SYNTHESIS, MOLECULAR MODELING, AND QUANTITATIVE STRUCTUREâ€“ACTIVITY RELATIONSHIP STUDIES OF UNDEC-10-ENEHYDRAZIDE DERIVATIVES AS ANTIMICROBIAL AGENTS
Objective: In recent years, an increasing frequency and severity of antimicrobial resistance to different antimicrobial agents, demands new remedies for the treatment of infections. Therefore, in this study, a series of undec-10-enehydrazide derivatives were synthesized and screened for in vitro activity against selected pathogenic microbial strains.
Methods: The synthesis of the intermediate and target compounds was performed by standard procedure. Synthesized compounds were screened for antimicrobial activity by tube dilution method. Molecular docking study of synthesized derivatives was also performed to find out their interaction with the target site of Î²-ketoacyl-acyl carrier protein synthase III, (FabH; pdb id:3IL7) by docking technique. Quantitative structureâ€“activity relationship (QSAR) studies were also performed to correlate antimicrobial activity with structural properties of synthesized molecules.
Results: Antimicrobial screening results showed that compound 8 having benzylidine moiety with methoxy groups at meta and para position and compound 16 having 3-chloro-2-(3-flourophenyl)-4-oxoazetidine moiety was found to be most potent. QSAR studies revealed the importance of Randic topology parameter (R) in describing the antimicrobial activity of synthesized derivatives. Molecular docking study indicated hydrophobic interaction of deeply inserted aliphatic side chain of the ligand with FabH. The N-atoms of hydrazide moiety interacts with Ala246 and Asn247 through H-bonding. The m- and p-methoxy groups form H-bond with water and side chain of Arg36, respectively.
Conclusion: Compound 8 having benzylidine moiety with methoxy groups at meta and para position and compound 16 having 3-chloro-2-(3- flourophenyl)-4-oxoazetidine moiety was found to most potent antibacterial and antifungal compounds, respectively.
2. Antimicrobial Resistance. World Health Organization. Available from: http://www.who.int/mediacentre/factsheets/fs194/en. [Last accessed on 2017 Feb 27].
3. Ventola CL. The antibiotic resistance crisis: Part 1: Causes and threats. P T 2015;40(4):277-83.
4. Ereaux LP, Craig GE. The oral administration of undecylenic acid in the treatment of psoriasis. Can Med Assoc J 1949;61(4):361-4.
5. Ammendola S, Lembo A, Battistoni A, Tagliatesta P, Ghisalberti C, Desideri A. 10-undecanhydroxamic acid, a hydroxamate derivative of the undecanoic acid, has strong antimicrobial activity through a mechanism that limits iron availability. FEMS Microbiol Lett 2009;294(1):61-7.
6. Narang R, Narasimhan B, Sharma S, Sriram D, Yogeeswari P, Clercq ED, et al. Nicotinic acid benzylidene/phenyl-ethylidene hydrazides: Synthesis, antitubercular, antiviral, antimicrobial evaluation and QSAR studies. Lett Drug Des Discov 2011;8:733-49.
7. Narang R, Narasimhan B, Sharma S, De Clercq E, Pannecouque C, Balzarini J. Substituted naphthalen-1-yl-acetic acid hydrazides: Synthesis, antimicrobial evaluation and QSAR analysis. Med Chem 2013;9(2):249-74.
8. Narang R, Narasimhan B, Sharma S, Sriram D, Yogeeswari P, Clercq ED, et al. Nicotinic acid benzylidene hydrazides: Synthesis, antitubercular, antiviral, antimicrobial evaluation and QSAR studies. Med Chem Res 2012;21(8):1557-76.
9. Narang R, Narasimhan B, Sharma S. Naphthalen-1-yloxy-acetic acid enzylidene/1-phenylethylidene-hydrazide derivatives: Synthesis, antimicrobial evaluation, and QSAR studies. Med Chem Res 2012;21:2526-47.
10. Narang R, Narasimhan B, Sharma S. A review on biological activities and chemical synthesis of hydrazide derivatives. Curr Med Chem 2012;19(4):569-612.
11. Kumar S, Narang R, Nayak SK, Singh SK, Narasimhan B. Synthesis, antimicrobial evaluation and QSAR studies of Nâ€™-benzylidene/ (1-phenylethylidene)undec-10-enehydrazides. J Appl Pharm Sci 2016;6(4):104-16.
12. Noshiranzadeh N, Heidari A, Haghi F, Bikas R, Lis T. Chiral lactic hydrazone derivatives as potential bioactive antibacterial agents: Synthesis, spectroscopic, structural and molecular docking studies. J Mol Struct 2017;1128:391-9.
13. Wang X, Dai ZC, Chen YF, Cao LL, Yan W, Li SK, et al. Synthesis of 1,2,3-triazole hydrazide derivatives exhibiting anti-phytopathogenic activity. Eur J Med Chem 2017;126:171-82.
14. Nayyar A, Monga V, Malde A, Coutinho E, Jain R. Synthesis, anti-tuberculosis activity, and 3D-QSAR study of 4-(adamantan-1-yl)-2- substituted quinolines. Bioorg Med Chem 2007;15(2):626-40.
15. Leite AC, de Lima RS, Moreira DR, Cardoso MV, Gouveia de Brito AC, Farias Dos Santos LM, et al. Synthesis, docking, and in vitro activity of thiosemicarbazones, aminoacyl-thiosemicarbazides and acyl-thiazolidones against Trypanosoma cruzi. Bioorg Med Chem 2006;14(11):3749-57.
16. Gemma S, Kukreja G, Fattorusso C, Persico M, Romano MP, Altarelli M, et al. Synthesis of N1-arylidene-N2-quinolyl- and N2-acrydinylhydrazones as potent antimalarial agents active against CQ-resistant P. Falciparum strains. Bioorg Med Chem Lett 2006;16(20):5384-8.
17. Bhandari SV, Bothara KG, Raut MK, Patil AA, Sarkate AP, Mokale VJ. Design, synthesis and evaluation of anti-inflammatory, analgesic and ulcerogenicity studies of novel S-substituted phenacyl-1,3,4- oxadiazole-2-thiol and Schiff bases of diclofenac acid as nonulcerogenic derivatives. Bioorg Med Chem 2008;16(4):1822-31.
18. Varache-LembÃ¨ge M, Moreau S, Larrouture S, Montaudon D, Robert J, Nuhrich A. Synthesis and antiproliferative activity of aryl- and heteroaryl-hydrazones derived from xanthone carbaldehydes. Eur J Med Chem 2008;43(6):1336-43.
19. Martins F, Santos S, Ventura C, Elvas-LeitÃ£o R, Santos L, Vitorino S, et al. Design, synthesis and biological evaluation of novel isoniazid derivatives with potent antitubercular activity. Eur J Med Chem 2014;81:119-38.
20. Yang F, Hu M, Lei Q, Xia Y, Zhu Y, Song X, et al. Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model. Cell Death Dis 2015;6:e1701.
21. Jackson Y, Alirol E, Getaz L, Wolff H, Combescure C, Chappuis F. Tolerance and safety of nifurtimox in patients with chronic chagas disease. Clin Infect Dis 2010;51(10):e69-75.
22. Johnson JR, Johnston B, Kuskowski MA. In vitro comparison of nitrofurazone- and silver alloy-coated foley catheters for contact-dependent and diffusible inhibition of urinary tract infection-associated microorganisms. Antimicrob Agents Chemother 2012;56(9):4969-72.
23. Safaralizadeh R, Siavoshi F, Malekzadeh R, Akbari MR, Derakhshan MH, Sohrabi MR, et al. Antimicrobial effectiveness of furazolidone against metronidazole-resistant strains of Helicobacter pylori. East Mediterr Health J 2006;12(3-4):286-93.
24. Ningaiah S, Bhadraiah UK, Doddaramappa SD, Keshavamurthy S, Javarasetty C. Novel pyrazole integrated 1,3,4-oxadiazoles: Synthesis, characterization and antimicrobial evaluation. Bioorg Med Chem Lett 2014;24(1):245-8.
25. Arya N, Jagdale AY, Patil TA, Yeramwar SS, Holikatti SS, Dwivedi J, et al. The chemistry and biological potential of azetidin-2-ones. Eur J Med Chem 2014;74:619-56.
26. Vilar S, Costanzi S. Predicting the biological activities through QSAR analysis and docking-based scoring. Methods Mol Biol 2012;914:271-84.
27. 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):146-57.
28. Shoichet BK, McGovern SL, Wei B, Irwin JJ. Lead discovery using molecular docking. Curr Opin Chem Biol 2002;6(4):439-46.
29. Qiu X, Choudhry AE, Janson CA, Grooms M, Daines RA, Lonsdale JT, et al. Crystal structure and substrate specificity of the beta-ketoacyl-acyl carrier protein synthase III (FabH) from Staphylococcus aureus. Protein Sci 2005;14(8):2087-94.
30. Choi KH, Heath RJ, Rock CO. Beta-ketoacyl-acyl carrier protein synthase III (FabH) is a determining factor in branched-chain fatty acid biosynthesis. J Bacteriol 2000;182(2):365-70.
31. Christensen CE, Kragelund BB, von Wettstein-Knowles P, Henriksen A. Structure of the human beta-ketoacyl [ACP] synthase from the mitochondrial Type II fatty acid synthase. Protein Sci 2007;16(2):261-72.
32. Lai CY, Cronan JE. Beta-ketoacyl-acyl carrier protein synthase III (FabH) is essential for bacterial fatty acid synthesis. J Biol Chem 2003;278(51):51494-503.
33. Ministry of Health Department. Pharmacopoeia of India. Vol. 1. New Delhi: Controller of Publications, Ministry of Health Department, Government of India; 2007. p. 37.
34. Cappuchino JG, Sherman N. Microbiology - A Laboratory Manual. Redwood City: Addison Wesley Longman Inc.; 1999. p. 263.
35. Hypercube, Inc. Hyperchem 6.0. Gainesville: Hypercube, Inc.; 1993.
36. Oxford Molecular Limited. TSAR 3D Version 3.3. Oxford: Oxford Molecular Limited; 2000.
37. Schaper KJ. Free-Wilson-type analysis of non-additive substituent effects on THPB dopamine receptor affinity using artificial neural networks. Quant Struct Act Relat 1999;18:354-60.
38. Gajiwala KS, Margosiak S, Lu J, Cortez J, Su Y, Nie Z, et al. Crystal structures of bacterial FabH suggest a molecular basis for the substrate specificity of the enzyme. FEBS Lett 2009;583(17):2939-46.
39. Emami S, Foroumadi A, Falahati M, Lotfali E, Rajabalian S, Ebrahimi SA, et al. 2-Hydroxyphenacyl azoles and related azolium derivatives as antifungal agents. Bioorg Med Chem Lett 2008;18(1):141-6.
40. Vicini P, Zani F, Cozzini P, Doytchinova I. Hydrazones of 1,2-benzisothiazole hydrazides: Synthesis, antimicrobial activity and QSAR investigations. Eur J Med Chem 2002;37(7):553-64.
41. Sharma P, Rane N, Gurram VK. Synthesis and QSAR studies of pyrimido[4,5-d]pyrimidine-2,5-dione derivatives as potential antimicrobial agents. Bioorg Med Chem Lett 2004;14(16):4185-90.
42. Kohanski MA, Dwyer DJ, Collins JJ. How antibiotics kill bacteria: From targets to networks. Nat Rev Microbiol 2010;8(6):423-35.
43. Sortino M, Delgado P, JuÃ¡rez S, Quiroga J, AbonÃa R, Insuasty B, et al. Synthesis and antifungal activity of (Z)-5-arylidenerhodanines. Bioorg Med Chem 2007;15(1):484-94.
44. Shahlaei M, Sabet R, Ziari MB, Moeinifard B, Fassihi A, Karbakhsh R. QSAR study of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2 using LS-SVM and GRNN based on principal components. Eur J Med Chem 2010;45(10):4499-508.
45. Hansch C, Fujita T. P-r-p analysis: A method for the correlation of biological activity and chemical structure. J Am Chem Soc 1964;86(8):1616-26.
46. Hansch C, Leo A, Unger SH, Kim KH, Nikaitani D, Lien EJ. Aromaticâ€ substituent constants for structure-activity correlations. J Med Chem 1973;16(11):1207-16.
47. Kier LB, Hall LH. Molecular Connectivity in Chemistry and Drug Research. New York: Academic Press; 1976.
48. Randic M. Comparative regression analysis. Regressions based on a single descriptor. Croat Chem Acta 1993;66(2):289-312.
49. Balaban AT. Highly discriminating distance-based topological index. Chem Phys Lett 1982;89(2):399-404.
50. Wiener H. Structural determination of paraffin boiling points. J Am Chem Soc 1947;69(1):17-20.
51. Randic M. Characterization of molecular branching. J Am Chem Soc 1975;97(24):6609-15.
52. Oltulu O, Yasar MM, Eroglu E. A QSAR study on relationship between structure of sulfonamides and their carbonic anhydrase inhibitory activity using the eigenvalue (EVA) method. Eur J Med Chem 2009;44(9):3439-44.
53. Prado-Prado FJ, Gonzalez-Diaz H, Vega OM, Ubeira FM, Chou KC. Unified QSAR approach to antimicrobials. Part 3: First multi-tasking QSAR model for Input-Coded prediction, structural back-projection, and complex networks clustering of antiprotozoal compounds. Bioorg Med Chem 2008;16(11):5871-80.
54. GonzÃ¡lez-DÃaz H, GonzÃ¡lez-DÃaz Y, Santana L, Ubeira FM, Uriarte E. Proteomics, networks and connectivity indices. Proteomics 2008;8(4):750-78.
55. GonzÃ¡lez-DÃaz H, Vilar S, Santana L, Uriarte E. Medicinal chemistry and bioinformatics - Current trends in drugs discovery with networks topological indices. Curr Top Med Chem 2007;7(10):1015-29.
56. GonzÃ¡lez-DÃaz H, Prado-Prado FJ. Unified QSAR and network-based computational chemistry approach to antimicrobials, part 1: Multispecies activity models for antifungals. J Comput Chem 2008;29(4):656-67.
57. Cruz-Monteagudo M, GonzÃ¡lez-DÃaz H, AgÃ¼ero-ChapÃn G, Santana L, Borges F, DomÃnguez ER, et al. Computational chemistry development of a unified free energy Markov model for the distribution of 1300 chemicals to 38 different environmental or biological systems. J Comput Chem 2007;28(11):1909-23.
58. Arora P, Narang R, Bhatia S, Nayak SK, Singh SK, Narasimhan B. Synthesis, molecular docking and QSAR studies of 2, 4-disubstituted thiazoles as antimicrobial agents. J Appl Pharm Sci 2015;5(2):28-42.
59. Gutman I. Degree-based topological indices. Croat Chem Acta 2013;86(4):351-61.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.