Novel pyrazole substituted oxazole derivatives: Design, insilico studies, synthesis & biological activities

A potent antibacterial drug was developed by synthesizing a set of new pyrazoles substituted oxazole derivatives using multi-step synthesis. FT-IR, 1H-NMR, Mass spectroscopy, and bases of microanalyses are employed to confirm the structure of compounds. Molinspiration online tool was used to predict the molecular properties and molecular docking was used to predict the antitubercular potency of the target compounds. 10-Fold serial dilution method, agar streak dilution test, and DPPH radical scavenging methods are utilized to evaluate antitubercular, antibacterial, and radical scavenging properties of test compounds and reference drugs, respectively. Varying degree of antitubercular, antibacterial, and radical scavenging activities (mild to good) was displayed by synthesized oxazole compounds. In general, unsubstituted oxazole derivatives exhibited superior antibacterial potency than substituted analogs. In addition, meta-substituted analogs displayed higher activity than the corresponding para-substituted analogs. Among fifteen tested target compounds, the potent compound of this series was found to be 4-(4-(5-phenyl- 4,5-dihydro-1H-pyrazol-3-yl)benzylidene)-2-methyloxazol-5(4H)-one (PBO8). Hence, this analog may be used as a lead molecule to find potent & safer antibacterial agents.

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[1] Janin YL. Antituberculosis drugs: ten years of research. Bioorg Med Chem. 2007; 15(7): 2479-2513. [CrossRef]
[2] Ibrahim M, Andries K, Lounis N, Chauffour A, Truffot-Pernot C, Jarlier V. Synergistic activity of R207910 combined with pyrazinamide against murine tuberculosis. Antimicrob Agents Chemother. 2007;51(3):1011-1015. [CrossRef]
[3] Iacobino A, Fattorini L, Giannoni F. Drug-resistant tuberculosis 2020: Where we stand. Appl Sci. 2020; 10(6): 2153. [CrossRef]
[4] Mirzayev F, Viney K, Linh NN, Gonzalez-Angulo L, Gegia M, Jaramillo E, Zignol M, Kasaeva T. World Health Organization recommendations on the treatment of drug-resistant tuberculosis 2020 update. Eur Respir J. 2021; 57: 2003300. [CrossRef]
[5] Kakkar S, Narasimhan BA. Comprehensive review on biological activities of oxazole derivatives. BMC Chem. 2019; 13(1): 1-24. [CrossRef]
[6] Borcea AM, Ionut I, Crisan O, Oniga O. An overview of the synthesis and antimicrobial, antiprotozoal, and antitumor activity of thiazole and bisthiazole derivatives. Molecules. 2021; 26(3): 624. [CrossRef]
[7] Kaspady M, Narayanaswamy VK, Raju M, Rao GK. Synthesis, antibacterial activity of 2, 4-disubstituted oxazoles and thiazoles as bioisosteres. Lett Drug Des Discov. 2009; 6(1): 21-28. [CrossRef]
[8] Tomi IHR, Tomma JH, Al-Daraji AHR, Al-Dujaili AH. Synthesis, characterization, and comparative study the microbial activity of some heterocyclic compounds containing oxazole and benzothiazole moieties. J Saudi Chem Soc. 2015; 19(4): 392-398. [CrossRef]
[9] Aguirre-Rentería SA, Carrizales-Castillo JJ, Corona MD, Hernández-Fernández E, Garza-González E, Rivas-Galindo VM, Arredondo-Espinoza E, Avalos-Alanís FG. Synthesis and in vitro evaluation of antimycobacterial and cytotoxic activity of new α, β-unsaturated amide, oxazoline and oxazole derivatives from L-serine. Bioorg Med Chem Lett. 2020; 30(9): 127074. [CrossRef]
[10] Shah SR, Katariya KD. 1, 3‐Oxazole‐isoniazid hybrids: Synthesis, antitubercular activity, and their docking studies. J Heterocycl Chem. 2020; 57(4): 1682-1691. [CrossRef]
[11] Mori M, Stelitano G, Chiarelli LR, Cazzaniga G, Gelain A, Barlocco D, Pini E, Meneghetti F, Villa S. Synthesis, characterization, and biological evaluation of new derivatives targeting MbtI as antitubercular agents. Pharmaceuticals. 2021; 14(2): 155. [CrossRef]
[12] Guerrero-Pepinosa NY, Cardona-Trujillo MC, Garzón-Castaño SC, Veloza LA, Sepúlveda-Arias JC. Antiproliferative activity of thiazole and oxazole derivatives: A systematic review of in vitro and in vivo studies. Biomed Pharmacother. 2021; 138: 111495. [CrossRef]
[13] Kumar G, Singh NP. Synthesis, anti-inflammatory, and analgesic evaluation of thiazole/oxazole substituted benzothiazole derivatives. Bioorg Chem. 2021; 107: 104608. [CrossRef]
[14] Zimecki M, Bąchor U, Mączyński M. Isoxazole derivatives as regulators of immune functions. Molecules. 2018; 23(10): 2724. [CrossRef]
[15] Shakya AK, Kaur A, Al-Najjar BO, Naik RR. Molecular modeling, synthesis, characterization, and pharmacological evaluation of benzo [d] oxazole derivatives as non-steroidal anti-inflammatory agents. Saudi Pharm J. 2016; 24(5): 616-624. [CrossRef]
[16] Katariya KD, Vennapu DR, Shah SR. Synthesis and molecular docking study of new 1, 3-oxazole clubbed pyridylpyrazolines as anticancer and antimicrobial agents. J Mol Struct. 2021; 1232: 130036. [CrossRef]
[17] Al-Soliemy AM, Sabour R, Farghaly TA. Pyrazoles and fused pyrimidines: Synthesis, structure elucidation, antitubercular activity, and molecular docking study. Med Chem (Shariqah (United Arab Emirates)) 2021; PMID: 33761862. [CrossRef]
[18] Jadhav SB, Fatema S, Sanap G, Farooqui M. Antitubercular activity and synergistic study of novel pyrazole derivatives. J Heterocycl Chem. 2017; 55(7): 1634-1644. [CrossRef]
[19] B’Bhatt H, Sharma S. Synthesis and antimicrobial activity of pyrazole nucleus containing 2-thioxothiazolidin-4-one derivatives. Arabian J Chem. 2017; 10: S1590-0S1596. [CrossRef]
[20] Kumar RS, Arif IA, Ahamed A, Idhayadhulla A. Anti-inflammatory and antimicrobial activities of novel pyrazole analogs. Saudi J Biol Sci. 2016; 23(5): 614-620. [CrossRef]
[21] Hassan SY. Synthesis, antibacterial and antifungal activity of some new pyrazoline and pyrazole derivatives. Molecules. 2013; 18(3): 2683-2711. [CrossRef]
[22] Alegaon SG, Alagawadi KR, Sonkusare PV, Chaudhary SM, Dadwe DH, Shah AS. Novel imidazo [2, 1-b][1, 3, 4] thiadiazole carrying rhodanine-3-acetic acid as potential antitubercular agents. Bioorg Med Chem Lett. 2012; 22(5): 1917-1921. [CrossRef]
[23] Parepally JMR, Mandula H, Smith QR. Brain uptake of nonsteroidal anti-inflammatory drugs: ibuprofen, flurbiprofen, and indomethacin. Pharm Res. 2006; 23(5): 873-881. [CrossRef]
[24] Wehenkel A, Fernandez P, Bellinzoni M, Catherinot V, Barilone N, Labesse G, Jackson M, Alzari PM. The structure of PknB in complex with mitoxantrone, an ATP-competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria. FEBS Lett. 2006; 580(13): 3018-3022. [CrossRef]
[25] Prisic S, Husson RN. Mycobacterium tuberculosis serine/threonine protein kinases. Microbiol Spectr. 2014; 2(5): 2-5. [CrossRef]
[26] Jung JE, Lee SY, Park H, Cha H, Ko W, Sachin K, Kim DW, Chi DY, Lee HS. Genetic incorporation of unnatural amino acids biosynthesized from α-keto acids by an aminotransferase. Chem Sci. 2014; 5(5): 1881-1885. [CrossRef]
[27] Ma XL, Chen C, Yang J. Predictive model of blood-brain barrier penetration of organic compounds. Acta Pharm Sin. 2005; 26(4): 500-512. [CrossRef]
[28] Mannhold R. Molecular drug properties-Measurement and prediction. Wiley-VHC Verlag GmbH & Co. KGaA Weinheim, Germany. 2008, pp. 30-35.
[29] Zhao YH, Le J, Abraham MH, Hersey A, Eddershaw PJ, Luscombe CN, Boutina D, Beck G, Sherborne B, Cooper I, Platts JA. Evaluation of human intestinal absorption data and subsequent derivation of a quantitative structureactivity relationship (QSAR) with the Abraham descriptors. J Pharm Sci. 2001; 90(6): 749-784. [CrossRef]
[30] Björkelid C, Bergfors T, Raichurkar AKV, Mukherjee K, Malolanarasimhan K, Bandodkar B, Jones TA. Structural and biochemical characterization of compounds inhibiting Mycobacterium tuberculosis pantothenate kinase. J Biol Chem. 2013; 288(25): 18260-18270. [CrossRef]
[31] Batt SM, Jabeen T, Bhowruth V, Quill L, Lund PA, Eggeling L, Alderwick LJ, Fütterer K, Besra GS. Structural basis of inhibition of Mycobacterium tuberculosis DprE1 by benzothiazinone inhibitors. Proceedings of the National Academy of Sciences. 2012; 109(28): 11354-11359. [CrossRef]
[32] Wehenkel A, Fernandez P, Bellinzoni M, Catherinot V, Barilone N, Labesse G, Jackson M, Alzari PM. The structure of PknB in complex with mitoxantrone, an ATP-competitive inhibitor, suggests a mode of protein kinase regulation in mycobacteria. FEBS Lett. 2006; 580(13): 3018-3022. [CrossRef]
[33] Luckner SR, Machutta CA, Tonge PJ, Kisker C. Crystal structures of Mycobacterium tuberculosis KasA show mode of action within cell wall biosynthesis and its inhibition by thiolactomycin. Structure. 2009; 17(7): 1004-1013. [CrossRef]
[34] Meng XY, Zhang HX, Mezei M, Cui M. Molecular docking: A powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des. 2011; 7(2): 146-157. [CrossRef]
[35] National committee for clinical laboratory standards: Antimycobacterial susceptibility testing for M. tuberculosis. Proposed standards M24-T. Villanova, PA: National Committee for clinical laboratory standards. 1995.
[36] Sriram D, Yogeeswari P, Dinakaran M, Thirumurugan R. Antimycobacterial activity of novel 1-(5-cyclobutyl-1, 3- oxazol-2-yl)-3-(sub)phenyl/pyridylthiourea compounds endowed with high activity toward multidrug-resistant Mycobacterium tuberculosis. J Antimicrob Chemother. 2007; 59(6): 1194-1196. [CrossRef]
[37] Hawkey PM, Lewis DA. Medical bacteriology: A practical approach Oxford University Press 1st edition. 1990; pp. 181-185.
[38] Hatano T, Kagawa H, Yasuhara T, Okuda T. Two new flavonoids and other constituents in licorice root: their relative astringency and radical scavenging effects. Chem Pharm Bull. 1988; 36(6): 2090-2097. [CrossRef]
[39] Sharma OP, Bhat TK. DPPH antioxidant assay revisited. Food Chem. 2009; 113(4): 1202-1205. [CrossRef]