Benzofuran-oxadiazole hybrids: Design, synthesis, antitubercular activity and molecular docking studies

Chemical Data Collections 19 (2019) 100178

Contents lists available at ScienceDirect

Chemical Data Collections journal homepage: www.elsevier.com/locate/cdc

Data Article

Benzofuran-oxadiazole hybrids: Design, synthesis, antitubercular activity and molecular docking studies Veerabhadrayya S. Negalurmath a, Sathish Kumar Boda b, Obelannavar Kotresh a,∗, P.V. Anantha Lakshmi b, Mahantesha Basanagouda c a

Department of Chemistry, Karnatak Science College, Dharwad 580001, Karnataka, India Department of Chemistry, Osmania University, Hyderabad 500007, Telangana, India c P.G. Department of Chemistry, P.C. Jabin Science College, Hubballi 580031, Karnataka, India b

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 24 November 2018 Revised 25 December 2018 Accepted 4 January 2019 Available online 8 January 2019

The fifteen benzofuran-oxadiazole derivatives 7(a-o) have been designed, synthesized, characterized and evaluated for preliminary antitubercular activity against Mycobacterium tuberculosis H37 RV and Mycobacterium phlei. The structure activity relationship (SAR) results have shown the compounds with chlorine (7j, 7k) and bromine (7l, 7m) on benzofuran exhibit excellent activity. The highest activity of 7m superior to standard drug pyrazinamide was further supported by molecular docking results. The in vitro antitubercular experimental results and structure activity relationship studies were supported using molecular docking studies on these novel hybrids. © 2019 Elsevier B.V. All rights reserved.

Keywords: Anti-tuberculosis Benzofuran Molecular dock Oxadiazole Structure activity relationship

Specifications table Subject area Compounds Data category Data acquisition format Data type Procedure

Data accessibility

Bioorganic Chemistry. Benzofuran-Oxadiazole hybrids Spectral IR, 1 H NMR, 13 C NMR, Mass spectral data and elemental analyses. Analyzed Benzofuran-oxadiazole derivatives have been designed, synthesized, characterized and evaluated for preliminary antitubercular activity and experimental results were supported using molecular docking studies. Data is present with this article.

1. Rationale Tuberculosis (TB) is a transmittable disease caused due to rod shaped Mycobacterium tuberculosis. The TB is one of the major health problem in the world and leading causes of death [1]. During the last decade there has been an increased interest for research on TB, and this has resulted in the launch of several new initiatives by international and national organizations, private charities including pharmaceutical companies. The innovative focus on TB has partly been triggered by the persistent larger number of TB case studies in developing countries, and partly by the increased occurrence of multidrug ∗

Corresponding author. E-mail address: [email protected] (O. Kotresh).

https://doi.org/10.1016/j.cdc.2019.100178 2405-8300/© 2019 Elsevier B.V. All rights reserved.

2

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

Fig. 1. Potent anti-tuberculosis agents containing benzofurans.

and extensively drug resistant TB (MDR- and XDR-TB) [2]. According to WHO 2017 report, the TB is the ninth foremost cause of death global and the leading cause from a single infectious agent, ranking above HIV/AIDS. In 2016, there were an estimated 1.3 million TB deaths cases among HIV-negative people and an additional 374,0 0 0 deaths among HIV-positive people. Hence, drug-resistant TB is a cause for continuing threat. In 2016, there were 60 0,0 0 0 new cases with resistance to most effective first-line drug rifampicin, of which 490,0 0 0 had multidrug-resistant TB (MDR-TB) [3]. Hence, the need for search the new and efficient anti-TB agents with a new mechanism of action remains a crucial task [4–6]. Benzofuran derivatives are important oxygen heterocycles in which furan is fused with benzene and are reported very well due to their physical properties [7,8] biological and pharmaceutical activities [9–14]. The benzofuran–coumarin conjugates reported as potential anti-microbial and cytotoxic agents [15]. The 3-substituted benzofurans have attracted the medicinal chemists due to their exciting biological properties such as cytotoxicity [16], inhibition of Aβ neurotoxicity, cholinesterase activity and β -amyloid aggregation [17], glycogen synthase kinase 3β inhibitors [18], antiviral and antitumor [19], ischemic cell death inhibitors [20], dual 5-HT1A receptor and serotonin transporter affinity [21], bone morphogenetic protein-2 up-regulators [22], orally bioavailable GPR40 agonist [23], calcium activated chloride channel inhibitors [24], Hepatitis C Virus inhibitors [25], antifungal and antitubercular agents [26], inhibitors of mycobacterium protein tyrosine phosphatase [27]. The potent antituberculosis properties exhibited by some compounds containing benzofuran [28–34] and 3-substituted benzofuran moieties [35–40] are provided in Figs. 1 and 2, respectively. The 1,3,4-oxadiazole is a five membered heterocycle and good bioisostere of amide and ester functional groups and is reported to contribute significant physical properties [41] and substantially to biological activity due to participating in hydrogen bonding interactions with various receptors [42]. The 1,3,4-oxadiazole derivatives display a wide-ranging spectrum of biological activities including cytotoxic and antimicrobial [43], anticonvulsant [44], antiepileptic [45], antiallergic [46], anticancer [47], antitubercular [48] activities. The 1,3,4-oxadiazole-2(3H)-thiones reported as in vitro antitubercular agent against Mycobacterium tuberculosis H37 Rv [49].

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

3

Fig. 2. Potent anti-tuberculosis agents containing 3-substituted benzofurans.

In view of above literature survey and in continuation of our attention on designing oxygen based heterocycles of biologically active molecules [50,51], we aimed to design benzofuran-–oxadiazole hybrids with hope of better therapeutic agents for the treatment of tuberculosis and to establish structure activity relationship, the compounds 7(a-o) were examined for their in vitro antitubercular activity against Mycobacterium Phlei and Mycobacterium tuberculosis H37 RV.

2. Procedure 2.1. Materials and methods The melting points were determined by open capillary method and are uncorrected. The IR spectra (KBr disc) were recorded on a Thermo Fisher Nicolet-6700 FT-IR spectrophotometer. 1 H NMR (500 MHz) and 13 C NMR (125 MHz) spectra were recorded on Bruker spectrometer using dimethylsulfoxide (DMSO-d6 ) as solvent and tetramethylsilane (TMS) as an internal standard. The chemical shifts were expressed in δ ppm and coupling constant (J) values were given in Hertz. The abbreviations used as follows: s, singlet; d, doublet; t, triplet; m, multiplet. The mass spectra were recorded using Shimadzu GCMS-QP2010S instrument. The elemental analysis was carried out using Heraus CHN rapid analyzer. Progress of the reaction was monitored by TLC using aluminium sheets precoated with UV fluorescent silica gel Merck 60 F254 and were visualized by UV lamp. All the chemicals purchased were of analytical grade, and were used without further purification unless otherwise stated, from Sigma-Aldrich Chemicals (India) and S.D. Fine Chemicals (India).

4

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

2.2. Synthesis 2.2.1. General procedure for synthesis of benzofuran-3-yl-acetic acid hydrazides 6(a-o) The (5-methyl-benzofuran-3-yl)-acetic acid 5a (1.90 g, 10 mmol) was converted into corresponding ethyl esters (the reaction progress was monitored by TLC) by refluxing with absolute ethanol (30 mL, 99.98%) in presence of 2–3 drops concentrated sulphuric acid (99.99%). To the resulting mixture, added hydrazine hydrate (1.50 g, 30 mmol, 99%) and continued the reflux for 6–8 h (the reaction progress was monitored by TLC). Excess of ethanol was removed under reduced pressure and then diluted with water. The separated carbohydrazide 6a was collected and recrystallized from ethanol. The similar procedure was adopted to prepare the remaining compounds 6(b-o) using substituted benzofuran-3-acetic acids 5(b-o). 2.2.2. General procedure for synthesis of benzofuran-oxadiazole-thiones 7(a-o) To a cold and stirred solution of (5-methyl-benzofuran-3-yl)-acetic acid hydrazide 6a (2.04 g, 10 mmol) in absolute ethanol (50 mL, 99.98%) containing potassium hydroxide (0.56 g, 10 mmol), carbon disulphide (3.80 g, 50 mmol) was added gradually. The reaction mixture was heated under reflux temperature on oil bath until hydrogen sulphide evolution ceased. The excess ethanol was removed by distillation under reduced pressure and the residue was poured on crushed ice, filtered and the filtrate was neutralised using dilute hydrochloric acid. The product 7a was filtered, washed with cold water and recrystallised from solvent mixture of ethanol and ethyl acetate (75% and 25%). The same procedure was used to synthesise compounds 7(b-o) using 6(b-o) as reactants. 2.3. Antitubercular activity The antitubercular activity of title compounds 7(a-o) were performed against M. tuberculosis H37 RV and M. phlei using well known procedure Microplate Alamar Blue Assay (MABA) [52]. This methodology is non-toxic, uses stable reagents and shows good correlation with proportional and BACTEC radiometric method. In brief, 200 μL of sterile deionized water was added to all outer perimeter wells of sterile 96-well plate to minimize evaporation of medium in the test wells during incubation. The 96-well plate received 100 μL of the Middlebrook 7H9 broth, and serial dilution of compounds was made directly on plate. The final drug concentrations tested were 100–0.2 μg/mL. Plates were covered and sealed with parafilm and incubated at 37 °C for 5 days. After this time, 25 μL of freshly prepared 1:1 mixture of Almar Blue reagent and 10% tween 80 were added to the plate and incubated for 24 h. A blue color in the well was interpreted as no bacterial growth, and pink color was scored as growth. The MIC was defined as lowest drug concentration that prevented the color change from blue to pink. 2.4. Molecular docking studies Molecular docking studies were performed to obtain a consistent and more accurate illustration of antitubercular activity of newly synthesized compounds at the atomic level that support the experimental findings to design novel therapeutic agents against TB. Here we were performed a molecular modeling approach involving docking study using Discovery Studio 2.1 to provide an insight into the binding conformation and the binding affinities of the compounds towards the target protein MurE ligase of Mycobacterium Tuberculosis which was reported as a considerable target for the inhibition of TB. 2.4.1. Preparation of protein target structure ˚ The X-ray crystallographic structure of the MurE ligase of Mycobacterium Tuberculosis (PDB: 2WTZ, resolution 3.0 A) [53] was retrieved from the Protein Data Bank and which was later imported in to Discovery Studio software. Water molecules and hetero atoms bound to protein molecule were removed. Further using DS clean protein protocol, the protein was prepared by adding hydrogen atoms for correct ionization and tautomeric states of amino acid residues. Missing loops are modeled and missing atoms were added in incomplete residues and alternate conformations were removed for refining crystallographic disorder. Also it corrects for the errors in connectivity and bond orders, standard order of the atoms within each amino acid residue and protonation states of ionizable side-chains and terminal groups by using predicted pKs. Following the above steps of preparation, the protein was subjected to energy minimization by applying the CHARMm force field using steepest descent algorithm with a maximum number of steps 10 0 0 at RMS gradient of 0.01 which continues by steepest descent and conjugate gradient algorithm until the protein satisfies with a convergence gradient of 0.001 kcal mol−1 . 2.4.2. Generation of ligand dataset The moderate to excellent antitubercular active compounds observed in experiment were selected for molecular docking studies. The chemical structures of compounds 7(g-m) were drawn using ChemDraw tool of PerkinElmer ChemOffice Ultra14.0 software [54] and imported in to Discovery Studio 2.1. The ligands were prepared using prepare ligands utility of DS with default parameters for consistency of ionization states, tautomer and isomer generation, removal of duplicate structures, conversion of 2D to 3D structures using DS catalyst algorithm. Further the ligands were energy-minimized with the forcefield CHARMm using the smart minimizer algorithm till it satisfied with the convergence gradient of 0.001 kcal mol−1 , in order to attain the lowest energy of each compound.

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

5

Scheme 1. Synthesis of benzofuran acetic acids 5(a-o).

Molecular docking studies were carried out by LibDock module in Discovery 4 Studio [55] to generate the bioactive binding poses of ligands in the defined binding site of MurE ligase of Mycobacterium Tuberculosis (PDB: 2WTZ). LibDock uses protein site features called “HotSpots” that were resolved with a grid fixed in active site which counts the hotspot map for polar and apolar cluster and further used for the alignment of the ligand conformations to the protein interaction sites. All other docking and consequent scoring parameters used were kept at their default settings. Finally at the end of the docking process, it returns all the minimized ligand poses and their rankings. Among all the obtained poses of each ligand, the ligand binding in a receptor cavity was evaluated based on the LibDock top score, which uses a simple pair-wise method. The ligands with high LibDock scores were preferred for estimating binding energies of the protein-ligand complex. The complex pose with the best binding energy was used for further binding mode analysis. In addition, all docked poses were scored by applying analyze ligand poses subprotocol in Discovery Studio 2.1.

3. Data, value and validation 3.1. Chemistry The precursor compounds benzofuran acetic acids 5(a-o) were prepared according our earlier report [56]. Further, these benzofuran-3-yl-acetic acids 5(a-o) were converted into corresponding ethyl esters by refluxing with ethanol in presence of concentrated sulphuric acid. The resulting mixture, was converted into the acid hydrazides 6(a-o) by the reaction with hydrazine hydrate at reflux temperature. The acid hydrazides 6(a-o) were reacted with potassium hydroxide and carbon disulphide in ethanol at reflux temperature to afford title compounds 7(a-o) as illustrated in Schemes 1 and 2.

6

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

Scheme 2. Synthesis of benzofuran-oxadiazoles 7(a-o).

The newly synthesized intermediates 6(a-o) and title compounds 7(a-o) were characterized using IR, 1 H- and 13 C NMR, mass spectral data as well as elemental analysis. The details of spectral data are given in the experimental section and spectra are provided in supplementary material. The IR spectrum of intermediate (5-methyl-benzofuran-3-yl)-acetic acid hydrazide (6a), showed a strong peak at 1628 cm−1 for carbonyl group whereas 3293 and 3462 cm−1 for NHNH2 stretching. The characteristic resonance peaks in 1 H NMR and 13 C NMR appeared in the expected resonances were assigned by their peak multiplicity and integration. Further the mass spectrum showed the molecular ion peak m/z 204 (M+1) (Supplementary material, spectrum 1–4). The IR spectrum of representative compound in the series 5-(5-methyl-benzofuran-3-ylmethyl)−3H-[1,3,4]oxadiazole-2thione (7a), showed absence of carbonyl group and NHNH2 stretching frequencies. Further, new bands appeared at 1292 (C=S), 1630 (C=N), 3071 (NH) indicate the cyclization. In 1 H NMR spectrum, the disappearance of NH2 protons at δ 4.25 (s, br, 2H, NH2, D2 O exchangeable) in the precursor compound 6a indicates the cyclization to the compound 7a. Further, the all the protons and carbons were resonated in the expected regions. The formation of the compound 7a was confirmed by its mass spectrum that showed molecular ion peak at m/z 246. (Supplementary material, spectrum 20–24) [51].

3.2. Data 3.2.1. 5-Methyl-benzofuran-3-yl-acetic acid hydrazide (6a)

HN NH2 O

H3C O 6a

Colorless solid (ethanol); m.p. 101–102 °C; yield 1.65 g (81%); IR (KBr, υ in cm−1 ): 1628 (C=O), 3293, 3462 (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 2.39 (s, 3H, 5-CH3 ), 3.42 (d, J = 1.0 Hz, 2H, C3–CH2 ), 4.25 (s, br, 2H, NH2, D2 O exchangeable), 7.09–7.11 (dd, J = 8.5 Hz, 1.5 Hz, 1H, C6–H), 7.39–7.42 (m, 2H, C4-H and C7-H), 7.75 (s, 1H, C2-H), 9.27 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 21.44, 29.18, 111.20, 115.00, 120.33, 125.70, 128.28, 131.75, 143.69, 153.39, 169.21; GCMS m/z: 204 [M+]; Anal.calcd. for C11 H12 N2 O2; C, 64.69; H, 5.92; N, 13.72; Found: C, 64.67; H, 5.92; N, 13.72.

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

7

3.2.2. (6-Methyl-benzofuran-3-yl)-acetic acid hydrazide (6b)

HN NH2 O O

H3C 6b

Colorless solid (ethanol); m.p. 133–134 °C; yield 1.61 g (79%); IR (KBr, υ in cm−1 ): 1643 (C=O), 3303 (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 2.41 (s, 3H, C6–CH3 ), 3.63 (d, J = 1.0 Hz, 2H, C3–CH2 ), 4.22 (s, br, 2H, NH2, D2 O exchangeable), 7.06 (d, J = 8.0 Hz, 1H, C5–H), 7.33 (s, 1H, C7-H), 7.43 (d, J = 8.0 Hz, 1H, C4–H), 7.73 (s, 1H, C2–H), 9.26 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 21.67, 29.26, 111.64, 113.99, 119.94, 124.12, 125.72, 134.36, 142.87, 155.12, 169.26; GCMS m/z: 204 [M+]; Anal.calcd. for C11 H12 N2 O2 ; C, 64.69; H, 5.92; N, 13.72; Found: C, 64.67; H, 5.92; N, 13.72. 3.2.3. (4,6-Dimethyl-benzofuran-3-yl)-acetic acid hydrazide (6c)

HN NH2 CH3

O O

H3C 6c

Colorless solid (ethanol); m.p. 175–176 °C; yield 1.65 g (76%); IR (KBr, υ in cm−1 ): 1625 (C=O), 3290, (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 2.34 (s, 3H, CH3 ), 2.50 (s, 3H, CH3 ), 3.55 (d, J = 1.0 Hz, 2H, C3–CH2 ), 4.24 (s, br, 2H, NH2, D2 O exchangeable), 6.79 (s, 1H, C5–H), 7.14 (s, 1H, C7–H), 7.65 (s, 1H, C2–H), 9.12 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 19.29, 21.43, 30.13, 109.52, 115.47, 124.25, 125.78, 131.38, 134.20, 143.16, 155.85, 169.88; GCMS m/z: 218 [M+]; Anal.calcd. for C12 H14 N2 O2 ; C, 66.04; H, 6.47; N, 12.84; Found: C, 66.01; H, 6.47; N, 12.84. 3.2.4. (6,7-Dimethyl-benzofuran-3-yl)-acetic acid hydrazide (6d)

HN NH2 O H 3C

O CH3 6d

Colorless solid (ethanol); m.p. 153–154 °C; yield 1.57 g (72%); IR (KBr, υ in cm−1 ): 1620 (C=O), 3295, (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 2.32 (s, 3H, CH3 ), 2.38 (s, 3H, CH3 ), 3.43 (d, J = 1.0 Hz, 2H, C3–CH2 ), 4.26 (s, br, 2H, NH2, D2 O exchangeable), 7.03 (d, J = 8.0 Hz, 1H, C5–H), 7.22 (d, J = 8.0 Hz, 1H, C4–H), 7.76 (s, 1H, C2–H), 9.15 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 18.10, 19.08, 29.09, 114.46, 117.60, 119.51, 124.86, 125.74, 132.46, 142.71, 154.32, 169.15; GCMS m/z: 218 [M+]; Anal.calcd. for C12 H14 N2 O2; C, 66.04; H, 6.47; N, 12.84; Found: C, 66.01; H, 6.47; N, 12.84. 3.2.5. (5-Isopropyl-benzofuran-3-yl)-acetic acid hydrazide (6e)

HN NH2 O O 6e Colorless solid (ethanol); m.p. 97–98 °C; yield 1.85 g (80%); IR (KBr, υ in cm−1 ): 1625 (C=O), 3296, 3460 (NHNH2 ); 1 H NMR

8

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

(500 MHz, DMSO-d6 ): δ 1.27 (d, 6H, isopropyl-CH3 , J = 6 Hz), 2.91–3.00 (m, 1H, isopropyl-CH), 3.42 (d, J = 1.0 Hz, 2H, C3–CH2 ), 4.26 (s, br, 2H, NH2, D2 O exchangeable), 7.08 (dd, J = 8.5 Hz, 1.5 Hz, 1H, C6–H), 7.38–7.41 (m, 2H, C4–H and C7–H), 7.76 (s, 1H, C2–H), 9.24 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 23.44, 29.10, 34.80, 111.12, 115.08, 120.38, 125.73, 128.34, 131.72, 143.60, 153.64, 169.05; GCMS m/z: 232 [M+]; Anal.calcd. for C13 H16 N2 O2 ; C, 67.22; H, 6.94; N, 12.06; Found: C, 67.20; H, 6.94; N, 12.06.

3.2.6. (5-tert-Butyl-benzofuran-3-yl)-acetic acid hydrazide (6f)

HN NH2 O O 6f Colorless solid (ethanol); m.p. 105–106 °C; yield 1.97 g (80%); IR (KBr, υ in cm−1 ): 1621 (C=O), 3286, 3451 (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 1.36 (s, 9H, CH3 ), 3.42 (d, J = 1.0 Hz, 2H, C3–CH2 ), 4.22 (s, br, 2H, NH2, D2 O exchangeable), 7.11 (dd, J = 8.5 Hz, 1.5 Hz, 1H, C6–H), 7.36–7.46 (m, 2H, C4–H and C7–H), 7.74 (s, 1H, C2–H), 9.29 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d ): δ 29.18, 31.08, 45.86, 111.16, 115.16, 120.38, 125.80, 128.22, 131.64, 143.68, 153.84, 169.54; 6 GCMS m/z: 246 [M+]; Anal.calcd. for C14 H18 N2 O2; C, 68.27; H, 7.37; N, 11.37; Found: C, 68.25; H, 7.37; N, 11.37.

3.2.7. (6-Hydroxy-benzofuran-3-yl)-acetic acid hydrazide (6g)

HN NH2 O HO

6g

O

Beige colored solid (ethanol); m.p. 131–132 °C, yield 1.97 g (96%); IR (KBr, ν in cm−1 ): 3410 (br, OH, NH–NH2 ), 1621 (C=O); 1 H NMR (500 MHz, DMSO-d ): δ 3.56 (d, J = 1.0 Hz, 2H, C3–CH ), 4.21 (s, br, 2H, NH D O exchangeable), 6.71 (dd, J = 8.4 Hz, 6 2 2, 2 2.0 Hz, 1H, C5-H), 6.83 (d, J = 2.0 Hz, 1H, C7–H), 7.30 (d, J = 8.4 Hz, 1H, C4–H), 7.40 (s, 1H, C2–H), 9.56 (s, br, 1H, OH, D2 O exchaneable), 10.16 (s, br, 1H, NH, D2 O exchaneable); 13 C NMR (125 MHz, DMSO-d6 ): δ 29.88, 98.15, 112.61, 114.48, 120.74, 120.95, 142.38, 156.22, 156.19, 169.34; GCMS m/z: 206 [M+]; Anal.calcd. for C10 H10 N2 O3; C, 58.25; H, 4.89; N, 13.59; Found: C, 58.21; H, 4.89; N, 13.59.

3.2.8. (5-Methoxy-benzofuran-3-yl)-acetic acid hydrazide (6h)

HN NH2 O

H3CO 6h

O

Beige colored solid (ethanol); m.p. 177–178 °C; yield 1.58 g (72%); IR (KBr, υ in cm−1 ): 1604 (C=O), 3197 (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 3.66 (s, 3H, 5–OCH3 ), 3.72 (d, J = 1.0 Hz, 2H, C3–CH2 ), 4.52 (s, br, 2H, NH2, D2 O exchangeable), 7.39– 7.41 (m, 1H, Ar–H), 7.69–7.72 (m, 2H, Ar–H), 8.05 (s, 1H, C2–H), 9.57 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 29.24, 56.01, 103.33, 112.13, 113.13, 113.39, 115.06, 128.68, 144.56, 149.83, 155.91, 168.64; GCMS m/z: 220 [M+]; Anal.calcd. for C11 H12 N2 O3; C, 59.99; H, 5.49; N, 12.72; Found: C, 59.96; H, 5.49; N, 12.72.

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

9

3.2.9. (6-Methoxy-benzofuran-3-yl)-acetic acid hydrazide (6i)

HN NH2 O H3CO

6i

O

Brown colored solid (ethanol); m.p. 121–122 °C; yield 1.78 g (81%); IR (KBr, υ in cm−1 ): 1626 (C=O), 3321 (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 3.56 (d, J = 1.0 Hz, 2H, C3–CH2 ), 3.76 (s, 3H, 6–OCH3 ), 4.20 (s, br, 2H, NH2, D2 O exchangeable), 6.86 (dd, J = 8.6 Hz, 1.6 Hz, 1H, C5–H), 7.15 (d, J = 1.6 Hz, 1H, C7–H), 7.43 (d, J = 8.6 Hz, 1H, C4–H), 7.75 (s, 1H, C2–H), 10.10 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 29.26, 55.87, 96.45, 111.86, 114.36, 120.96, 121.11, 142.59, 155.98, 156.06, 168.82; GCMS m/z: 220 [M+]; Anal.calcd. for C11 H12 N2 O3; C, 59.99; H, 5.49; N, 12.72; Found: C, 59.96; H, 5.49; N, 12.72. 3.2.10. (5-Chloro-benzofuran-3-yl)-acetic acid hydrazide (6j)

HN NH2 O

Cl O 6j

Black colored solid (ethanol), m.p. 193–194 °C, yield 1.57 g (70%); IR (KBr, υ in cm−1 ) 1644 (C=O), 3234, 3331 (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 3.49 (d, J = 1.0 Hz, 2H, C3–CH2 ), 4.22 (s, br, 2H, NH2, D2 O exchangeable), 7.30 (d, J = 8.8 Hz, 1H, C6–H), 7.56 (d, J = 8.8 Hz, 1H, C7–H), 7.63 (s, 1H, C4–H), 7.90 (s, 1H, C2–H), 10.21 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 29.47, 113.77, 115.72, 120.96, 125.06, 127.92, 130.08, 145.82, 153.90, 169.68; GCMS m/z: 224, 226 [M+, M+2]; Anal.calcd. for C10 H9 ClN2 O2 ; C, 53.47; H, 4.04, N, 12.47; Found: C, 53.40; H, 4.04, N, 12.47. 3.2.11. (6-Chloro-benzofuran-3-yl)-acetic acid hydrazide (6k)

HN NH2 O O

Cl 6k

Black colored solid (ethanol); m.p. 180–181 °C; yield 1.48 g (66%); IR (KBr, υ in cm−1 ): 1640 (C=O), 3245, 3369 (NHNH2 ); 1 H NMR (500 MHz, DMSO-d ): δ 3.72 (d, J = 1.0 Hz, 2H, C3–CH ), 4.12 (s, br, 2H, NH D O exchangeable), 7.06 (d, J = 8.0 Hz, 6 2 2, 2 1H, C5–H), 7.39 (s, 1H, C7-H), 7.42 (d, J = 8.0 Hz, 1H, C4–H), 7.74 (s, 1H, C2–H), 10.6 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 29.78, 114.77, 114.98, 120.68, 125.41, 128.08, 130.42, 146.04, 154.18, 170.03; GCMS m/z: 224, 226 [M+, M+2]; Anal.calcd. for C10 H9 ClN2 O2; C, 53.47; H, 4.04, N, 12.47; Found: C, 53.43; H, 4.04, N, 12.47. 3.2.12. (5-Bromo-benzofuran-3-yl)-acetic acid hydrazide (6l)

HN NH2 O

Br

6l

O

Colorless solid (ethanol); m.p. 161–162 °C; yield 1.87 g (70%); IR (KBr, υ in cm−1 ): 1641 (C=O), 3316 (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 3.45 (d, J = 0.5 Hz, 2H, C3–CH2 ), 4.27 (s, br, 2H, NH2, D2 O exchangeable), 7.43–7.45 (dd, J = 9.0 Hz, 2.0 Hz, 1H, C6–H), 7.53 (m, 1H, C7-H), 7.88 (m, 1H, C4–H), 7.89 (s, 1H, C2–H), 9.30 (s, br, 1H, NH, D2 O exchangeable); 13 C

10

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

NMR (125 MHz, DMSO-d6 ): δ 29.02, 113.78, 115.14, 115.38, 123.37, 127.37, 130.49, 145.17, 153.83, 168.91; GCMS m/z: 267 [M+]; Anal.calcd. for C10 H9 BrN2 O2 ; C, 44.63; H, 3.37; N, 10.41; Found: C, 44.61; H, 3.37; N, 10.41.

3.2.13. (6-Bromo-benzofuran-3-yl)-acetic acid hydrazide (6m)

HN NH2 O O

Br 6m

Colorless solid (ethanol + ethyl acetate; 75:25); m.p. 173–174 °C; yield 1.66 g (62%); IR (KBr, υ in cm−1 ): 1636 (C=O), 3236, 3366 (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 3.73 (d, J = 1.0 Hz, 2H, C3–CH2 ), 4.18 (s, br, 2H, NH2, D2 O exchangeable), 7.08 (d, J = 8.0 Hz, 1H, C5–H), 7.36 (s, 1H, C7–H), 7.41 (d, J = 8.0 Hz, 1H, C4–H), 7.74 (s, 1H, C2–H),), 10.61 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): 29.88, 114.63, 114.92, 120.64, 125.33, 128.39, 130.66, 146.32, 154.28, 169.96; GCMS m/z: 267, 269 [M+, M+2]; Anal.calcd. for C10 H9 BrN2 O2 ; C, 44.63; H, 3.37; N, 10.41; Found: C, 44.60; H, 3.37; N, 10.40.

3.2.14. Naphtho[2,1-b]furan-1-yl-acetic acid hydrazide (6n)

HN NH2 O O 6n Beige colored solid (ethanol); m.p. 189–190 °C; yield 1.82 g (76%); IR (KBr, υ in cm−1 ): 1649 (C=O), 3326 (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 4.04 (d, J = 1.0 Hz, 2H, C3–CH2 ), 4.18 (s, br, 2H, NH2, D2 O exchangeable), 7.42 (dt, J = 8.0 Hz, 1.20 Hz, 1H, Ar–H), 7.54 (dt, J = 8.0 Hz, 1.20 Hz, 1H, Ar–H), 7.72 (d, J = 8.8 Hz, 1H, Ar-H), 7.76 (d, J = 9.2 Hz, 1H, Ar–H), 8.00 (s, 1H, C2–H), 8.01 (d, J = 8.4 Hz, 1H, Ar–H), 8.13 (d, J = 8.4 Hz, 1H, Ar–H), 9.80 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 31.13, 112.82, 115.98, 121.48, 123.58, 124.76, 125.86, 126.92, 128.43, 129.33, 130.85, 143.84, 152.94, 169.42; GCMS m/z: 240 [M+]; Anal.calcd. for C14 H12 N2 O2 ; C, 69.99; H, 5.03; N, 11.66; Found: C, 69.63; H, 5.03; N, 11.66.

3.2.15. Naphtho[1,2-b]furan-3-yl-acetic acid hydrazide (6o)

HN NH2 O O 6o Brown colored solid (ethanol); m.p. 167–168 °C; yield 1.78 g (74%); IR (KBr, υ in cm−1 ): 1658 (C=O), 3297 (NHNH2 ); 1 H NMR (500 MHz, DMSO-d6 ): δ 3.74 (d, J = 1.0 Hz, 2H, C3–CH2 ), 4.16 (s, br, 2H, NH2, D2 O exchangeable), 7.45 (dt, J = 8.0 Hz, 1.20 Hz, 1H, Ar-H), 7.60 (dt, J = 8.0 Hz, 1.20 Hz, 1H, Ar–H), 7.63 (d, J = 8.4 Hz, 1H, Ar-H), 7.67 (d, J = 8.8 Hz, 1H, Ar-H), 8.01 (m, 2H, Ar-H), 8.17 (d, J = 8.0 Hz, 1H, Ar-H), 10.12 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 29.24, 115.64, 119.43, 119.66, 120.95, 123.38, 123.86, 125.64, 126.81, 128.69, 131.09, 143.14, 149.85, 169.24; GCMS m/z: 240 [M+]; Anal.calcd. for C14 H12 N2 O2 ; C, 69.99; H, 5.03; N, 11.66; Found: C, 69.66; H, 5.03; N, 11.66.

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

11

3.2.16. 5-(5-Methyl-benzofuran-3-ylmethyl)-3H-[1,3,4]oxadiazole-2-thione (7a)

S

O N

H3C

NH

O 7a Colorless solid (ethanol + ethyl acetate; 75:25); m.p. 158 °C; yield 1.99 g (81%); IR (KBr, υ in cm−1 ): 1292 (C=S), 1630 (C=N), 3071 (NH); 1 H NMR (500 MHz, DMSO-d6 ): δ 2.37 (s, 3H, 5-CH3 ), 4.22 (d, J = 0.5 Hz, 2H, C3–CH2 ), 7.13–7.15 (dd, J = 8.5 Hz, 1.0 Hz, 1H, C6–H), 7.40 (s, 1H, C4-H), 7.44 (d, J = 8.5 Hz, C7–H), 7.95 (s, 1H, C2–H), 14.50 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d ): δ 20.54, 21.39, 111.50, 112.58, 119.90, 126.37, 127.46, 132.34, 144.58, 153.50, 162.53, 178.34; 6 GCMS m/z: 246 [M+]; Anal.calcd. for C12 H10 N2 O2 S; C, 58.52; H, 4.09;; N, 11.37; Found: C, 58.51; H, 4.09; N, 11.37 [51].

3.2.17. 5-(6-Methyl-benzofuran-3-ylmethyl)-3H-[1,3,4]oxadiazole-2-thione (7b) S O

N

NH

O

H3C 7b

Beige solid (ethanol); m.p. 163–164 °C; yield 2.07 g (84%); IR (KBr, υ in cm−1 ): 1291 (C=S), 1626 (C=N), 3199 (NH); 1 H NMR (500 MHz, DMSO-d6 ): δ 2.39 (s, 3H, 6-CH3 ), 4.22 (s, 2H, C3–CH2 ), 7.07 (d, J = 7.5 Hz, 1H, C5–H), 7.37 (s, 1H, C7-H), 7.45 (d, J = 7.5 Hz, 1H, C4–H), 7.91 (s, 1H, C2–H), 14.42 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 20.61, 21.59, 111.96, 112.73, 119.79, 120.03, 124.69, 124.89, 135.08, 143.78, 155.47, 162.54, 178.31; GCMS m/z: 246 [M+]; Anal.calcd. for C12 H10 N2 O2 S; C, 58.52; H, 4.09; N, 11.37; Found: C, 58.50; H, 4.09; N, 11.37.

3.2.18. 5-(4,6-Dimethyl-benzofuran-3-ylmethyl)−3H-[1,3,4]oxadiazole-2-thione (7c)

O

CH3

N

S

NH

O

H3C 7c

Beige solid (ethanol); m.p. 161–162 °C, yield 2.21 g (85%); IR (KBr, υ in cm−1 ) 1309 (C=S), 1627 (C=N), 3440 (NH); 1 H NMR (500 MHz, DMSO-d6 ): δ 2.34 (s, 3H, CH3 ), 2.46 (s, 3H, CH3 ), 4.33 (s, 2H, C3–CH2 ), 6.82 (s, 1H, C5–H), 7.19 (s, 1H, C7-H), 7.85 (s, 1H, C2–H), 14.33 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): 19.05, 21.41, 21.87, 109.77, 113.18, 123.32, 126.22, 131.02, 134.91, 143.95, 155.97, 163.16, 178.29; GCMS m/z: 260 [M+]; Anal.calcd. for C13 H12 N2 O2 S; C, 59.98; H, 4.65; N, 10.76; Found: C, 59.96; H, 4.65; N, 10.76.

12

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

3.2.19. 5-(6,7-Dimethyl-benzofuran-3-ylmethyl)−3H-[1,3,4]oxadiazole-2-thione (7d)

O N

S

NH

O

H3C CH3

7d

Colorless solid (ethanol); m.p. 173–174 °C; yield 2.13 g (82%); IR (KBr, υ in cm−1 ): 1301 (C=S), 1629 (C=N), 3234 (NH); 1 H NMR (500 MHz, DMSO-d6 ): δ 2.35 (s, 3H, CH3 ), 2.47 (s, 3H, CH3 ), 4.33 (s, 2H, C3-CH2 ), 7.06 (d, J = 8.0 Hz, 1H, C5–H), 7.23 (d, J = 8.0 Hz, 1H, C4–H), 7.77 (s, 1H, C2–H), 14.22 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 18.24, 19.48, 23.14, 111.12, 114.28, 122.14, 124.33, 126.57, 131.38, 142.18, 154.28, 165.42, 178.22; GCMS m/z: 260 [M+]; Anal.calcd. for C13 H12 N2 O2 S; C, 59.98; H, 4.65; N, 10.76; Found: C, 59.95; H, 4.65; N, 10.76.

3.2.20. 5-(5-Isopropyl-benzofuran-3-ylmethyl)-3H-[1,3,4]oxadiazole-2-thione (7e)

O N

S NH

O 7e Colorless solid (ethanol); m.p. 160–161 °C; yield 2.14 g (78%); IR (KBr, υ in cm−1 ): 1306 (C=S), 1638 (C=N), 3248 (NH); 1 H NMR (500 MHz, DMSO-d ): δ 1.26 (d, 6H, isopropyl-CH , J = 6 Hz), 2.95–3.08 (m, 1H, isopropyl-CH), 4.22 (d, J = 1.0 Hz, 6 3 2H, C3–CH2 ), 7.10 (dd, J = 8.5 Hz, 1.5 Hz, 1H, C6–H), 7.41–7.46 (m, 2H, C4–H and C7-H), 7.77 (s, 1H, C2–H), 14.28 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 23.51, 29.26, 34.92, 110.14, 114.33, 121.24, 123.36, 128.48, 134.78, 144.75, 154.16, 166.44, 177.19; GCMS m/z: 274 [M+]; Anal.calcd. for C14 H14 N2 O2 S; C, 61.29; H, 5.14; N, 10.21; Found: C, 61.27; H, 5.14; N, 10.21.

3.2.21. 5-(5-tert-Butyl-benzofuran-3-ylmethyl)−3H-[1,3,4]oxadiazole-2-thione (7f)

O N

S

NH

O 7f Colorless solid (ethanol + ethyl acetate; 75:25); m.p. 153–154 °C; yield 2.33 g (81%); IR (KBr, υ in cm−1 ): 1301 (C=S), 1632 (C=N), 3239 (NH); 1 H NMR (500 MHz, DMSO-d6 ): δ 1.36 (s, 9H, CH3 ), 4.21 (d, J = 1.0 Hz, 2H, C3–CH2 ), 7.11 (dd, J = 8.5 Hz, 1.5 Hz, 1H, C6-H), 7.42–7.48 (m, 2H, C4–H and C7–H), 7.78 (s, 1H, C2–H), 14.32 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO–d6 ): 29.32, 31.40, 45.92, 112.18, 116.44, 121.02, 126.11, 128.18, 131.65, 144.14, 156.07, 166.15. 177.48; GCMS m/z: 288 [M+]; Anal.calcd. for C15 H16 N2 O2 S; C, 62.48; H, 5.59; N, 9.71; Found: C, 62.47; H, 5.59; N, 9.71.

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

13

3.2.22. 5-(6-Hydroxy-benzofuran-3-ylmethyl)−3H-[1,3,4]oxadiazole-2-thione (7g)

S

O N

NH

O

HO 7g

Colorless solid (ethanol+ethyl acetate; 75:25); m.p. 121–122 °C; yield 1.93 g (78%); IR (KBr, υ in cm−1 ): 1312 (C=S), 1638 (C=N), 3240 (Broad, OH and NH); 1 H NMR (500 MHz, DMSO-d6 ): δ 4.23 (d, J = 1.0 Hz, 2H, C3–CH2 ), 6.74 (dd, J = 8.4 Hz, 2.0 Hz, 1H, C5–H), 6.86 (d, J = 2.0 Hz, 1H, C7-H), 7.32 (d, J = 8.4 Hz, 1H, C4–H), 7.41 (s, 1H, C2–H), 9.62 (s, br, 1H, OH, D2 O exchangeable), 14.41 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 29.96, 99.68, 113.14, 115.31, 121.28, 121.68, 142.67, 157.45, 157.78, 166.58, 178.12.; GCMS m/z: 248 [M+]; Anal.calcd. for C11 H8 N2 O3 S; C, 53.22; H, 3.25; N, 11.28; Found: C, 53.20; H, 3.25; N, 11.28.

3.2.23. 5-(5-Methoxy-benzofuran-3-ylmethyl)-3H-[1,3,4]oxadiazole-2-thione (7h)

S

O N

H3CO

NH

O 7h Brown solid (ethanol); m.p. 127–128 °C; yield 2.10 g (80%); IR (KBr, υ in cm−1 ): 1301 (C=S), 1630 (C=N), 3414 (NH); 1 H NMR (500 MHz, DMSO–d6 ): δ 3.56 (s, 3H, 5-OCH3 ), 4.22 (d, J = 1.0 Hz, 2H, C3–CH2 ), 6.82–6.88 (dd, J = 8.0 Hz, 2.0 Hz, 1H, C6-H), 7.24 (d, J = 2.0 Hz, 1H, C4-H), 7.40 (d, J = 8.0 Hz, 1H, C7-H), 7.81 (s, 1H, C2–H), 14.18 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 29.38, 56.44, 104.10, 114.02, 114.34, 115.38, 127.24, 143.33, 150.12, 156.08, 167.81, 178.12; GCMS m/z: 262 [M+]; Anal.calcd. for C12 H10 N2 O3 S; C, 54.95; H, 3.84; N, 10.68; Found: C, 54.92; H, 3.84; N, 10.68.

3.2.24. 5-(6-Methoxy-benzofuran-3-ylmethyl)−3H-[1,3,4]oxadiazole-2-thione (7i)

O N

S

NH

O

H3CO 7i

Brown solid (ethanol+dioxane, 80:20); m.p. 193–194 °C; yield 2.12 g (81%); IR (KBr, υ in cm−1 ): 1308 (C=S), 1635 (C=N), 3216 (NH); 1 H NMR (500 MHz, DMSO–d6 ): δ 3.58 (s, 3H, 6-OCH3 ), 4.21 (d, J = 1.0 Hz, 2H, C3–CH2 ), 6.85 (dd, J = 9.0 Hz, 2.0 Hz, 1H, C5–H), 7.13 (d, J = 2.0 Hz, 1H, C7-H), 7.42 (d, J = 9.0 Hz, 1H, C4–H), 7.74 (s, 1H, C2–H), 14.40 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 21.62, 56.08, 101.88, 102.66, 112.92, 113.36, 124.52, 143.37, 143.52, 174.70, 174.86; GCMS m/z: 262 [M+]; Anal.calcd. for C12 H10 N2 O3 S; C, 54.95; H, 3.84; N, 10.68; Found: C, 54.93; H, 3.84; N, 10.68.

14

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178 Table 1 Results of antitubercular activity of compounds 7(a-o) MICs (μg/mL). Compound

Mycobacterium tuberculosis (H37 RV)

Mycobacterium Phlei

7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 7n 7o Pyrazinamide Streptomycin

12.5 12.5 25 12.5 12.5 12.5 6.25 6.25 6.25 3.125 3.125 3.125 1.56 25 25 3.125 6.25

>100 >100 50 50 50 50 12.5 25 25 3.125 3.125 3.125 1.56 50 50 3.125 6.25

3.2.25. 5-(5-Chloro-benzofuran-3-ylmethyl)-3H-[1,3,4]oxadiazole-2-thione (7j)

O N

Cl

S NH

O 7j Beige solid (ethanol); m.p. 167–168 °C; yield 1.97 g (74%); IR (KBr, υ in cm−1 ): 1312 (C=S), 1629 (C=N), 3444 (NH); 1 H NMR (500 MHz, DMSO-d6 ): δ 4.21 (s, 2H, C3–CH2 ), 7.32 (d, J = 9.0 Hz, 1H, C6–H), 7.57 (d, J = 9.0 Hz, 1H, C7–H), 7.62 (s, 1H, C4–H), 7.88 (s, 1H, C2–H), 14.18 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): 29.62, 114.02, 115.43, 121.08, 125.33, 127.98, 131.16, 145.90, 154.15, 167.28, 177.10; GCMS m/z: 266, 268 [M+, M+2]; Anal.calcd. for C11 H7 ClN2 O2 S; C, 49.54; H, 2.65; N, 10.50; Found: C, 49.50; H, 2.65; N, 10.50.

3.2.26. 5-(6-Chloro-benzofuran-3-ylmethyl)-3H-[1,3,4]oxadiazole-2-thione (7k)

O N

S NH

O

Cl 7k

Colorless solid (ethanol); m.p. 181–182 °C; yield 1.92 g (72%); IR (KBr, υ in cm−1 ): 1310 (C=S), 1633 (C=N), 3420 (NH); 1 H NMR (500 MHz, DMSO-d ): δ 4.20 (d, J = 1.0 Hz, 2H, C3–CH ), 7.08 (d, J = 8.0 Hz, 1H, C5–H), 7.40 (s, 1H, C7–H), 7.43 6 2 (d, J = 8.0 Hz, 1H, C4–H), 7.72 (s, 1H, C2–H), 14.13 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 29.92, 115.12, 116.14, 121.34, 125.82, 128.38, 131.19, 146.44, 155.15, 164.48, 178.18; GCMS m/z: 266 [M+]; Anal.calcd. for C11 H7 ClN2 O2 S; C, 49.54; H, 2.65; N, 10.50; Found: C, 49.50; H, 2.65; N, 10.50.

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

15

Table 2 Details of LibDock score and ligand interaction data revealed through molecular docking (PDB: 2WTZ). Compound

LibDock Score

7g

95.157

7h

98.227

7i

101.521

7j

93.995

7k

97.12

7l

101.526

7m

109.364

Pyrazinamide

106.193

Streptomycin

132.286

Interacting atoms

˚ Bond distance (A)

Donor atoms

Acceptor sAtoms

7g:H25–A:THR86:O 7g:H25–A:THR86:C 7g:H19–A:GLY83:HA2 7g:O7–A:LEU81:HB1 7g:H22–A:GLY88:CA A:LEU81:HN–7h:O7 7h:H21–A:LEU81:HB1 7h:C9–A:GLY88:HA2 7h:H23–A:GLY88:CA A:THR86:HN–7i:O17 7i:H2–A:GLY88:CA 7i:H20–A:THR86:CG2 A:LEU81:HN– - 7j:N12 7j:H23–A:LEU81:HB1 A:THR86:HN–7k:Cl17 A:GLY83:HA2–7k:Cl17 A:THR86:HG22 –7k:H19 A:GLY88:CA–7k:H22 A:LEU81:HN–7l:N12 A:LEU81:HB1–7l:H23 A:THR86:HN–7m:Br17 7m:Br17–A:GLY83:HA2 7m:H19–A:THR86:HG22 7m:H22–A:GLY88:CA A:THR86:HG1–pyra:O1 A:SER84:HN–pyra:N3 Strepto:H52–A:LEU81:O Strepto:H51–A:LEU81:O A:ARG68:HH12 –Strept:N15

2.1180 0 0 2.1890 0 0 1.5030 0 0 1.9960 0 0 1.7260 0 0 2.0880 0 0 1.7440 0 0 2.1260 0 0 1.9460 0 0 2.2630 0 0 1.9280 0 0 2.0 060 0 0 1.9440 0 0 1.6170 0 0 2.3460 0 0 2.2490 0 0 1.1580 0 0 1.8730 0 0 1.9610 0 0 1.6310 0 0 2.4190 0 0 2.0870 0 0 1.1540 0 0 1.660 0 0 0 2.4230 0 0 2.080 0 0 0 2.1270 0 0 2.4210 0 0 2.3730 0 0

H25 H25 H19 O7 H22 HN H21 C9 H23 HN H23 H20 HN H23 HN HA2 HG22 CA HN HB1 HN Br17 H19 H22 HG1 HN H52 H51 HH12

O C HA2 HB1 CA O7 HB1 HA2 CA O17 CA CG2 N12 HB1 Cl17 Cl17 H19 H22 N12 H23 Br17 HA2 HG22 CA O1 N3 O O N15

No. of H-bonds

1

1

1

1 1

1

1

2 3

Fig. 3. (A) Structural model of MurE ligase of M. Tuberculosis (PDB: 2WTZ) binding site (sphere); (B) Binding site and binding pattern of title compounds.

3.2.27. 5-(5-Bromo-benzofuran-3-ylmethyl)−3H-[1,3,4]oxadiazole-2-thione (7l)

O N

Br

S

NH

O 7l Colorless solid (ethanol); m.p. 167–168 °C; yield 2.17 g (70%); IR (KBr, υ in cm−1 ): 1311 (C=S), 1627 (C=N), 3443 (NH);

16

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

Fig. 4. Binding modes of MurE ligase of M. Tuberculosis (PDB: 2WTZ) protein with active compounds and its hydrogen bonding interactions with residues.

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

17

Fig. 4. Continued

NMR (500 MHz, DMSO-d6 ): δ 4.22 (s, 2H, C3–H2 ), 7.40–7.43 (dd, J = 9.0 Hz, 2.0 Hz, 1H, C6–H), 7.52 (d, J = 9.0 Hz, 1H, C7-H), 7.86 (d, J = 2.0 Hz, 1H, C4-H), 7.86 (s, 1H, C2-H), 14.32 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSOd6 ): δ 29.12, 113.98, 115.66, 115.84, 124.12, 127.97, 131.58, 145.62, 154.20, 166.38, 176.96; GCMS m/z: 310, 312 [M+, M+2]; Anal.calcd. for C11 H7 BrN2 O2 S; C, 42.46; H, 2.27; N, 9.00; Found: C, 42.44; H, 2.27; N, 9.00. 1H

3.2.28. 5-(6-Bromo-benzofuran-3-ylmethyl)-3H-[1,3,4]oxadiazole-2-thione (7m)

O N

S NH

O

Br 7m

Colorless solid (ethanol); m.p. 174–175 °C; yield 2.04 g (66%); IR (KBr, υ in cm−1 ): 1308 (C=S), 1628 (C=N), 3412 (NH); 1 H NMR (500 MHz, DMSO-d ): δ 4.21 (d, J = 1.0 Hz, 2H, C3–CH ), 7.08 (d, J = 8.0 Hz, 1H, C5–H), 7.38 (s, 1H, C7–H), 7.42 6 2

18

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

Fig. 5. Receptor-ligand hydrogen bonds (green colour) and bumps (pink colour) of compound 7 m and with active site residues of MurE ligase of M. Tuberculosis (PDB: 2WTZ). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

(d, J = 8.0 Hz, 1H, C4–H), 7.73 (s, 1H, C2–H), 14.26 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): 29.94, 114.92, 115.16, 121.33, 126.18, 128.48, 131.82, 147.28, 155.34, 168.42, 176.90; GCMS m/z: 310, 312 [M+, M+2]; Anal.calcd. for C11 H7 BrN2 O2 S; C, 42.46; H, 2.27; N, 9.00; Found: C, 42.41; H, 2.27; N, 9.00.

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

19

3.2.29. 5-(Naphtho[2,1-b]furan-3-ylmethyl)-3H-[1,3,4]oxadiazole-2-thione (7n)

O N

S NH

O 7n Beige solid (ethanol+dioxane; 80:20); m.p. 165–166 °C; yield 2.14 g (76%); IR (KBr, υ in cm−1 ): 1293 (C=S), 1625 (C=N), 3445 (NH); 1 H NMR (500 MHz, DMSO-d6 ): δ 4.64 (s, 2H, C3–CH2 ), 7.50–7.53 (t, J = 7.5 Hz, 1H, Ar–H), 7.58–7.61 (t, J = 7.5 Hz, 1H, Ar–H), 7.79–7.81 (d, J = 9.0 Hz, 1H, Ar–H), 7.85–7.87 (d, J = 9.0 Hz, 1H, Ar–H), 8.04–8.05 (d, J = 8.5 Hz, 1H, Ar–H), 8.15 (s, 1H, C2–H), 8.20–8.21 (d, J = 8.5 Hz, 1H, Ar–H), 13.77 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 22.48, 113.16, 114.50, 120.74, 123.60, 125.06, 126.57, 127.12, 127.91, 129.46, 130.81, 144.57, 153.30, 162.67, 178.35; GCMS m/z: 282 [M+]; Anal.calcd. for C15 H10 N2 O2 S; C, 63.81; H, 3.57; N, 9.92; Found: C, 63.80; H, 3.57; N, 9.92. 3.2.30. 5-(Naphtho[1,2-b]furan-3-ylmethyl)-3H-[1,3,4]oxadiazole-2-thione (7o)

O N

S NH

O 7o Brown solid (ethanol+dioxane; 75:25); m.p. 117–118 °C; yield 2.08 g (74%); IR (KBr, υ in cm−1 ): 1299 (C=S), 1629 (C=N), 3425 (NH); 1 H NMR (500 MHz, DMSO-d6 ): δ 4.62 (s, 2H, C3-CH2 ), 7.46 (dt, J = 8.0 Hz, 1.20 Hz, 1H, Ar–H), 7.62 (dt, J = 8.0 Hz, 1.20 Hz, 1H, Ar–H), 7.64 (d, J = 8.4 Hz, 1H, Ar–H), 7.69 (d, J = 8.8 Hz, 1H, Ar–H), 8.02 (m, 2H, Ar–H), 8.19 (d, J = 8.0 Hz, 1H, Ar–H), 14.36 (s, br, 1H, NH, D2 O exchangeable); 13 C NMR (125 MHz, DMSO-d6 ): δ 29.62, 116.44, 119.64, 119.98, 121.25, 124.38, 124.15, 126.57, 127.84, 128.90, 132.06, 144.33, 149.91, 168.02, 177.60; GCMS m/z: 282 [M+]; Anal.calcd. for C15 H10 N2 O2 S; C, 63.81; H, 3.57; N, 9.92; Found: C, 63.80; H, 3.57; N, 9.92. 3.3. Antitubercular evaluation The in vitro antitubercular activity against Mycobacterium tuberculosis H37 RV and Mycobacterium phlei was carried out by using standard procedure, Microplate Alamar Blue Assay (MABA) [52]. The MIC values of all the title compounds 7(a-o) along with standard drugs pyrazinamide and streptomycin for the comparison are summarized in Table 1. The MIC ranges in between 1.56 and 100 μg/mL. 3.4. Molecular docking studies To understand the ligand orientation and the inhibitory ability towards MurE ligase of M. Tuberculosis, we initially carried out docking of the title compounds 7(a-o) which have potent against Mycobacterium Tuberculosis and later with the known inhibitor/antituberculosis drugs pyrazinamide and streptomycin. The used docking program LibDock produces several poses, each producing their corresponding LibDock scores with different orientations within the defined active site of the protein. The high LibDock score of the ligand pose was taken into account for the prediction of the best ligand binding conformation. Therefore, the results of above prevalidated analysis was used to categorize the retrieved hit molecules and then those were further validated with visualization method to determine the suitable binding mode of the inhibitors based on the critical interactions with the active site residues. The docked compounds were found to have similar binding poses to the co-crystallized ligand, thus validating the adopted docking methodology. Finally, the analyze ligand poses subprotocol was performed to count hydrogen bonds and close contacts (vander Waals clashes) between the compounds and protein. The summary of docking with top ranked poses from moderate to excellent compounds 7(g-m) are tabulated in Table 2. Active site of the MurE ligase protein, binding pattern of docked compounds are shown in Fig. 3 and binding mode of proteins with compounds, hydrogen bonding interactions are shown in Fig. 4. Docking analysis of anti-TB potent active compound 7m with the MurE ligase, revealed that the compound 7m fitted well in the active site pocket (Fig. 5) and showing the best docking score of 109.364, higher than standard drug pyrazinamide

20

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

(106.193). From the Fig. 5 the compound 7m is revealed that one hydrogen bond and three close contacts are formed between compound 7m with the protein. The hydrogen bond is formed with the Thr86 amino acid residue of the proteins. This bond is formed between hydrogen atom of nitrogen molecule of the amino acid Thr86 with the 17th bromine atom of the compound 7m (THR86:HN-7m: Br17) with a hydrogen bond distance of 2.419 Ao . In addition to that, the compound 7m also formed three close contacts with Gly83, Thr86 and Gly88 amino acid residues of target protein. 4. Conclusion In conclusion, a novel benzofuran-oxadiazole hybrids were designed, synthesized, characterized following simple heterocyclic transformation from coumarins to benzofurans, then to title compounds. The intermediates 6(a-o) and title compounds 7(a-o) were characterized using both spectroscopic and analytical methods. The title compounds 7(a-o) were evaluated for their antitubercular property. The SAR indicate the compounds bearing chlorine (7j, 7k) and bromine (7l, 7m) on benzofuran were effective. The compound 7m exhibited higher activity compared to standard drug pyrazinamide was supported by molecular docking studies. Further biological investigations on 3-substitued benzofurans are under progress in our group and will be reported in near future. Acknowledgments The authors thank to the SAIF, Indian Institute of Technology Madras, Chennai, for the 1 H NMR and and USIC K.U. Dharwad for IR, GCMS spectral data.

13 C

NMR spectra;

Supplementary materials Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.cdc.2019.100178. References [1] V. Bhowruth, L.G. Dover, G.S. Besra, 4 Tuberculosis Chemotherapy:, Recent Developments and Future Perspectives, Prog. Med. Chem. 45 (2007) 169– 203, doi:10.1016/S0079- 6468(06)45504- 1. [2] H. Lang, G. Quaglio, O. Olesen, Tuberculosis research in the European Union: past achievements and future challenges, Tuberculosis 90 (2010) 1–6. doi:10.1016/j.tube.2009.10.002. [3] WHO Global Tuberculosis Report, 2017. [4] L.G. Dover, G.D. Coxon, Current status and research strategies in tuberculosis drug development, J. Med. Chem. 54 (2011) 6157–6165, doi:10.1021/ jm200305q. [5] B. Rawat, D.S. Rawat, Antituberculosis Drug Research, A critical overview, Med. Res. Rev 33 (2013) 693–764, doi:10.1002/med.21262. [6] S.H. Pattanashetty, K.M. Hosamani, D.A. Barretto, Microwave assisted synthesis, computational study and biological evaluation of novel quinolin-2(1H)one based pyrazoline hybrids, Chem. Data Collect. 15-16 (2018) 184–196, doi:10.1016/j.cdc.2018.06.003. [7] M. Prakashni, A. Joshi, C.N. Ramachandran, Electronic and optical absorption properties of the derivatives of 1,3,4-Oxadiazole, Chem. Data Collect. 5-6 (2016) 88–95, doi:10.1016/j.cdc.2016.11.004. [8] G. Krishnaswamy, P.K. Murthy, P.A. Suchetan, N.R. Desai, D.B.A. Kumar, R.S. Rao, Synthesis, crystal structure, Hirshfeld surface studies and frontier orbitals analysis of 4-(1-benzofuran-2-yl)-2-methyl-6-phenylpyrimidine, Chem. Data Collect. 9-10 (2017) 143–151, doi:10.1016/j.cdc.2017.06.001. [9] K.M Dawood, Benzofuran derivatives: a patent Review, Expert Opin. Ther. Patents 23 (2013) 1133–1156, doi:10.1517/13543776.2013.801455. [10] R. Naik, D.S. Harmalkar, X. Xu, K. Jang, K. Lee, Bioactive benzofuran derivatives: Moracins A-Z in medicinal chemistry, Eur. J. Med. Chem. 90 (2015) 379–393, doi:10.1016/j.ejmech.2014.11.047. [11] A. Radadiya, A. Shah, Bioactive benzofuran derivatives: An insight on lead developments, radioligands and advances of the last decade, Eur. J. Med. Chem. 97 (2015) 356–376, doi:10.1016/j.ejmech.2015.01.021. [12] H.K. Shamsuzzaman, Bioactive benzofuran derivatives: a review, Eur. J. Med. Chem. 97 (2015) 483–504, doi:10.1016/j.ejmech.2014.11.039. [13] R.J. Nevagi, S.N. Dighe, S.N. Dighe, Biological and medicinal significance of benzofuran, Eur. J. Med. Chem. 97 (2015) 561–581, doi:10.1016/j.ejmech. 2014.10.085. [14] A. Hiremathad, M.R. Patil, K.R. Chethana, K. Chand, M.A. Santos, R.S. Keri, Benzofuran: an emerging scaffold for antimicrobial agents, RSC Adv 5 (2015) 96809–96828, doi:10.1039/C5RA20658H. [15] P. Boregowda, S. Kalegowda, V.P. Rasal, J. Eluru, E. Koyye, Synthesis and biological evaluation of 4-(3-hydroxy-benzofuran-2-yl)coumarins, Organic Chem. Int. (2014) 297586, doi:10.1155/2014/297586. [16] L. Bigler, C. Spirili, R. Fiorotto, A. Pettenozzo, E. Duner, A. Baritussio, F. Follath, H.R. Ha, Synthesis and cytotoxicity properties of amiodarone analogues, Eur. J. Med. Chem. 42 (2007) 861–867, doi:10.1016/j.ejmech.2006.12.031. [17] S. Rizzo, C. Riviere, L. Piazzi, A. Bisi, S. Gobbi, M. Bartolini, V. Andrisano, F. Morroni, A. Tarozzi, J.P. Monti, A. Rampa, Benzofuran-based hybrid compounds for the inhibition of cholinesterase activity, β -amyloid aggregation, and Aβ ; neurotoxicity, J. Med. Chem 51 (2008) 2883–2886, doi:10.1021/jm8002747. [18] I.N. Gaisina, F. Gallier, A.V. Ougolkov, K.H. Kim, T. Kurome, S. Guo, D. Holzle, D.N. Luchini, S.Y. Blond, D.D. Billadeau, A.P. Kozikowski, From a natural product lead to the identification of potent and selective benzofuran-3-yl-(indol-3-yl)maleimides as glycogen synthase kinase 3β ; inhibitors that suppress proliferation and survival of pancreatic cancer cells, J. Med. Chem 52 (2009) 52 1853-1863, doi:10.1021/jm801317h. [19] S.A. Galal, A.S. Abd El-All, M.M. Abdallah, H.I. El-Diwani, Synthesis of potent antitumor and antiviral benzofuran derivatives, Bioorg. Med. Chem. Lett. 19 (2009) 2420–2428, doi:10.1016/j.bmcl.2009.03.069. [20] J. Suh, K.Y. Yi, Y.S. Lee, E. Kim, E.K. Yum, S. Yoo, Synthesis and biological evaluation of 3-substituted-benzofuran-2-carboxylic esters as a novel class of ischemic cell death inhibitors, Bioorg. Med. Chem. Lett. 20 (2010) 6362–6365, doi:10.1016/j.bmcl.2010.09.102. [21] A.M. Venkatesan, O.D. Santos, J. Ellingboe, D.A. Evrard, B.L. Harrison, D.L. Smith, R. Scerni, G.A. Hornby, L.E. Schechter, T.H. Andree, Novel benzofuran derivatives with dual 5-HT1A receptor and serotonin transporter affinity, Bioorg, Med. Chem. Lett. 20 (2010) 824–827, doi:10.1016/j.bmcl.2009.12.093. [22] H.F. Guo, H.Y. Shao, Z.Y. Yang, S.T. Xue, X. Li, Z.Y. Liu, X.B. He, J.D. Jiang, Y.Q. Zhang, S.Y. Si, Z.R. Li, Substituted benzothiophene or benzofuran derivatives as a novel class of bone morphogenetic protein-2 up-regulators: synthesis, structure-activity relationships, and preventive bone loss efficacies in senescence accelerated mice (SAMP6) and ovariectomized Rats, J. Med. Chem. 53 (2010) 1819–1829, doi:10.1021/jm901685n. [23] N. Negoro, S. Sasaki, S. Mikami, M. Ito, M. Suzuki, Y. Tsujihata, R. Ito, A. Harada, K. Takeuchi, N. Suzuki, J. Miyazaki, T. Santou, T. Odani, N. Kanzaki, M. Funami, T. Tanaka, A. Kogame, S. Matsunaga, T. Yasuma, Y. Momose, Discovery of TAK-875: A potent, selective, and orally bioavailable GPR40 agonist, ACS Med. Chem. Lett. 1 (2010) 290–294, doi:10.1021/ml10 0 0855.

V.S. Negalurmath, S.K. Boda and O. Kotresh et al. / Chemical Data Collections 19 (2019) 100178

21

[24] S. Kumar, W. Namkung, A.S. Verkman, P.K. Sharma, Novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids as calcium activated chloride channel inhibitors, Bioorg. Med. Chem. 20 (2012) 4237–4244, doi:10.1016/j.bmc.2012.05.074. [25] S. He, P. Jain, B. Lin, M. Ferrer, Z. Hu, N. Southall, X. Hu, W. Zheng, B. Neuenswander, C.H. Cho, Y. Chen, S.A. Worlikar, J. Aube, R.C. Larock, F.J. Schoenen, J.J. Marugan, T.J. Liang, K.J. Frankowski, High-throughput screening, discovery and optimization to develop a benzofuran class of Hepatitis C Virus inhibitors, ACS Comb. Sci 17 (2015) 641–652, doi:10.1021/acscombsci.5b00101. [26] V.N. Telvekar, A. Belubbi, V.K. Bairwa, K. Satardekar, Novel N’-benzylidene benzofuran-3-carbohydrazide derivatives as antitubercular and antifungal agents, Bioorg. Med. Chem. Lett. 22 (2012) 2343–2346, doi:10.1016/j.bmcl.2012.01.067. [27] Y. He, J. Xu, Z.H. Yu, A.M. Gunawan, L. Wu, L. Wang, Z.Y. Zhang, Discovery and evaluation of novel inhibitors of mycobacterium protein tyrosine phosphatase B from the 6-hydroxy-benzofuran-5-carboxylic acid scaffold, J. Med. Chem. 56 (2013) 832–842, doi:10.1021/jm301781p. [28] J.C. Sacchettini, A. Aggarwal, M.K. Parai, Substituted benzofuran derivatives as novel antimycobacterial agents, Patent WO 2016172498 A1 (2016). [29] K. Manna, Y.K. Agrawal, Design, synthesis, and antitubercular evaluation of novel series of 3-benzofuran-5-aryl-1-pyrazolyl-pyridylmethanone and 3-benzofuran-5-aryl-1-pyrazolylcarbonyl-4-oxo-naphthyridin analogs, Eur J. Med. Chem. 45 (2010) 3831–3839, doi:10.1016/j.ejmech.2010.05.035. [30] J. Renuka, K.I. Reddy, K. Srihari, V.U. Jeankumar, M. Shravan, J.P. Sridevi, P. Yogeeswari, K.S. Babu, D. Sriram, Design, synthesis, biological evaluation of substituted benzofurans as DNA gyraseB inhibitors of Mycobacterium tuberculosis, Bioorg. Med. Chem. 22 (2014) 4924–4934, doi:10.1016/j.bmc.2014. 06.041. [31] R.S Yamgar, B.R. Thorat, B. Nazirkar, V.B. Thorat, M. Mandewale, A. Nagarsekar, Synthesis, molecular docking and anti-tb activity of 1-benzofuran-2-carbohydrazide„ J. Chem. Sci. Photon 110 (2016) 279–291. [32] B. Nazirkar, U. Patil, B. Thorat, M. Mandewale, H. Gaokar, A. Pandhare, R. Yamgar, Synthesis and anti-tubercular study of some transition metal complexes of hydrazone derivatives derived from benzofuran-2-carbohydrazide, Der. Pharma. Chemica. 9 (2017) 45–53. [33] S. Santoshkumar, N.D. Satyanarayan, R. Anantacharya, P. Sameer, antimicrobial Synthesis, antitubercular and cheminformatic studies of 2-(1benzofuran-2-yl)-N’-[(3Z)-2-oxo-1,2-dihydro-3H-indol-3-ylidene]quinoline-4-carbohydrazide and its derivatives, Int. J. Pharm. Pharm. Sci. 9 (2017) 260– 267, doi:10.22159/ijpps.2017v9i5.17564. [34] T. Aboul-Fadl, H.A. Abdel-Aziz, M.K. Abdel-Hamid, T. Elsaman, J. Thanassi, M.J. Pucci, Schiff Bases of Indoline-2,3-dione: potential novel inhibitors of mycobacterium tuberculosis (Mtb) DNA Gyrase, Molecules 16 (2011) 7864–7879, doi:10.3390/molecules16097864. [35] B. Zhou, Y. He, X. Zhang, J. Xu, Y. Luo, Y. Wang, S.G. Franzblau, Z. Yang, R.J. Chan, Y. Liu, J. Zheng, Z.-Y. Zhang, Targeting mycobacterium protein tyrosine phosphatase B for anti-tuberculosis agents, Proc. Natl. Acad. Sci. U.S.A. 107 (2010) 4573–4578, doi:10.1073/pnas.0909133107. [36] L. Encinas, H. O’Keefe, M. Neu, M.J. Remuinan, A.M. Patel, A. Guardia, C.P. Davie, N. Perez-Macias, H. Yang, M.A. Convery, J.A. Messer, E. Perez-Herran, P.A. Centrella, D. Alvarez-Gomez, M.A. Clark, S. Huss, G.K. O’Donovan, F. Ortega-Muro, W. McDowell, P. Castaneda, C.C. Arico-Muendel, S. Pajk, J. Rullas, I. Angulo-Barturen, E. Alvarez-Ruiz, A. Mendoza-Losana, L. Ballell Pages, J. Castro-Pichel, G. Evindar, Encoded library technology as a source of hits for the discovery and lead optimization of a potent and selective class of bactericidal direct inhibitors of Mycobacterium tuberculosis InhA, J. Med. Chem. 57 (2014) 1276–1288, doi:10.1021/jm401326j. [37] S. Iqbal, M. Kesherwani, S. Dixit, D. Velmurugan, G. Krishnasamy, Insights in binding mechanism of benzofuran salicylic acid inhibitors against mycobacterium protein tyrosine phosphatases (PTP1B) using molecular modelling and simulation approaches, Int. J. Innov. Res. Comput. Commun. Eng. 3 (2015) 11428–11443. [38] P. Karunakar, C.R. Girija, V. Krishnamurthy, V. Krishna, K.V. Shivakumar, In Silico antitubercular activity analysis of benzofuran and naphthofuran derivatives, Tuberculosis Res. Treatment (2014) 697532, doi:10.1155/2014/697532. [39] B.R. Thorat, B. Nazirkar, V.B. Thorat, K. More, R. Jagtap, R. Yamgar, SAR Synthesis, Molecular docking and anti-TB study of 3-hydroxy-1-benzofuran-2-carbohydrazide, Asian J. Research Chem. 9 (2016) 116–126. [40] B.R. Thorat, B. Nazirkar, V.B. Thorat, K. More, R. Jagtap, R. Yamgar, SAR Synthesis, Molecular docking and antituberculosis study of 3-methyl-1benzofuran-2-carbohydrazide, Asian J. Chem. 28 (2016) 2346–2352, doi:10.14233/ajchem.2016.19894. [41] K. Kumara, K.P. Harish, N. Shivalingegowda, H.C. Tandon, K.N. Mohana, N.K. Lokanath, Crystal structure studies, Hirshfeld surface analysis and DFT calculations of novel 1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-piperazine derivatives, Chem. Data Collect. 11-12 (2017) 40–58, doi:10.1016/j.cdc. 2017.07.007. [42] C.R.W. Guimaraes, D.L. Boger, W.L. Jorgensen, Elucidation of fatty acid amide hydrolase inhibition by potent α -ketoheterocycle derivatives from monte carlo simulations, J. Am. Chem. Soc. 127 (2005) 17377–17384, doi:10.1021/ja055438j. [43] N.C. Desai, N. Bhatt, H. Somani, A. Trivedi, Synthesis, antimicrobial and cytotoxic activities of some novel thiazole clubbed 1,3,4-oxadiazoles, Eur. J. Med. Chem. 67 (2013) 54–59, doi:10.1016/j.ejmech.2013.06.029. [44] K.P. Harish, K.N. Mohana, L. Mallesha, B.N. Prasanna Kumar, Synthesis of novel 1-[5-(4-methoxy-phenyl)-[1,3,4]oxadiazol-2-yl]-piperazine derivatives and evaluation of their in vivo anticonvulsant activity, Eur. J. Med. Chem. 67 (2013) 276–283, doi:10.1016/j.ejmech.2013.04.054. [45] H. Rajak, B. Singh Thakur, A. Singh, K. Raghuvanshi, A.K. Sah, R. Veerasamy, P.C. Sharma, R. Singh Pawar, M.D. Kharya, Novel limonene and citral based 2,5-disubstituted-1,3,4-oxadiazoles: a natural product coupled approach to semicarbazones for antiepileptic activity, Bioorg. Med. Chem. Lett. 23 (2013) 864–868, doi:10.1016/j.bmcl.2012.11.051. [46] D.R. Guda, S.J. Park, M.W. Lee, T.J. Kim, M.E. Lee, Syntheses and anti-allergic activity of 2-((bis(trimethylsilyl)methylthio/methylsulfonyl)methyl)-5-aryl1,3,4-oxadiazoles, Eur. J. Med. Chem. 62 (2013) 84–88, doi:10.1016/j.ejmech.2012.12.035. [47] J. Sun, H. Zhu, Z.M. Yang, H.L. Zhu, Synthesis, molecular modeling and biological evaluation of 2-aminomethyl-5-(quinolin-2-yl)-1,3,4-oxadiazole-2(3H)thione quinolone derivatives as novel anticancer agent, Eur. J. Med. Chem. 60 (2013) 23–28, doi:10.1016/j.ejmech.2012.11.039. [48] M.J. Ahsan, J.G. Samy, C.B. Jain, K.R. Dutt, H. Khalilullah, M.S. Nomani, Discovery of novel antitubercular 1,5-dimethyl-2-phenyl-4-([5-(arylamino)-1,3,4oxadiazol-2-yl]methylamino)-1,2-dihydro-3H-pyrazol-3-one analogues, Bioorg. Med. Chem. Lett. 22 (2012) 969–972, doi:10.1016/j.bmcl.2011.12.014. [49] F. Macaev, Z. Ribkovskaia, S. Pogrebnoi, V. Boldescu, G. Rusu, N. Shvets, A. Dimoglo, A. Geronikaki, R. Reynolds, The structure–antituberculosis activity relationships study in a series of 5-aryl-2-thio-1,3,4-oxadiazole derivatives, Bioorg. Med. Chem. 19 (2011) 6792–6807, doi:10.1016/j.bmc.2011.09.038. [50] M. Neelgundmath, K.R. Dinesh, C.D. Mohan, F. Li, X. Dai, K.S. Siveen, S. Paricharak, D.J. Mason, J.E. Fuchs, G. Sethi, A. Bender, K.S. Rangappa, O. Kotresh, Basappa, Novel synthetic coumarins that targets NF-κ B in Hepatocellular carcinoma, Bioorg. Med. Chem. Lett. 25 (2015) 893–897, doi:10.1016/j.bmcl. 2014.12.065. ´ S. Armakovic, ´ [51] S.M. Hiremath, A. Suvitha, N.R. Patil, C.S. Hiremath, S.S. Khemalapure, S.K. Pattanayak, V.S. Negalurmath, K. Obelannavar, S.J. Armakovic, Synthesis of 5-(5-methyl-benzofuran-3-ylmethyl)-3H- [1, 3, 4] oxadiazole-2-thione and investigation of its spectroscopic, reactivity, optoelectronic and drug likeness properties by combined computational and experimental approach, Spectrochim. Acta Part A 205 (2018) 95–110, doi:10.1016/j.saa.2018. 07.003. [52] M.C.S. Lourenco, M.V.N. deSouza, A.C. Pinheiro, M.L. Ferreira, R.B. Goncalves, T.C.M. Nogneira, M.A. Peralta, Evaluation of anti-tubercular activity of nicotinic and isoniazid analogues, Arkivoc 15 (2007) 181–191, doi:10.3998/ark.5550190.0 0 08.f18. [53] C. Basavannacharya, G. Robertson, T. Munshi, N.H. Keep, S. Bhakta, ATP-dependent MurE ligase in Mycobacterium tuberculosis, Biochem. Struct. Character. Tuberculosis 90 (2010) 16–24, doi:10.1016/j.tube.2009.10.007. [54] http://www.cambridgesoft.com/literature/pdf/ChemBioDraw.pdf. [55] S.N. Rao, M.S. Head, A. Kulkarni, J.M. Lalonde, Validation studies of the site-directed docking Program LibDock, J. Chem. Inf. Model. 47 (2007) 2159– 2171, doi:10.1021/ci6004299. [56] M.B. Narayanachar, I.B. Majati, S.S. Mulimani, S.B. Sunnal, R.V. Nadiger, A.S. Ghanti, S.F. Gudageri, R. Naik, A. Nayak, Efficient and convenient method for synthesis of benzofuran-3-acetic acids and naphthafuranacetic acids, Synth. Commun. 45 (2015) 2195–2202, doi:10.1080/00397911.2015.1068943.