- Email: [email protected]
Combinatorial Chemistry Online Volume 16, Issue 2, February 2014
Combinatorial Chemistry - An Online Journal 16 (2014) 5–7
Contents lists available at ScienceDirect
Combinatorial Chemistry - An Online Journal journal homepage: www.elsevier.com/locate/comche
Combinatorial Chemistry Online Volume 16, Issue 2, February 2014 N.K. Terrett Ensemble Therapeutics Corp., Cambridge, MA 02139, USA
1. Current literature highlights 1.1. Parallel synthesis of sultams in water by a cascade reaction
meta-chloro-peroxybenzoic acid to give 4. The vinyl sulphonamide was inert to these conditions due to its electron deficiency and thus remained unaffected.
Sulphonamides are frequently found in molecules with pharmacological activity, and there are several examples where cyclic sulphonamides, sultams, occur in drug molecules. Examples include HIV integrase inhibitors, carbonic anhydrase inhibitors and MMP-2 inhibitors. However the production of sultams has historically required the use of complex synthetic methods in organic solvents. A recent publication describes the ready synthesis of sultams by two sequential cascade reactions in water as solvent [1]. This method is ideally suited for the rapid parallel production of sultams for further pharmacological investigation.
The key reaction employed in this approach is the nucleophilic attach of an oxygen or sulphur anion onto a vinyl sulphonamide. The vinyl sulphonamides employed in this reaction sequence were prepared by the reaction of an amine with 2chloroethylsulphonyl chloride (1). In addition to generating the sulphonamide, the amine also catalysed the elimination of the 2-chloro group to generate a vinyl substituent on the sulphonamide (2). Alkylation of the secondary sulphonamide with allyl bromide introduced a second alkene substituent in the product (3) which could be selectively epoxidised by the reaction of
E-mail: [email protected] http://dx.doi.org/10.1016/j.comche.2014.01.001
Sodium hydroxide or sodium hydrogen sulphide, both readily soluble in water were used to initiate the reaction by nucleophilic attack onto the vinyl sulphonamide in 4. Although this reaction was sluggish at room temperature, heating to 90 °C resulted in rapid reaction. The intermediate anion could undergo a shift of a proton to the more stable oxy- or thio-anion (5) which could then react by an 8-exo-tet opening of the epoxide to provide the eight-membered sultam product. Only one product was observed from this reaction in yields that varied from 62% to 82% for the reaction with sodium hydroxide, and between 63% and 77% for reaction with sodium hydrogen sulphide. Spectroscopic analysis unequivocally revealed the products to be from 8-exo-tet opening of the epoxide rather than the alternative 7exo-tet mechanism. Attempts were made to prepare the 9 membered ring product by alkylation of the secondary sulphonamide with 4-bromobut-1-ene, but this reaction proceeded very poorly with the majority of the bromide being eliminated to generate butadiene. Overall these cascade reactions, which proceed with high synthetic efficiency and regioselectivity, provide an effective and parallel approach to interesting 8-membered sultam rings. Furthermore, the reaction occurs efficiently in water under mild conditions and in moderate to good synthetic yields.
6
N.K. Terrett / Combinatorial Chemistry - An Online Journal 16 (2014) 5–7
2. A summary of the papers in this month’s issue 2.1. Polymer supported synthesis No papers this month.
ence of Amberlyst-15 under ultrasound irradiation. A variety of pyrrole derivatives were synthesised by this simple and straightforward method in good yields. The rapid synthesis of a pyrrolebased library of small molecules useful for chemical and pharmaceutical applications has been described [7].
2.2. Solution-phase synthesis
2.5. Novel resins, linkers and techniques
An efficient one-pot synthesis of functionalised indole-3-yl pyridines by condensation of 3-formylchromones, cyanoacetylindoles and ammonium acetate has been described. A series of 17 new compounds were synthesised and all of them were characterised by FT-IR and NMR. The crystal structure of a typical compound was determined by X-ray diffraction. A variety of substrates can participate in the process resulting in high purity and good yields, making this methodology suitable for library synthesis in drug discovery [2]. Copper(I) promoted Huisgen 1,3-dipolar cycloaddition of terminal alkynes with azides has been used as an efficient protocol for the one-pot five-component synthesis of glycoside annulated dihydropyrimidinone derivatives. The 1,2,3-triazole group was formed from tert-butyl b-ketoester, arylaldehyde, urea, propargyl alcohol, and glycosyl azide through the combination of transesterification and Biginelli reaction in aqueous medium. This protocol provides an access to generate scaffolds with molecular diversity from readily available starting materials [3]. An innovative synthetic pathway for the preparation of a new series of triazole-decorated dihydropyrimidinone peptidomimetics with skeletal a or b-amino acid residues has been reported. The protocol involves two synthetic steps with an initial solvent-free and catalyst-free synthesis of propargylated dihydropyrimidinone precursors using Biginelli condensations. The subsequent cycloaddition reactions of pyrimidinone alkynes with small peptide like azides prepared from Ugi or alternate Mannich type multi-component reactions afforded the triazole decorated pyrimidinone peptide conjugates in excellent yield with high regio and stereospecificities. In total, a scaffold diversity of 11 new pyrimidinone alkynes and 18 new pyrimidinone peptidomimetics were prepared in this chemical space [4]. A series of peptide-like 25–28 membered macrocycles containing 1,3,4-oxadiazoles and pyridines bearing a chiral center scaffold have been synthesised by using known coupling reagents and common protecting groups. The yield of the purified macrocycles was poor on average, yet it seems to be independent of amino acid substitution or stereochemistry. These macrocycles represent a new class of structures for further development and for future application in high-throughput screening against a variety of biological targets [5].
In a recent publication, the potential of N-alkoxymethyl groups as protectants for the peptide backbone has been investigated. These groups were found to be compatible with the standard conditions of Fmoc/tBu solid-phase peptide synthesis, and could be cleaved from the peptide backbone by acids. Thus, backbone N-alkoxymethyl groups may be useful to prevent undesired side-reactions and/or interchain aggregation during peptide elongation on the solid-phase [8]. An efficient synthesis of new pharmaceutically relevant dioxopyrrolidines, spirobenzo thiazine-2,30 -chromans, and benzothiazepines via isocyanide-based multicomponent condensation reactions at room temperature has been reported. This synthesis serves as a nice addition to group-assistant-purification chemistry in which purification via chromatography and recrystallisation can be avoided, and the pure products are obtained simply by washing the crude products with 95% ethanol. This approach is suitable for the efficient synthesis of compound libraries [9]. A synthetic route for the solid phase synthesis of N-linked glycoconjugates containing high mannose oligosaccharides which allows the incorporation of useful functional handles on the Nterminus of asparagine has recently been described. In this strategy, the C-terminus of an Fmoc protected aspartic acid residue is first attached to a solid phase support. The side chain of aspartic acid was protected by a 2-phenylisopropyl protecting group, which allows selective deprotection for the introduction of glycosylation. By using a convergent on-resin glycosylamine coupling strategy, an N-glycosidic linkage was successfully formed on the free side chain of the resin bound aspartic acid with a large high mannose oligosaccharide, Man8GlcNAc2. This on-resin glycosylamine coupling provides excellent glycosylation yield and can be applied to couple other types of oligosaccharides [10].
2.3. Scaffolds and synthons for combinatorial libraries No papers this month. 2.4. Solid-phase supported reagents 1-Glycyl-3-methyl imidazolium chloride–palladium(II) complex was found to be a catalyst for the Suzuki–Miyaura reaction with excellent yields and high turnover number. Aryl bromides reacted efficiently with phenyl boronic acid at ambient temperature in the presence of the catalyst. The reagent is better than most of the reported catalysts and could be reused for eight consecutive cycles without any significant loss of its catalytic activity [6]. A fast and efficient synthesis of polysubstituted pyrroles has been achieved via a four-component reaction from b-ketoesters, benzylamines, aromatic aldehydes, and nitromethane in the pres-
2.6. Library applications The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to a wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists, but elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by a lack of orally bioavailable, highly selective small molecule probes. A recent paper describes the discovery and optimisation of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists. A compound from this series optimised by library synthesis was a potent 2-SORA and demonstrated potent sleep promotion when dosed orally to EEG telemetrised rats [11]. A class of a-methyltryptamine sulphonamide glucocorticoid receptor modulators was optimised for agonist activity. The design of ligands was aided by molecular modelling, and key functionregulating pharmacophoric points were identified that are critical in achieving the desired agonist effect in cell-based assays. Additional analogues could be rapidly prepared in a parallel approach from aziridine building blocks [12]. A library of hydrazide derivatives has been synthesised to target non-structural protein 1 of influenza A virus (NS1) as a
N.K. Terrett / Combinatorial Chemistry - An Online Journal 16 (2014) 5–7
means to develop anti-influenza drug leads. The lead compound 3-hydroxy-N-[(Z)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethylideneamino]naphthalene-2-carboxamide (HENC), was identified by its ability to increase the melting temperature of the effector domain (ED) of the NS1 protein, as assayed using differential scanning fluorimetry. A library of HENC analogs was tested for inhibitory effect against influenza A virus replication in MDCK cells [13].
References [1] Ji T, Wang Y, Wang M, Niu B, Xie P, Pittman CU, et al. Parallel syntheses of eightmembered ring sultams via two cascade reactions in water. ACS Comb Sci 2013;15(12):595–600. [2] Poomathi N, Muralidharan D, Perumal PT. Stannous chloride mediated one pot synthesis of functionalized indole-3-yl pyridines using 3-cyanoacetylindoles and 3-formylchromones. Tetrahedron Lett 2013;54(52):7091–4. [3] Rao GBD, Anjaneyulu B, Kaushik MP. A facile one-pot five-component synthesis of glycoside annulated dihydropyrimidinone derivatives with 1,2,3-triazol linkage via transesterification/Biginelli/click reactions in aqueous medium. Tetrahedron Lett 2014;55(1):19–22. [4] Balan B, Bahulaya D. A novel green synthesis of a/b-amino acid functionalized pyrimidinone peptidomimetics using triazole ligation through click-multicomponent reactions. Tetrahedron Lett 2014;55(1):227–31. [5] Poojari S, Naik PP, Krishnamurthy G. Synthesis of macrocycles containing 1,3,4oxadiazole and pyridine moieties. Tetrahedron Lett 2014;55(2):305–9. [6] Karthikeyan P, Vanitha A, Radhika P, Suresh K, Sugumaran A. Imidazolium supported palladium–chloroglycine complex: recyclable catalyst for SuzukiMiyaura coupling reactions. Tetrahedron Lett 2013;54(52):7193–7. [7] Murthi PRK, Rambabu D, Rao MVB, Pal M. Synthesis of substituted pyrroles via Amberlyst-15 mediated MCR under ultrasound. Tetrahedron Lett 2014;55(2):507–9. [8] Fernández-Llamazares AI, Spengler J, Albericio F. The potential of N-alkoxymethyl groups as peptide backbone protectants. Tetrahedron Lett 2014;55(1):184–8. [9] Akbarzadeh R, Amanpour T, Khavasi HR, Bazgir A. Atom-economical isocyanidebased multicomponent synthesis of 2,5-dioxopyrrolidines, spirobenzothiazinechromans and 1,5-benzothiazepines. Tetrahedron 2014;70(2):169–75. [10] Chen R, Pawlicki MA, Tolbert TJ. Versatile on-resin synthesis of high mannose glycosylated asparagine with functional handles. Carbohydr Res 2014;383:69–75. [11] Mercer SP, Roecker AJ, Garson S, Reiss DR, Harrell CM, Murphy KL, et al. Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs). Bioorg Med Chem Lett 2013;23(24):6620–4. [12] Kuzmich D, Bentzien J, Betageri R, DiSalvo D, Fadra-Khan T, Harcken C, et al. Function-regulating pharmacophores in a sulfonamide class of glucocorticoid receptor agonists. Bioorg Med Chem Lett 2013;23(24):6640–4. [13] Barman S, You L, Chen R, Codrea V, Kago G, Edupuganti R, et al. Exploring naphthyl-carbohydrazides as inhibitors of influenza A viruses. Eur J Med Chem 2014;71:81–90.
7
Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Brust A, Wang C-IA, Daly NL, Kennerly J, Sadeghi M, Christie MJ, et al. Vicinal disulfide constrained cyclic peptidomimetics: a turn mimetic scaold targeting the norepinephrine transporter. Angew Chem (International ed. in English) 2013;52(46):12020–3. Espeel P, Carrette LLG, Bury K, Capenberghs S, Martins JC, Du Prez FE, et al. Multifunctionalized sequence-defined oligomers from a single building block. Angew Chem (International ed. in English), 2013;52(50):13261–4. Zhersh S, Karpenko OV, Ripenko V, Tolmachev A, Grygorenko OO. Synthesis of 1(pyrrolidin-2-ylmethyl)-1H-azoles and their piperidine-derived homologues. Cent Eur J Chem 2014;12(1):67–73. Lichtenecker RJ, Ellinger B, Han H-M, Jadhav KB, Baumann S, Makarewicz O, et al. Iterative antimicrobial candidate selection from informed D-/L-peptide dimer libraries. Chembiochem: a European Journal of. Chem Biol 2013;14(18):2492–9. Vulpetti A, Dalvit C. Design and generation of highly diverse fluorinated fragment libraries and their efficient screening with improved (19) F NMR methodology. ChemMedChem 2013;8(12):2057–69. Toraskar MP, Singasane NS, Pichake JB, Kadam V. Fragment based drug discovery - a tool for drug discovery. Int J Drug Des Discovery 2013;4(2):1083–92. Sharma S, Kushwah V. Synthesis and anti-inflammatory screening of azetidinyindoles and thiazolidinylindoles. Int J Drug Des Discovery 2013;4(2):1098–105. Knight AS, Zhou EY, Pelton JG, Francis MB. Selective chromium(VI) ligands identified using combinatorial peptoid libraries. J Am Chem Soc 2013;135(46):17488–93. Malakoutikhah M, Peyralans JJ-P, Colomb-Delsuc M, Fanlo-Virgos H, Stuart MCA, Otto S. Uncovering the selection criteria for the emergence of multi-building-block replicators from dynamic combinatorial libraries. J Am Chem Soc 2013;135(49):18406–17. Gentry PR, Kokubo M, Bridges TM, Kett NR, Harp JM, Cho HP, et al. Discovery of the first M5-selective and CNS penetrant negative allo-steric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). J Med Chem 2013;56(22):9351–5. Janin YL. Preparations of 4-substituted 3-carboxypyrazoles. J Heterocycl Chem 2013;50(6):1410–4. Chen T, Takrouri K, Hee-Hwang S, Rana S, Yefido-Freedman R, Halperin J, et al. Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase. J Med Chem 2013;56(23):9457–70. Garcia-Ramos Y, Lubell WD. Synthesis and alkylation of aza-glycinyl dipeptide building blocks. J Pept Sci: O Publ Eur Pept Soc 2013;19(12):725–9. Vasilevich NI, Afanasyev II, Rastorguev EA, Genis DV, Kochubey VS. Dual mode of action of phenyl-pyrazole-phenyl (6-5-6 system)-based PPI inhibitors: alphahelix backbone versus alpha-helix binding epitope. MedChemComm 2013;4(12):1597–603. Deuss PJ, Arzumanov AA, Williams DL, Gait MJ. Parallel synthesis and splicing redirection activity of cell-penetrating peptide conjugate libraries of a PNA cargo. Org Biomol Chem 2013;11(43):7621–30. Naganna N, Madhavan N. Soluble and reusable poly(norbornene) supports with high loading capacities for peptide synthesis. Org Lett 2013;15(22):5870–3.
Contents lists available at ScienceDirect
Combinatorial Chemistry - An Online Journal journal homepage: www.elsevier.com/locate/comche
Combinatorial Chemistry Online Volume 16, Issue 2, February 2014 N.K. Terrett Ensemble Therapeutics Corp., Cambridge, MA 02139, USA
1. Current literature highlights 1.1. Parallel synthesis of sultams in water by a cascade reaction
meta-chloro-peroxybenzoic acid to give 4. The vinyl sulphonamide was inert to these conditions due to its electron deficiency and thus remained unaffected.
Sulphonamides are frequently found in molecules with pharmacological activity, and there are several examples where cyclic sulphonamides, sultams, occur in drug molecules. Examples include HIV integrase inhibitors, carbonic anhydrase inhibitors and MMP-2 inhibitors. However the production of sultams has historically required the use of complex synthetic methods in organic solvents. A recent publication describes the ready synthesis of sultams by two sequential cascade reactions in water as solvent [1]. This method is ideally suited for the rapid parallel production of sultams for further pharmacological investigation.
The key reaction employed in this approach is the nucleophilic attach of an oxygen or sulphur anion onto a vinyl sulphonamide. The vinyl sulphonamides employed in this reaction sequence were prepared by the reaction of an amine with 2chloroethylsulphonyl chloride (1). In addition to generating the sulphonamide, the amine also catalysed the elimination of the 2-chloro group to generate a vinyl substituent on the sulphonamide (2). Alkylation of the secondary sulphonamide with allyl bromide introduced a second alkene substituent in the product (3) which could be selectively epoxidised by the reaction of
E-mail: [email protected] http://dx.doi.org/10.1016/j.comche.2014.01.001
Sodium hydroxide or sodium hydrogen sulphide, both readily soluble in water were used to initiate the reaction by nucleophilic attack onto the vinyl sulphonamide in 4. Although this reaction was sluggish at room temperature, heating to 90 °C resulted in rapid reaction. The intermediate anion could undergo a shift of a proton to the more stable oxy- or thio-anion (5) which could then react by an 8-exo-tet opening of the epoxide to provide the eight-membered sultam product. Only one product was observed from this reaction in yields that varied from 62% to 82% for the reaction with sodium hydroxide, and between 63% and 77% for reaction with sodium hydrogen sulphide. Spectroscopic analysis unequivocally revealed the products to be from 8-exo-tet opening of the epoxide rather than the alternative 7exo-tet mechanism. Attempts were made to prepare the 9 membered ring product by alkylation of the secondary sulphonamide with 4-bromobut-1-ene, but this reaction proceeded very poorly with the majority of the bromide being eliminated to generate butadiene. Overall these cascade reactions, which proceed with high synthetic efficiency and regioselectivity, provide an effective and parallel approach to interesting 8-membered sultam rings. Furthermore, the reaction occurs efficiently in water under mild conditions and in moderate to good synthetic yields.
6
N.K. Terrett / Combinatorial Chemistry - An Online Journal 16 (2014) 5–7
2. A summary of the papers in this month’s issue 2.1. Polymer supported synthesis No papers this month.
ence of Amberlyst-15 under ultrasound irradiation. A variety of pyrrole derivatives were synthesised by this simple and straightforward method in good yields. The rapid synthesis of a pyrrolebased library of small molecules useful for chemical and pharmaceutical applications has been described [7].
2.2. Solution-phase synthesis
2.5. Novel resins, linkers and techniques
An efficient one-pot synthesis of functionalised indole-3-yl pyridines by condensation of 3-formylchromones, cyanoacetylindoles and ammonium acetate has been described. A series of 17 new compounds were synthesised and all of them were characterised by FT-IR and NMR. The crystal structure of a typical compound was determined by X-ray diffraction. A variety of substrates can participate in the process resulting in high purity and good yields, making this methodology suitable for library synthesis in drug discovery [2]. Copper(I) promoted Huisgen 1,3-dipolar cycloaddition of terminal alkynes with azides has been used as an efficient protocol for the one-pot five-component synthesis of glycoside annulated dihydropyrimidinone derivatives. The 1,2,3-triazole group was formed from tert-butyl b-ketoester, arylaldehyde, urea, propargyl alcohol, and glycosyl azide through the combination of transesterification and Biginelli reaction in aqueous medium. This protocol provides an access to generate scaffolds with molecular diversity from readily available starting materials [3]. An innovative synthetic pathway for the preparation of a new series of triazole-decorated dihydropyrimidinone peptidomimetics with skeletal a or b-amino acid residues has been reported. The protocol involves two synthetic steps with an initial solvent-free and catalyst-free synthesis of propargylated dihydropyrimidinone precursors using Biginelli condensations. The subsequent cycloaddition reactions of pyrimidinone alkynes with small peptide like azides prepared from Ugi or alternate Mannich type multi-component reactions afforded the triazole decorated pyrimidinone peptide conjugates in excellent yield with high regio and stereospecificities. In total, a scaffold diversity of 11 new pyrimidinone alkynes and 18 new pyrimidinone peptidomimetics were prepared in this chemical space [4]. A series of peptide-like 25–28 membered macrocycles containing 1,3,4-oxadiazoles and pyridines bearing a chiral center scaffold have been synthesised by using known coupling reagents and common protecting groups. The yield of the purified macrocycles was poor on average, yet it seems to be independent of amino acid substitution or stereochemistry. These macrocycles represent a new class of structures for further development and for future application in high-throughput screening against a variety of biological targets [5].
In a recent publication, the potential of N-alkoxymethyl groups as protectants for the peptide backbone has been investigated. These groups were found to be compatible with the standard conditions of Fmoc/tBu solid-phase peptide synthesis, and could be cleaved from the peptide backbone by acids. Thus, backbone N-alkoxymethyl groups may be useful to prevent undesired side-reactions and/or interchain aggregation during peptide elongation on the solid-phase [8]. An efficient synthesis of new pharmaceutically relevant dioxopyrrolidines, spirobenzo thiazine-2,30 -chromans, and benzothiazepines via isocyanide-based multicomponent condensation reactions at room temperature has been reported. This synthesis serves as a nice addition to group-assistant-purification chemistry in which purification via chromatography and recrystallisation can be avoided, and the pure products are obtained simply by washing the crude products with 95% ethanol. This approach is suitable for the efficient synthesis of compound libraries [9]. A synthetic route for the solid phase synthesis of N-linked glycoconjugates containing high mannose oligosaccharides which allows the incorporation of useful functional handles on the Nterminus of asparagine has recently been described. In this strategy, the C-terminus of an Fmoc protected aspartic acid residue is first attached to a solid phase support. The side chain of aspartic acid was protected by a 2-phenylisopropyl protecting group, which allows selective deprotection for the introduction of glycosylation. By using a convergent on-resin glycosylamine coupling strategy, an N-glycosidic linkage was successfully formed on the free side chain of the resin bound aspartic acid with a large high mannose oligosaccharide, Man8GlcNAc2. This on-resin glycosylamine coupling provides excellent glycosylation yield and can be applied to couple other types of oligosaccharides [10].
2.3. Scaffolds and synthons for combinatorial libraries No papers this month. 2.4. Solid-phase supported reagents 1-Glycyl-3-methyl imidazolium chloride–palladium(II) complex was found to be a catalyst for the Suzuki–Miyaura reaction with excellent yields and high turnover number. Aryl bromides reacted efficiently with phenyl boronic acid at ambient temperature in the presence of the catalyst. The reagent is better than most of the reported catalysts and could be reused for eight consecutive cycles without any significant loss of its catalytic activity [6]. A fast and efficient synthesis of polysubstituted pyrroles has been achieved via a four-component reaction from b-ketoesters, benzylamines, aromatic aldehydes, and nitromethane in the pres-
2.6. Library applications The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to a wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX1R/OX2R) orexin receptor antagonists, but elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by a lack of orally bioavailable, highly selective small molecule probes. A recent paper describes the discovery and optimisation of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists. A compound from this series optimised by library synthesis was a potent 2-SORA and demonstrated potent sleep promotion when dosed orally to EEG telemetrised rats [11]. A class of a-methyltryptamine sulphonamide glucocorticoid receptor modulators was optimised for agonist activity. The design of ligands was aided by molecular modelling, and key functionregulating pharmacophoric points were identified that are critical in achieving the desired agonist effect in cell-based assays. Additional analogues could be rapidly prepared in a parallel approach from aziridine building blocks [12]. A library of hydrazide derivatives has been synthesised to target non-structural protein 1 of influenza A virus (NS1) as a
N.K. Terrett / Combinatorial Chemistry - An Online Journal 16 (2014) 5–7
means to develop anti-influenza drug leads. The lead compound 3-hydroxy-N-[(Z)-1-(5,6,7,8-tetrahydronaphthalen-2-yl)ethylideneamino]naphthalene-2-carboxamide (HENC), was identified by its ability to increase the melting temperature of the effector domain (ED) of the NS1 protein, as assayed using differential scanning fluorimetry. A library of HENC analogs was tested for inhibitory effect against influenza A virus replication in MDCK cells [13].
References [1] Ji T, Wang Y, Wang M, Niu B, Xie P, Pittman CU, et al. Parallel syntheses of eightmembered ring sultams via two cascade reactions in water. ACS Comb Sci 2013;15(12):595–600. [2] Poomathi N, Muralidharan D, Perumal PT. Stannous chloride mediated one pot synthesis of functionalized indole-3-yl pyridines using 3-cyanoacetylindoles and 3-formylchromones. Tetrahedron Lett 2013;54(52):7091–4. [3] Rao GBD, Anjaneyulu B, Kaushik MP. A facile one-pot five-component synthesis of glycoside annulated dihydropyrimidinone derivatives with 1,2,3-triazol linkage via transesterification/Biginelli/click reactions in aqueous medium. Tetrahedron Lett 2014;55(1):19–22. [4] Balan B, Bahulaya D. A novel green synthesis of a/b-amino acid functionalized pyrimidinone peptidomimetics using triazole ligation through click-multicomponent reactions. Tetrahedron Lett 2014;55(1):227–31. [5] Poojari S, Naik PP, Krishnamurthy G. Synthesis of macrocycles containing 1,3,4oxadiazole and pyridine moieties. Tetrahedron Lett 2014;55(2):305–9. [6] Karthikeyan P, Vanitha A, Radhika P, Suresh K, Sugumaran A. Imidazolium supported palladium–chloroglycine complex: recyclable catalyst for SuzukiMiyaura coupling reactions. Tetrahedron Lett 2013;54(52):7193–7. [7] Murthi PRK, Rambabu D, Rao MVB, Pal M. Synthesis of substituted pyrroles via Amberlyst-15 mediated MCR under ultrasound. Tetrahedron Lett 2014;55(2):507–9. [8] Fernández-Llamazares AI, Spengler J, Albericio F. The potential of N-alkoxymethyl groups as peptide backbone protectants. Tetrahedron Lett 2014;55(1):184–8. [9] Akbarzadeh R, Amanpour T, Khavasi HR, Bazgir A. Atom-economical isocyanidebased multicomponent synthesis of 2,5-dioxopyrrolidines, spirobenzothiazinechromans and 1,5-benzothiazepines. Tetrahedron 2014;70(2):169–75. [10] Chen R, Pawlicki MA, Tolbert TJ. Versatile on-resin synthesis of high mannose glycosylated asparagine with functional handles. Carbohydr Res 2014;383:69–75. [11] Mercer SP, Roecker AJ, Garson S, Reiss DR, Harrell CM, Murphy KL, et al. Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs). Bioorg Med Chem Lett 2013;23(24):6620–4. [12] Kuzmich D, Bentzien J, Betageri R, DiSalvo D, Fadra-Khan T, Harcken C, et al. Function-regulating pharmacophores in a sulfonamide class of glucocorticoid receptor agonists. Bioorg Med Chem Lett 2013;23(24):6640–4. [13] Barman S, You L, Chen R, Codrea V, Kago G, Edupuganti R, et al. Exploring naphthyl-carbohydrazides as inhibitors of influenza A viruses. Eur J Med Chem 2014;71:81–90.
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Further reading Papers on combinatorial chemistry or solid-phase synthesis from other journals Brust A, Wang C-IA, Daly NL, Kennerly J, Sadeghi M, Christie MJ, et al. Vicinal disulfide constrained cyclic peptidomimetics: a turn mimetic scaold targeting the norepinephrine transporter. Angew Chem (International ed. in English) 2013;52(46):12020–3. Espeel P, Carrette LLG, Bury K, Capenberghs S, Martins JC, Du Prez FE, et al. Multifunctionalized sequence-defined oligomers from a single building block. Angew Chem (International ed. in English), 2013;52(50):13261–4. Zhersh S, Karpenko OV, Ripenko V, Tolmachev A, Grygorenko OO. Synthesis of 1(pyrrolidin-2-ylmethyl)-1H-azoles and their piperidine-derived homologues. Cent Eur J Chem 2014;12(1):67–73. Lichtenecker RJ, Ellinger B, Han H-M, Jadhav KB, Baumann S, Makarewicz O, et al. Iterative antimicrobial candidate selection from informed D-/L-peptide dimer libraries. Chembiochem: a European Journal of. Chem Biol 2013;14(18):2492–9. Vulpetti A, Dalvit C. Design and generation of highly diverse fluorinated fragment libraries and their efficient screening with improved (19) F NMR methodology. ChemMedChem 2013;8(12):2057–69. Toraskar MP, Singasane NS, Pichake JB, Kadam V. Fragment based drug discovery - a tool for drug discovery. Int J Drug Des Discovery 2013;4(2):1083–92. Sharma S, Kushwah V. Synthesis and anti-inflammatory screening of azetidinyindoles and thiazolidinylindoles. Int J Drug Des Discovery 2013;4(2):1098–105. Knight AS, Zhou EY, Pelton JG, Francis MB. Selective chromium(VI) ligands identified using combinatorial peptoid libraries. J Am Chem Soc 2013;135(46):17488–93. Malakoutikhah M, Peyralans JJ-P, Colomb-Delsuc M, Fanlo-Virgos H, Stuart MCA, Otto S. Uncovering the selection criteria for the emergence of multi-building-block replicators from dynamic combinatorial libraries. J Am Chem Soc 2013;135(49):18406–17. Gentry PR, Kokubo M, Bridges TM, Kett NR, Harp JM, Cho HP, et al. Discovery of the first M5-selective and CNS penetrant negative allo-steric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375). J Med Chem 2013;56(22):9351–5. Janin YL. Preparations of 4-substituted 3-carboxypyrazoles. J Heterocycl Chem 2013;50(6):1410–4. Chen T, Takrouri K, Hee-Hwang S, Rana S, Yefido-Freedman R, Halperin J, et al. Explorations of substituted urea functionality for the discovery of new activators of the heme-regulated inhibitor kinase. J Med Chem 2013;56(23):9457–70. Garcia-Ramos Y, Lubell WD. Synthesis and alkylation of aza-glycinyl dipeptide building blocks. J Pept Sci: O Publ Eur Pept Soc 2013;19(12):725–9. Vasilevich NI, Afanasyev II, Rastorguev EA, Genis DV, Kochubey VS. Dual mode of action of phenyl-pyrazole-phenyl (6-5-6 system)-based PPI inhibitors: alphahelix backbone versus alpha-helix binding epitope. MedChemComm 2013;4(12):1597–603. Deuss PJ, Arzumanov AA, Williams DL, Gait MJ. Parallel synthesis and splicing redirection activity of cell-penetrating peptide conjugate libraries of a PNA cargo. Org Biomol Chem 2013;11(43):7621–30. Naganna N, Madhavan N. Soluble and reusable poly(norbornene) supports with high loading capacities for peptide synthesis. Org Lett 2013;15(22):5870–3.