SYNTHESIS, ANTIMICROBIAL ACTIVITY AND MOLECULAR DOCKING STUDY OF SOME NEW N-BENZYL AND N-BENZOYL-3-INDOLYL HETEROCYCLES
DOI:
https://doi.org/10.22159/ijpps.2016v8i9.13184Keywords:
Indole-3-carboxaldehyde, Heterocycle, Nil, Nil, Antimicrobial, Molecular dockingAbstract
Objective: Chalcones are one of the major classes of the natural products, which display a wide range of pharmacological properties. Also, chalcones are well-known intermediates for synthesizing various heterocyclic compounds like pyrazoline and pyrimidine derivatives. The present work is designed to synthesize new 3-indolylheterocycles starting from N-benzyl and N-benzoyl-1H-indole-3-carboxaldehyds and evaluating theirs in vitro antimicrobial activity. In addition, the probability of the most promising antimicrobial compounds to inhibit ATPase, enoyl reductase and dihydrofolate reductase were studied theoretically via molecular docking.
Methods: A new series of 3-indolylchalcones 2a,b were prepared and allowed to react with hydrazine hydrate, phenyl hydrazine, hydroxylamine, urea, thiourea and guanidine to afford the corresponding pyrazoles 3a,b-6a,b and pyrimidines derivatives 7a,b-9a,b. On the other hand, the reaction of 2a, b with malononitrile afforded 10a, b, which upon cyclo-condensation with formic acid, formamide, urea or thiourea yielded the fused pyrido [2,3-d]pyrimidine 11a,b-14a,b. Moreover, cyclo-condensation of 2a, b with thiosemicarbazide gave pyrazolin-1-carbothioamides 15a, b, which under cyclization with phenacyl bromide afforded thiazole derivatives 16a and 16b. While the reaction of 2a, b with cyano thioacetamide afforded 2-mercaptonicotinonitriles 17a, b. The reaction of 17a, b with some halo-compounds gave S-alkyl derivatives 18a-d and 19a-d, respectively,which under heating in the presence of piperidine gave the fused thienopyridines 20a-d and 21a-d, respectively. All the newly prepared compounds were evaluated for their in vitro antimicrobial activity. In addition, molecular docking study of the most promising antimicrobial compounds against ATPase, enoyl reductase and dihydrofolate reductase theoretically is discussed.
Results: Compounds 17a and 17b were found to be the most potent compounds with MIC of 0.98, 0.49 and 0.98µg/ml against S. pneumoniae (RCMB 010010), E. coli (RCMB 010052) and A. fumigatus (RCMB 02568), respectively compare to the reference drugs. Also, compounds 17a and 17b exhibited good docking scores and could act as inhibitors of enzymes understudied.
Conclusion: Further work is recommended to confirm the ability of compounds 17a and 17b to inhibit ATPase, enoyl reductase and dihydrofolate reductase in a specific bioassay.
Downloads
References
Okwu DE, Ukanwa N. Isolation and characterization of flavonoids chalcones and anthocynidines from bridelia ferruginea benth. Chem Sin 2010;1:21-8.
Karthikeyan C, Moorthy NS, Ramasamy S, Vanam U, Manivannan E, Karunagaran D, et al. Advances in chalcones with anticancer activities. Recent Pat Anti-Cancer Drug Discovery 2015;10:97-115.
Fang X, Yang B, Cheng Z, Zhang P, Yang M. Synthesis and antimicrobial activity of novel chalcone derivatives. Res Chem Intermed 2014;40:1715–25.
Ngameni B, Watching J, Boyom FF, Keumedjio F, Ngadjui BT, Gut J, et al. Antimalarial prenylated chalcones from the twigs of Dorstenia barteri var. subtriangular. ARKIVOC 2007;xiii:116-23.
Iqbal H, Prabhakar V, Sangith A, Chandrika B, Balasubramanian R. Synthesis, anti-inflammatory and antioxidant activity of ring-A-monosubstituted chalcone derivatives. Med Chem Res 2014;23:4383-94.
Wan Z, Hu D, Li P, Xie D, Gan X. Synthesis, antiviral bioactivity of novel 4-thioquinazoline derivatives containing chalcone moiety. Molecules 2015;20:11861-74.
El-Sawy ER, Mandour AH, Mahmoud K, Islam IE, Abo-Salem HM. Synthesis, antimicrobial and anti-cancer activities of some new N-ethyl, N-benzyl and N-benzoyl-3-indolyl heterocycles. Acta Pharm 2012;62:157-79.
Gupta P, Gupta JK, Bansal S, Halve AK. Synthesis and in vitro antimicrobial studies of some new pyrazolones. Int J Cur Pharm Res 2015;7:25-9.
Mandour AH, El-Sawy ER, Ebaid MS, Hassan SM. Synthesis and potential biological activity of some novel 3-((N-substituted-indol-3-yl)methyleneamino)-6-amino-4-aryl-pyrano(2,3-c)pyrazole-5-carbonitriles and 3,6-diamino-4-(N-substituted-indol-3-yl)pyrano(2,3-c)pyrazole-5-carbonitriles. Acta Pharm 2012;62:15-30.
Abo-Salem HM, El-Sawy ER, Fathy A, Mandour AH. Synthesis, antifungal activity and molecular docking study of some novel highly substituted 3-indolylthiophene derivatives. Egypt Pharm J 2014;13:71-91.
Ramathilagam C, Upgade A, Bhaskar A, Umarani PR, Manivannan V. Synthesis and molecular docking studies of ethyl 1-benzenesulfonyl-2-[(E)-2-(2-methylphenyl) ethenyl] indole-3-carboxylate with human renin complexed with inhibitor. Asian J Pharm Clin Res 2013;6:96-9.
Saravanan B, Upgade A, Bhaskar A, Manivannan V. Synthesis and molecular docking studies of 2 cholromethyl-3-methyl-1-phenyl sulfonyl-1h-indole compound. Asian J Pharm Clin Res 2013;6:262-5.
Rajbir K, Saroj A. Alkaloids-important therapeutic secondary metabolites of plant origin. J Critical Rev 2015;2:1-8.
El-Sawy ER, Abo-Salem HM, Mahmoud K, Zarie ES, El-Metwally AM, Mandour AH. Synthesis, anticancer activity and molecular docking study of novel 1, 3-diheterocycles indole derivatives. Int J Pharm Pharm Sci 2015;7:377-85.
El-Sawy ER, Bassyouni FA, Abu-Bakr SH, Rady HM, Abdlla MM. Synthesis and biological activity of some new 1-benzyl and 1-benzoyl 3-heterocyclic indole derivatives. Acta Pharm 2010;60:55–71.
El-Sawy ER, Mandour AH, El-Hallouty SM, Shaker KH, Abo-Salem HM. Synthesis, antimicrobial and anticancer activities of some new N-methylsulfonyl and N-benzenesulphonyl-3-indolyl heterocycles. Arabian J Chem 2013;6:67–78.
Mndzhoyan AL, Papayan GL, Zhuruli LD, Karagezyan SG, Galstyan LS, Sarafyan VG. Synthesis and biological study of hydrazino hydrazones of indole aldehydes and ketons series. Arm Khim Zh 1969;22:707–13.
Brunskill JSA, De A, Ewing DF. Dimerisation of 3-aryl-2-cyanothioacrylamides. A [2s+ 4s] cycloaddition to give substituted 3,4-dihydro-2H-thiopyrans. J Chem Soc Perkin Trans 1 1978;6:629-33.
Dotsenko VV, Krivokolysko SG, Polovinko VV, Litvinov PV. On the regioselectivity of the reaction of cyano thioacetamide with 2-acetylcyclo-hexanone, 2-acetylcyclopentanone, and 2-acetyl-1-(morpholin-4-yl)-1-cycloalkenes. Chem Heterocycl Compd 2012;48:309–19.
Scott AC. Laboratory control of antimicrobial therapy. In: Collee JG. Eds. Practical Medical Microbiology. 13th edn. Edinburgh, Churchill Livingstone; 1989. p. 161–81.
Saini RK, Choudhary AS, Joshi YC, Joshi P. Solvent-free synthesis of chalcones and their antimicrobial activities. E J Chem 2005;2:224–7.
Mesleh MF, Cross JB, Zhang J, Kahmann J, Andersen OA, Barker J, et al. Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB. Bioorg Med Chem Lett 2016;26:1314–8.
Qiu X, Janson CA, Court RI, Smyth MG, Payne DJ, Abdel-Meguid SS. Molecular basis for triclosan activity involves a flipping loop in the active site. Protein Sci 1999;8:2529-32.
Sogabe S, Masubuchi M, Sakata K, Fukami TA, Morikami K, Shiratori Y, et al. Crystal structures of Candida albicans N-Myristoyltransferase with two distinct inhibitors. Chem Biol 2002;9:1119-28.
Kaminski G, Jorgensen WL. The performance of the AMBER94, MMFF94 and OPLS-AA forcefields for modeling organic liquids. J Phys Chem 1996;100:18010-3.
Lensink MF, Méndez R, Wodak SJ. Docking and scoring protein complexes: Capri 3rd Edition. Proteins 2007;69:704–18.
Zhang F, Zhao Y, Sun L, Ding L, Gu Y, Gong P. Synthesis and anti-tumor activity of 2-amino-3-cyano-6-(1H-indol-3-yl)-4-phenylpyridine derivatives in vitro. Eur J Med Chem 2011;46:3149-57.
Published
How to Cite
Issue
Section
