DESIGN, SYNTHESIS, QUANTUM MECHANICAL CALCULATION AND INSILICO SCREENING OF BENZOYLATED ISONIAZID HYDRAZONE DERIVATIVES AS MYCOBACTERIUM TUBERCULOSIS ENOYL REDUCTASE INHIBITORS

Authors

  • J R Tulasi Department of pharmaceutical chemistry, Sir C.R. Reddy College of pharmaceutical sciences, Eluru-534007
  • T. Durga Snehitha Department of pharmaceutical chemistry, Sir C.R. Reddy College of pharmaceutical sciences, Eluru-534007

Keywords:

InhA, Hydrazide derivatives, enoyl reductase inhibitors, Docking, Benzoylation.

Abstract

A series of novel isonicotinic acid hydrazide derivatives were synthesized and benzoylated. The compounds were purified and characterized by IR, NMR, Mass spectral studies. Drug likeliness assessment conferred all compounds obeying rule of thumb. Binding energy calculation revealed compounds having electron donating groups having high HOMO values (ISB9, ISB10, BI9, and BI10). Structure based drug design was performed for 48 structures having various heterocyclic moieties, INH, and 10 compounds which are reported in literature as active Inh A inhibitors.

Docking and scoring study unravels that our compounds were having 1-5 H-bonding interactions with Tyr158, Ile95, Ile194, Pro 193 H2O 856, 502, 563, and 552. Hydrophobic interactions of compounds were found to be with Ala157, Gly96, Ile215, Leu218, Met103, Tyr158, Phe97, Pro156, Ser123 and Iys165. All the compounds have good docking score compared to INH. In vitro anti oxidant activity by nitric oxide scavenging assay was also performed and the results inferred compounds having good docking score are having good activity. The compounds having electron donating groups are having good activity.

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References

John S. Blanchard. Molecular mechanisms of Drug resistance in Mycobacterium Tuberculosis, Annu. Rev. Biochem., 1996; 65: 215-239.

Reddy Y.N, Murthy S.V, Krishna D.R, Prabhakar M.C. Role of free radicals and antioxidants in tuberculosis patients, Indian J Tuberc., 2004; 51: 213-218.

Khisimuzi , Spigelman M. Novel targets for tuberculosis drug discovery, Current opinion pharmacolo.,2006; 6: 459-467.

Sunduru N, Sharma M, Chauhan P.M.S. Recent advances in the design and synthesis of Heterocycles as anti-tubercular agents, Futur. Med Chem., 2010; 2(9): 1469-1500.

Rollas S, Kucukguzel S.G. Biological Activities of Hydrazone Derivatives, Molecules., 2007; 12: 1910-1939.

Hearn M. J, Cynamon M. H.Design and synthesis of antituberculars: preparation and evaluation against Mycobacterium tuberculosis of an Isoniazid Schiff base. J. Antimicrob. Chemother., 2004; 53: 185–191.

Ferreira M, Gonacalves R, Souza M. Synthesis and Antitubercular Activity of Heteroaromatic Isonicotinoyl and 7-Chloro-4-Quinolinyl Hydrazone Derivatives. The Scientific World JOURNAL., 2010; 10: 1347–1355.

Rajput A P, Rajput S S. A novel method for the synthesis of formyl pyrazoles using vilsmeier-haack reaction. Int J Pharm Pharm Sci., 2011; 3(4): 346-351.

Lourenco M.C.S, Souza M.V.N, Pinheiro A.C, Gonacalves R.S.B, Ferreira M.L. Evaluation of Anti-tubercular activity of Nicotinic and Isoniazid analogues. ARKIVOC., 2007; (xv): 181-191.

Sharma R.N, Sharma K.P, Dixit S.N. Synthesis, characterization and biological activities of some new acid hydrazones. Oriental J. Chem., 2010; 26(1): 69-74.

Commeiras L, Woodcock S.C, Baldwin J.E, Adlington R.M, Cowley R, Wilkinso P.J. New access to the 1H-pyrazolo [4, 3-c] pyridine core from bis-acetylenic-N-benzoylhydrazones. Tetrahedron., 2004; 60: 933–938.

Judge V, Narasimhan B, Ahuja M, Sriram D, Yogeeswari P, Clercq E.D, Pannecouque C, Balzarini J. Isonicotinic acid hydrazide derivatives: synthesis, antimicrobial activity, and QSAR studies, Med Chem Res., 2012; 21: 1451–1470.

Narang R, Sharma S, Sriram D, Yogeeswari P, Clercq E, Pannecouque C, Balzarini J, Narasimhan B. Synthesis, antimycobacterial, antiviral, antimicrobial activities, and QSAR studies of nicotinic acid benzylidene hydrazide derivatives. Med. Chem. Res., 2012; 21: 1557–1576.

Tripathi L, Kumar P, Singh R, Stables J P.Design, synthesis and anticonvulsant evaluation of novel N-(4-substituted phenyl)-2-[4-(substituted) benzylidene]-hydrazinecarbothio amides. Eur.J .Med Chem., 2012; 47: 153-166.

Nerkar A. G, Saxena A.K, .Ghone S.K, Thaker A.K. In Silico Screening, Synthesis and In Vitro Evaluation of Some Quinazolinone and Pyridine Derivatives as Dihydrofolate Reductase Inhibitors for Anticancer Activity. e-Journal of Chemistry., 2009; 6(S1): S97-102.

Nalini C.N, Arivukkarasi, Devi R. Structure based drug design, Synthesis, Characterisation and Biological evaluation of Novel Isoniazid derivatives.RASAYAN J.Chem., 2011; 4(4): 868-874.

Punkvang A, Saparpakorn P, Hannongbua S, Wolschann P, Pungpo P. Elucidating Drug-Enzyme Interactions and Their Structural Basis for Improving the Affinity and Potency of Isoniazid and Its Derivatives Based on Computer Modeling Approaches. Molecules., 2010; 15: 2791-2813.

Himaja M, Rajesh K, Venkateshwarareddy M, Asif K, Ramana M.V. Docking, Synthesis and Antitubercular evaluation of Isonicotinoyl Hydrazino-Aminoacids. Int.J.Res.Ayur.Pharm., 2011; 2(5): 1549-1552.

Yogeeswari P, Sriram D, Thirumurugan R, Raghavendran J.V,Sudhan K,Pavana R.K, Stables J. Discovery of N-(2,6-Dimethylphenyl)-Substituted Semicarbazones as Anticonvulsants: Hybrid Pharmacophore-Based Design.J. Med. Chem., 2005; 4:6202-6211.

Aanandhi V.M, Mansoori H.M, Shanmugapriya S, Shiny G, Shanmugasundaram P. Synthesis and In- vitro antioxidant activity of substituted Pyridinyl 1, 3, 4 oxadiazole derivatives. Res. J Phar. Biol.Chem .Sci., 2010; 1(4): 1083-1090.

Kumar P.P, Rani B.L. Synthesis and characterization of new Schiff bases containing pyridine moiety and their derivatives as antioxidant agents. Int. J. ChemTech. Res., 2011; 3(1): 155-160

Silvermann R B. The organic chemistry of drug design and action. 2nd Ed. London: Academic press (Elseveir); 2004.

Saleh B A, Abood H A, Miyamoto R, Bortoluzzi M. Theoretical Study of Substituent Effects on Electronic and Structural Properties of 2,4-Diamino-5-para-substituted-phenyl-6-ethyl-pyrimidines. J. Iran. Chem. Soc., 2011; 8(3): pp. 653-661.

Rando D.G, Sato D.N, Siqueira L, Malrezzi A, Leite C.Q, Amarat A.T, Ferreira E, Tavares L. C. Potential Tuberculostatic Agents. Topliss Application on Benzoic Acid [(5-Nitro-thiophen-2-yl)-methylene]-hydrazide Series. Bioorg. Med. Chem., 2002; 10: 557–5

Published

2016-03-15

How to Cite

J R Tulasi, & Snehitha, T. D. . (2016). DESIGN, SYNTHESIS, QUANTUM MECHANICAL CALCULATION AND INSILICO SCREENING OF BENZOYLATED ISONIAZID HYDRAZONE DERIVATIVES AS MYCOBACTERIUM TUBERCULOSIS ENOYL REDUCTASE INHIBITORS. International Journal of Research and Development in Pharmacy & Life Sciences, 5(2), 2063-2073. Retrieved from https://ijrdpl.com/index.php/ijrdpl/article/view/220