity of 6.25 µg/ml. Ladani et al.24 further combined chloroquinolines and 1,3,4-oxadiazoles, employing chloro-amine coupling reactions with different catalysts. The synthesized molecules were evaluated for their antituberculosis activity along with their anti-infective potential. However, molecules had low activity, with four molecules 14a-14d (Fig. 4) showing inhibition at the concentration of 250 µg/ml and MIC values ranging from 60 to 200 µM. Vazquez et al.25 synthesized a series of 4-(5-substituted-1,3,4-oxadiazol-2-yl) pyridine derivatives with long aliphatic side chains and evaluated the in vitro antimycobacterial activity. Compounds 15a and 15b (Fig. 4) showed activities comparable to INH and streptomycin against Mycobacterium tuberculosis (Mtb) with MIC values of 0.35 µM and 0.65 µM respectively. Both these molecules have a highly lipophilic chain at the 5 position of the oxadiazole moiety which is possibly an important factor for enhanced permeability of these molecules. Further, these were tested against five clinical isolates (drug-sensitive and -resistant strains). Interestingly these compounds were more than 10 times as active as the first line anti-TB drugs (INH, streptomycin and ethambutol) against the drug-resistant strain CIBIN 112. Armakovic and co-workers26–28 reported molecules containing 1,3,4-oxadiazole moiety attached to a pyrazine ring, 16 (Fig. 4). The molecule with unsubstituted phenyl ring (16a) and the one with furan ring (16b) displayed activity of 1.6 µg/ml, while the most active molecules of the series, 16c, 16d and 16e displayed inhibitory activity of 0.8 µg/ml, which was 4 times more active than the reference, pyrazinamide. Mtb shikimate kinase (MtSK), is an important enzyme of the shikimate pathway, especially for synthesis of metabolites like folic acid, quinones and aromatic amino acids in Mtb. As this pathway is absent in mammals, MtSK inhibitors could be potentially selective and non-toxic antituberculosis agents. Simithy et al.29 synthesized a series of oxadiazole-amides, and tested them for their Mtb shikimate kinase (MtSK) inhibitory activity through a LC-MS based functional assay, where the formation of shikimate-3-phospate (S3P) was quantified. Compounds 17a and 17b (Fig. 5) were found to be the most potent molecules within the oxadiazole series with MIC values < 1 µg/ml against Mtb H37Rv. Additionally, MtSK IC50 values for these 2 compounds were found to be 3.79 µM and 3.43 µM, respectively. The trans-translation process, which is absent in humans, is the only mechanism in Mtb to rescue the stalled ribosomes at 3′end of m-RNA. Alumasa et al.30 exploited this pathway and reported an oxadiazole containing molecule, 17c, as a ribosome rescue inhibitor. The molecule was bactericidal and was found to be active against both, replicating as well as non-replicating bacteria (with 8 µg/ml and 1.6 µg/ml of drug killing > 90% of the replicating and non-replicating cells respectively). The MIC values against Mtb Erdman strain and M. smegmatis were found
to be 1.6 µg/ml and 0.4 µg/ml respectively. The molecule at concentrations more than 20 fold the MIC, showed no cytotoxicity on HepG2 cells. Docking studies were also carried out for 17c on the 50S ribosome region of Mtb (PDB ID: 4ABR). The in-vitro as well as in-silico studies suggested that 17c binds to a pocket adjacent to the polypeptidyl-transfer centre (PTC) at the base of Helix 89 in the ribosome, in such a way that it selectively inhibits the trans-translation process but does not inhibit the process of translation initiation, elongation, or termination. The researchers explain that the polar interactions between the carbonyl oxygen atom and the oxadiazole core of the 17c, with the H89, limits the flexibility of H89, preventing structural changes that are required for ribosome rescue but not for translation. Mtb is capable of adapting to the availability of varying carbon sources within the host environment. To simulate this host environment, Early et al.31 developed and ran a phenotypic screen using butyrate as the sole carbon source. They screened a library of ∼87,000 small compounds and identified potential anti-TB compounds. Interestingly, six out of forty eight potential compounds which were considered for further evaluation studies, contained oxadiazole moiety in the structure. These compounds were found to be selectively active against Mtb grown in medium with butyrate as the source of fatty acids, but were inactive in medium with glucose. The most active compound 18 (Fig. 5), displayed an activity of 0.4 µM against Mtb grown in butyrate containing medium. Thus, it could be assumed that these molecules act on the novel targets which are not expressed in the presence of glucose as the primary carbon source. Further studies can be carried out to identify such unique and novel targets. 1,2,4-Oxadiazoles A few research groups have explored 1,2,4-oxadiazoles as linkers in antituberculosis agents, similar to 1,3,4-oxadiazoles. Sriram and co-workers32 reported the synthesis and biological evaluation of 1,2,4-oxadiazole containing molecules by 1,3-cycloaddition reaction with 4(H)-pyrans, These molecules were screened for their in vitro antimycobacterial activity against Mtb and MDR-TB by agar dilution method and one of the compounds, 19a (Fig. 6) displayed activities of 0.07 µM and 0.14 µM respectively against Mtb and MDR TB. The stereochemistry of the pyran was seen to be important for Mtb activity but unimportant for MDR TB. Further, employing chemoselective cycloaddition reactions, they also reported hybrids of 1,2,4-oxadiazole with pyranopyridine and chromene moieties.33 Among the pyranopyridines hybrids, 4-chlorophenyl and 2,4-dichlorophenyl substituted molecules displayed MICs of 0.3 µM which was comparable with INH. The importance of tertiary nitrogen was established from the observation that the hybrids containing chromene moiety displayed lower activity compared to their pyranopyridine counterparts. Willand et al.34 designed a series of 1,2,4-oxadiazole containing molecules as EthR inhibitors and studied their binding properties with the help of X-ray crystallography. Like many anti-TB drugs, ethionamide is a prodrug activated by flavin monooxygenase, EthA, which is regulated by the transcriptional repressor EthR. Thus, inhibiting EthR can be used to improve the therapeutic index of ethionamide. Taking this into consideration, they studied the ligand binding domain of EthR, and reported the existence of two mobile phenylalanine residues that control the access to a hydrophobic pocket, which if exploited further could lead to development of structurally diverse EthR inhibitors. The study revealed that the oxadiazole ring of the ligand is involved in a Tshape interaction with Trp103. A thorough SAR of these molecules concluded that 1,2,4-oxadiazole ring was essential for the activity. Specifically, the position of the oxygen atom in the heterocyclic ring was found to play a critical role in binding. As a linker to oxadiazole ring, 5 or 6 membered cyclic amide was preferred, which when replaced with cyclic sulphonamide or cyclic urea, led to decrease in activity. Moreover the cyclic amide, when attached to cyclopropyl,
Fig. 5. 1,3,4-Oxadiazoles as inhibitors of Mycobacterial enzymes. 5
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Fig. 6. 1,2,4-Oxadiazoles as antituberculosis agents.
cyclopentyl or cyclohexyl rings, showed better activity compared to their 5/6 membered aromatic counterparts. The most active molecule of the series, 20 (Fig. 6) displayed IC50 of 0.4 µM along with suitable physicochemical properties and microsomal stability. Further, it was able to boost ethionamide activity by 10-fold on Mtb infected macrophages at nanomolar concentration.35,36 Taking into consideration various anti-infective 1,2,4-oxadiazole and benzimidazole derivatives reported in literature, Shruthi et al.37 reported novel hybrids of these two moieties as antimycobacterial agents. Molecules containing chloro substituted phenyl ring or benzyl ring as aromatic substitutions on oxadiazole ring, along with disubstituted phenyl ring attached to the benzimidazole moiety, 21a-21d (Fig. 6), were found to display MIC of 1.6 µg/ml. A series of substituted 2-nitro-1-(4-tolylsulfonyl)-2-(3-methylphenyl-1,2,4-oxadiazol-5-yl)ethanes were synthesized and their antimycobacterial activity was studied by Tyrkov et al.38 The most active compound among the series, 22 (Fig. 6) displayed activity of 3.2 µg/ml along with high LD50 values. Taking into consideration the antituberculosis activity of nicotinamide and pyrazinamide, Gezginci et al.39 reported synthesis and
biological evaluation of pyridines and pyrazines substituted with 1,2,4oxadiazole-5-ones and 1,2,4-oxadiazole-5-thiones. Further, pivaloyloxymethyl (POM) derivatives were also prepared in order to increase their lipophilicity and therefore improve their cellular permeability. All the molecules, 23a,b and c (Fig. 6), displayed MIC of > 50 µg/ml against Mycobacterium tuberculosis H37Rv strain. Jain et al.40 reported a series of novel quinoline-oxadiazole hybrid compounds which were designed based on stepwise rational modifications involving bioisosteric replacement of isoxazole ring with 1,2,4-oxadiazole ring, along with replacement of ester functionality with various hydrophobic moieties. The synthesized compounds were then screened for anti-TB activity against Mtb H37Rv strain and for cytotoxicity in HepG2 cell line. Several molecules (24a-24c, Fig. 6) exhibited good to excellent anti-TB activity and selectivity (minimum inhibitory concentration values < 0.5 μM and selectivity index > 500). The activity data of the series showed that substituted benzyl ring was preferred over 2-furan or pyridyl ring as the “R” group. One of the compounds when tested for microsomal stability using rat microsomes, proved that the quinolone oxadiazole derivatives were 99% metabolically stable for 60 min. 6
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Fig. 7. Molecules containing 1,2,5-oxadiazole moiety.
As can be seen from the above publications, generally 1,2,4-oxadiazole ring is flanked by 2 hydrophobic groups, with or without linker, in most cases of active compounds.
commercially developed for the treatment of TB, but its clinical utility is limited due to toxicity issues arising from lack of target-specificity. Hence, inhibitors which are not substrate analogs and act through different mechanisms of enzyme inhibition could prove useful. With this aim in mind, Karen et al.42 synthesized a series of molecules, where one of the molecules, 26 (Fig. 7) had an oxadiazole ring. Though the derivative was inactive against Mtb, the window for exploring oxadiazoles derivatives against this target has been opened. Though both the studies reported molecules with moderate to poor anti-tuberculosis activity, the targets explored were new and hence can be further explored by researchers for the development of newer oxadiazole containing anti-tuberculosis agents.
1,2,5-Oxdiazoles There have been only a couple of reports where, 1,2,5-oxadiazole containing molecules have been explored for their anti-tuberculosis activity. Nitric Oxide (NO) is an important mediator produced by macrophages during Mycobacterium tuberculosis (Mtb) infection. It has been demonstrated that NO can disrupt bacterial DNA, proteins, signalling mediators, and/or cause induction of macrophage apoptosis. Furoxan (1,2,5-oxadiazole N-oxide) is one such nitric oxide donor with promising antituberculosis activity. Taking this into consideration, Fernandes et al.41 reported the hybrids of furoxan and isonicotinic acid hydrazide derivatives obtained from phenotypic screening of their compound library. The molecules were tested against Mtb H37Rv along with INH and Rifampicin resistant strains of Mtb. Molecule 25 (Fig. 7) displayed MIC90 of 1 µM and 7 µM against the above mentioned strains respectively. Alanine racemase is an essential enzyme of the cell wall synthesis pathway, that racemizes L-alanine into D-alanine, which is a key
Analysis of oxadiazole containing molecules as antituberculosis agents In case of 1,2,4-oxadiazole containing molecules, the substitutions are carried out on 3 and 5 positions of the oxadiazole ring. These substitutions have been summarized in Fig. 8. At position 3, various aromatic and heteroaromatic substitutions such as phenyl, benzyl, pyridyl and thiazolyl are preferred while at 5 position a variety of unique moieties have been explored such as pyranopyridine, substituted piperidine, benzimidazole and thio linked POM.
Fig. 8. Structural analysis of 1,2,4-oxadiazoles as antituberculosis agents.
In case of 1,3,4-oxadiazoles, on the other hand, the substitutions take place at 2 and 5 positions of the ring giving the molecule a different shape. Fig. 9. shows different substitutions at A and B positions.
building block in the biosynthesis of peptidoglycan. This key enzyme of Mtb, could become a very attractive target as the enzyme is absent in humans. Till date cycloserine is the only alanine racemase inhibitor,
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Fig. 9. Structural analysis of 1,3,4-oxadiazoles as antituberculosis agents.
Conclusion
(F.25-1/2014-15(BSR)/No. F.5-63/2007(BSR)) and Mihir Khambete is thankful to DST-INSPIRE, India (IF130396) for financial support.
As seen from the above data, oxadiazole ring has been introduced into drug discovery programs for several different purposes. Very few have been designed to be an essential part of the pharmacophore, favourably contributing to ligand binding. Many may act as flat, aromatic linkers to place substituents in the appropriate orientation. Most oxadiazoles prove to be a good option for bioisosteric replacement of carbonyl containing compounds such as esters, amides, carbamates, and hydroxamic esters. Structural analysis shows that oxadiazole regioisomers have been attached with chemically diverse moieties ranging from simple alkyl groups to various aromatic and heteroaromatic moieties such as phenyl, benzyl, pyridyl, thiazolyl, benzimidazole and pyranopyridine to name a few. It has also recently been shown that two structurally related oxadiazole regioisomers, can be used to achieve significant differences in thermodynamic properties. Most of the research on anti-TB drug development has focused on molecules where the oxadiazole ring is present at the centre part of the molecule, unlike several current oxadiazole containing drugs (Fig. 1), where the ring, with or without small functional groups, is towards the end of the molecule and a key part of the pharmacophore. Moreover, with availability of several probable targets such as EthR, InhA, shikimate kinase, alanine racemase along with ability to act as nitric oxide donor, there is still a wide scope to explore potential of oxadiazoles from these perspectives.
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