SYNTHESIS, DOCKING STUDIES AND EVALUATION OF ANTIMICROBIAL AND IN VITRO ANTIPROLIFERATIVE ACTIVITY OF 5H-CHROMENO 4,3-D PYRIMIDIN-2-AMINE DERIVATIVES
Keywords:
Chromenes, Chromeno 4, 3-d]pyrimidine-2-amine, Antimicrobial, HeLa cell lines, Autodock VinaAbstract
Objective: Docking studies and synthesis of 4-aryl-5H-chromeno [4,3 -d]pyrimidine-2-amine derivatives to evaluate antimicrobial and in vitro cytotoxicity activity.
Methods: Docking studies were performed on Autodock Vina. Computational work was carried out with UCSF Chimera, Argus lab, Marvin beans. Antimicrobial activity was carried out with the agar cup plate method on two gram-positive organisms viz. Bacillus Subtilis and Staphylococcus Aureus and two gram-negative organisms viz. Escherichia Coli and Pseudomonas Aeruginosa. In vitro cytotoxicity was performed on HeLa cell lines with Sulfo Rhodamine B (SRB) assay method.
Results: In docking studies compounds CHR 7, CHR 8 and CHR 9 gave highest docking score (binding free energy) and moderate antimicrobial activity against gram positive organisms. All the synthesized compounds showed poor antimicrobial activity against gram negative organisms. In vitro cytotoxicity activity, in terms of growth inhibitory concentration 50 % (GI50) was in the range 37.9 - 57.1 µM. Though synthesised compounds possess moderate GI50, in comparison to standard Adrinamycin the compounds are inactive.
Conclusion: A series of 4-aryl-5H-chromeno[4,3 -d]pyrimidine-2-amine derivatives were synthesized and evaluated for antimicrobial and in vitro cytotoxicity studies. The compound CHR 9 was found most active among all the synthesised compounds.
Downloads
References
Abbas S, Radineh M, Omidreza F, Savis M, Ahmad R, Ramin M. Synthesis and cytotoxic activity of novel benzopyrano [3,2-c]chromene-6,8-dione derivatives. Med Chem Res 2011;20:466-74.
Reddy RK, Rao SP, Dev JG, Poornachandra Y, Ganesh Kumar C, Rao SP, et al. Synthesis of novel 1,2,3-triazole/isoxazole functionalized 2H-chromene derivatives and their cytotoxic activity. Bioorg Med Chem Lett 2014;24(7):1661-3.
Gourdeau H, Leblond L, Hamelin B, Desputeau C, Dong K, Kianicka I, et al. Antivascular and antitumor evaluation of 2-amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-4H-chromenes, a novel series of anticancer agents. Mol Cancer Ther 2004;3:1375-84.
Mladenovic M, Vukovic N, Sukdolak S, Solujic S. Design of novel 4-hydroxy-chromene-2-one derivatives as antimicrobial agents. Mol 2010;15:4294-308.
Serbetci T, Birteksoz S, Prado S, Michel S, Tillequin F. Synthesis and antimicrobial activities of some sulphur containing chromene derivatives. Nat Prod Commun 2012;7(7):891-4.
Fadda AA, Berghot MA, Amer FA, Badawy DS, Bayoumy NM. Synthesis and antioxidant and antitumor activity of novel pyridine, chromene, thiophene and thiazole derivatives. Arch Pharm (Weinheim) 2012;345(5):378-85.
Cheng JF, Ishikawa A, Ono Y, Arrhenius T, Nadzan A. Novel chromene derivatives as TNF-alpha inhibitors. Bioorg Med Chem Lett 2003;3(13, Suppl 21):3647-50.
Ali TA, Abdel-Aziz SA, El-Shaaer HM, Hanafy FI, El-Fauomy AZ. Synthesis of some new 4-oxo-4H-chromene derivatives bearing nitrogen heterocyclic systems as antifungal agents. Turk J Chem 2008;32:365-74.
Zghab I, Trimeche B, Mansour M, Hassine M, Touboul D, Jannet H. Regiospecific synthesis, antibacterial and anticoagulant activities of novel isoxazoline chromene derivatives. Arabian J Chem Forthcoming 2013.
Drug Bank version 4.1 [Internet]. Drug Bank: Open Data Drug and Drug Target Database; Available from: http://www.drugbank.ca/drugs/DB01148.html.
Nardi D, Leonardi A, Pennini R, Tajana A, Cazzulani P, Testa R. New basic esters of 2-phenyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid endowed with spasmolytic properties. Synthesis and pharmacological pharmacokinetic evaluation. Arzneimittelforsch 1993;43(1):28-34.
Sun W, Cama LD, Birzin ET, Warrier S, Locco L, Mosley R, et al. 6H-Benzo[c]chromen-6-one derivatives as selective ERbeta agonists. Bioorg Med Chem Lett 2006;16(6):1468-72.
Hussain MK, Ansari MI, Yadav N, Gupta PK, Gupta AK, Saxena R, et al. Design and synthesis of ERα/ERβ selective coumarin and chromene derivatives as potential anti-breast cancer and anti-osteoporotic agents. RSC Adv 2014;4:8828–45.
Mori J, Iwashima M, Takeuchi M, Saito H. A synthetic study on antiviral and antioxidative chromene derivative. Chem Pharm Bull 2006;54(3):391-6.
Naga Sudha B, Sridhara C, Girija Sastry C, Reddy YSR, Sreevidya O, Lavanya S, et al. Synthesis, characterisation and anthelmintic activity of 3-(4-acetyl-5-phenyl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2H-chromen-2-one derivatives. Indian J Chem 2013;52B:422-27.
Bhavsar D, Trivedi J, Parekh S, Savant M, Thakrar S, Bavishi A, et al. Synthesis and in vitro anti-HIV activity of N-1,3-benzo[d]thiazol-2-yl-2-(2-oxo-2H-chromen-4-yl)acetamide derivatives using MTT method. Bioorg Med Chem Lett 2011;21(11):3443-6.
Mungra DC, Patel MP, Rajani DP, Patel RG. Synthesis and identification of β-aryloxyquinolines and their pyrano[3,2-c]chromene derivatives as a new class of antimicrobial and antituberculosis agents. Eur J Med Chem 2011;46(9):4192-00.
Vijaya Kumar P, Rajeswar Rao V. Synthesis and antitubercular, antiviral and anticancer activity of 3-(3-mercaptoalkyl-7H-[1,2,4]triazolo[3,4-b][1,3,4]-thiadiazin-6-yl)chromen-2-one and its derivatives. Indian J Chem 2008;47B:106-11.
Chen JJ, Wang TY, Hwang TL. Neolignans. A coumarinolignan, lignan derivatives, and a chromene: anti-inflammatory constituents from Zanthoxylum avicennae. J Nat Prod 2008;71(2):212-7.
Asrondkar Al, Patil VN, Mishra NU, Bobade AS, Chowdhary AS. Synthesis and study of (5Z)-5-[(4-oxo-4H-chromen-3-yl)methylidene]-1, 3-thiazolidine-2, 4-dione derivative. Der Pharm Chem 2013;5(4):288-92.
Bin L, Long-Guan X, Xiao-Hua X, Yong-Hong L. Synthesis, crystal structure and herbicidal activity of 3-benzoyl-4-hydroxycoumarin derivatives. Chin J Org Chem 2011;31(12):2067-73.
Sivakumar KK, Rajasekaran A. Synthesis, in vivo analgesic and in vitro anti-microbial activity of 3-amino-4-[2-(substituted phenyl)hydrazin-1-ylidene]-1-[(2-oxo-2h-chromen-3-yl)carbonyl]-4, 5-dihydro-1hpyrazol-5-one and its schiff bases. Int J Res Pharm Chem 2014;4(3):517-27.
Hegab MI, Abdulla MM. 4-Chloro-2,2-disubstituted chromen-3-carboxaldehyde: synthesis of some fused polycyclic heterocycles as anti-inflammatory, analgesic, anticonvulsant, and antiparkinsonian agents. Arch Pharm (Weinheim) 2006;339(1):41-7.
Ronad PM, Maddi VS, Koti BC, Kurhe YV, Swamy A, Swamy Ahmt, et al. Evaluation of anticonvulsant activity of novel series of benzopyran-2-one derivatives by PTZ induced seizure model in mice. Indian J Novel Drug Delivery 2010;2(4):158-61.
Galm U, Heller S, Shapiro S, Page M, Li S, Heide L. Antimicrobial and DNA gyrase-inhibitory activities of novel clorobiocin derivatives produced by mutasynthesis. Antimicrob Agents Chemother 2004;48(4):1307-12.
Hooper DC, Wolfson JS, Mchugh GL, Winters MB, Swartz MN. Effects of novobiocin, coumermycin Al, clorobiocin, and their analogs on escherichia coli DNA gyrase and bacterial growth. Antimicrob Agents Chemother 1982;22(4):662-71.
Richardson TI, Dodge JA, Durst GL, Pfeifer LA, Shah J, Wang Y, et al. Benzopyrans as selective estrogen receptor b agonists (SERBAs). Part 3: Synthesis of cyclopentanone and cyclohexanone intermediates for C-ring modification. Bioorg Med Chem Lett 2007;17:4824-28.
Colotta V, Cecchi L, Melani F, Filacchioni G, Martini C, Giannaccini G, et al. Tricyclic heteroaromatic systems. [1]benzopyranopyrrol-4-ones and [1]benzopyrano-1,2,3-triazol-4-ones as benzodiazepine receptor ligands. Synthesis and structure-activity relationships. J Med Chem 1990;33:2646-51.
Pettersen EF, Goddard TD, Huang CC, Couch GS. UCSF Chimera-a visualization system for exploratory research and analysis. J Comput Chem 2004;25:1605-12.
Trott O, Olson AJ. Auto Dock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization and multithreading. J Comput Chem 2010;31(2):455–61.
Morris GM, Huey R, Lindstrom W, Sanner MF. Autodock4 and Auto Dock Tools 4: automated docking with selective receptor flexibility. J Comput Chem 2009;16:2785-91.
Skehn P, Storeng R, Scudiero A, Monks J, McMohan D, Vistica D, et al. New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 1990;82:1107-52.