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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

An Efficient Protocol for the Synthesis, Biological Screening and Molecular Docking Studies of 3,4-Dihydropyrimidine-2-one/thione Derivatives

Author(s): Ehsan Ullah Mughal*, Hafiz Umar Farooq, Amina Sadiq, Hummera Rafique, Sajjad Hussain Sumrra, Muhammad Naveed Zafar, Nighat Fatima, Syed Aun Muhammad, Abdul Manan, Chaudhary Omer Javed and Muhammad Tayyab

Volume 17, Issue 3, 2020

Page: [330 - 340] Pages: 11

DOI: 10.2174/1570180816666190329224458

Price: $65

Abstract

Introduction: Heterocyclic compounds are vital to life, since they constitute the most interesting part of the pharmacologically active drugs. Dihydropyrimidine-2-one/thione (DHPM) as the heterocyclic nucleus is the basic part of the most natural as well as synthetic drugs. Synthesis of new derivatives of DHPM and screening their pharmacological potential appear to be an important goal.

Methodology: In this study, we have synthesized 15 derivatives of 3,4-dihydropyrimidin-2(1H)- ones/thiones through simple one-step synthetic method comprising one-pot condensation of variously substituted benzaldehydes, urea/thiourea and ethyl acetoacetate using ammonium chloride in methanol as well as under solvent-free conditions. In comparison, the former methodology was proved more efficient, convenient and gave higher yields. Moreover, those compounds were screened for their potential against bacterial strains (S. aureus and E. coli) and fungal strains (C. albicans and C. parapsilosis).

Results and Discussion: The experimental results revealed that the synthesized compounds are more active against C. albicans fungus as compared to other tested microbes. Amongst all the synthesized derivatives, compound 3 showed significant non-competitive potential antifungal activity in vitro antimicrobial assay. Theoretically, molecular docking studies showed that these compounds can bind effectively to oxidoreductase enzyme of E. coli and CYP-51 oxidoreductase of C. albicans.

Conclusion: Herein, we report improved and high yield reaction conditions for the synthesis of biologically active dihydropyrimidine-2-one, and-thione derivatives. Remarkably, most of the synthesized compounds demonstrated moderate to very good antifungal activity in comparison to the antibacterial activity.

Keywords: Dihydropyrimidine, heterocyclic compounds, antimicrobial activities, anti-fungal agents, anti-bacterial agents, molecular docking studies.

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[1]
Al-Mulla, A.; Review, A. Biological importance of heterocyclic compounds. Pharma Chem., 2017, 9(13), 141-147.
[2]
(a) Karelson, M.M.; Katritzky, A.R.; Szafran, M.; Zerner, M.C. Quantitative predictions of tautomeric equilibria for 2-, 3-, and 4-Substituted pyridines in both the gas phase and aqueous solution: Combination of AM1 with reaction field theory. J. Org. Chem., 1989, 54(26), 6030-6034.
[http://dx.doi.org/10.1021/jo00287a012]
(b) Mohammadi, B.; Behbahani, F.K. Recent developments in the synthesis and applications of dihydropyrimidin-2(1H)-ones and thiones. Mol. Divers., 2018, 22(2), 405-446.
[http://dx.doi.org/10.1007/s11030-017-9806-z] [PMID: 29349521]
[3]
Dansena, H.; Dhongade, H.; Chandrakar, K. Pharmacological potentials of pyrimidine derivative: A review. Asian J. Pharm. Clin. Res., 2015, 8(4), 171-177.
[4]
Matsuda, T.; Hirao, I. Antibacterial activity of 5-nitrofuran derivatives. Nippon Kagaku Zasshi, 1965, 86, 1195-1197.
[5]
de Fátima, Â.; Braga, T.C. Neto, Lda.S.; Terra, B.S.; Oliveira, B.G.; da Silva, D.L.; Modolo, L.V. A mini-review on Biginelli adducts with notable pharmacological properties. J. Adv. Res., 2015, 6(3), 363-373.
[http://dx.doi.org/10.1016/j.jare.2014.10.006] [PMID: 26257934]
[6]
Agarwal, N.; Srivastava, P.; Raghuwanshi, S.K.; Upadhyay, D.N.; Sinha, S.; Shukla, P.K.; Ji Ram, V. Chloropyrimidines as a new class of antimicrobial agents. Bioorg. Med. Chem., 2002, 10(4), 869-874.
[http://dx.doi.org/10.1016/S0968-0896(01)00374-1] [PMID: 11836092]
[7]
Aly, H.M.; Kamal, M.M. Efficient one-pot preparation of novel fused chromeno [2,3-d]pyrimidine and pyrano[2,3-d]pyrimidine derivatives. Eur. J. Med. Chem., 2012, 47(1), 18-23.
[http://dx.doi.org/10.1016/j.ejmech.2011.09.040] [PMID: 22000923]
[8]
Trivedi, A.R.; Bhuva, V.R.; Dholariya, B.H.; Dodiya, D.K.; Kataria, V.B.; Shah, V.H. Novel dihydropyrimidines as a potential new class of antitubercular agents. Bioorg. Med. Chem. Lett., 2010, 20(20), 6100-6102.
[http://dx.doi.org/10.1016/j.bmcl.2010.08.046] [PMID: 20813528]
[9]
Callery, P.; Gannett, P. Cancer and cancer chemotherapy. Foye’s Principles of medicinal. Chemistry, 2002, 934-935.
[10]
Montgomery, J.; Johnston, T.; Shealy, Y. In Burgers Medicinal Chemistry, Part II; Wiley-Interscience: Newyork, 1979.
[11]
Cheng, C. Progress in Medicinal Chemistry; Butterworths: London, 1982.
[12]
Biginelli, P. Aldehyde-urea derivatives of aceto-and oxaloacetic acids. Gazz. Chim. Ital., 1893, 23(1), 360-413.
[13]
Shaabani, A.; Bazgir, A.; Teimouri, F. Ammonium chloride-catalyzed one-pot synthesis of 3, 4-dihydropyrimidin-2-(1H)-ones under solvent-free conditions. Tetrahedron Lett., 2003, 44(4), 857-859.
[http://dx.doi.org/10.1016/S0040-4039(02)02612-6]
[14]
Tamay-Cach, F.; Villa-Tanaca, M.L.; Trujillo-Ferrara, J.G.; Alemán-González-Duhart, D.; Quintana-Pérez, J.C.; González-Ramírez, I.A.; Correa-Basurto, J. M.; G Trujillo-Ferrara, J.; Aleman- Gonzalez-Duhart, D.; C Quintana-Pérez, J.; A González- Ramírez, I.; Correa-Basurto, J. In silico studies most employed in the discovery of new antimicrobial agents. Curr. Med. Chem., 2016, 23(29), 3360-3373.
[http://dx.doi.org/10.2174/0929867323666160210141912] [PMID: 26860996]
[15]
Mughal, E.U.; Sadiq, A.; Hamayun, M.; Zafar, M.N.; Fatima, N.; Yameen, M.A.; Muhammad, S.A.; Mumtaz, A.; Ahmed, I.; Fatima, T. Design, synthesis and biological evaluation of novel dihydropyrimidine-2-thione derivatives as potent antimicrobial agents: Experimental and molecular docking approach. Lett. Drug Des. Discov., 2018, 15(11), 1189-1201.
[http://dx.doi.org/10.2174/1570180815666180209151516]
[16]
Taylor, A. Aminopeptidases: structure and function. FASEB J., 1993, 7(2), 290-298.
[http://dx.doi.org/10.1096/fasebj.7.2.8440407] [PMID: 8440407]
[17]
Bickerton, G.R.; Paolini, G.V.; Besnard, J.; Muresan, S.; Hopkins, A.L. Quantifying the chemical beauty of drugs. Nat. Chem., 2012, 4(2), 90-98.
[http://dx.doi.org/10.1038/nchem.1243] [PMID: 22270643]
[18]
(a) El Mejdoubi, K.; Sallek, B.; Cherkaoui, H.; Chaair, H.; Oudadesse, H. One-pot synthesis of dihydropyrimidinones/thiones catalyzed by white marble a metamorphic rock: An efficient and reusable catalyst for the biginelli reaction. Kinet. Catal., 2018, 59(3), 290-295.
[http://dx.doi.org/10.1134/S0023158418030126]
(b) Foroughifar, N.; Karimi Beromi, S.; Pasdar, H.; Shahi, M. Synthesis of some new tetrahydropyrimidine derivatives as possible antibacterial agents. Iran. J. Pharm. Res., 2017, 16(2), 596-601.
[PMID: 28979312]
(c) Bose, D.S.; Sudharshan, M.; Chavhan, S.W. New protocol for Biginelli reaction-a practical synthesis of Monastrol. ARKIVOC, 2005, (iii), 228-236.
(d) Lu, J.; Bai, Y. Catalysis of the Biginelli reaction by ferric and nickel chloride hexahydrates. One-pot synthesis of 3, 4-dihydropyrimidin-2 (1H)-ones. Synthesis, 2002, 4, 466-470.
[http://dx.doi.org/10.1055/s-2002-20956]
(e) Pasunooti, K.K.; Chai, H.; Jensen, C.N.; Gorityala, B.K.; Wang, S. X.-W, Liu. A microwave-assisted, copper-catalyzed three-component synthesis of dihydropyrimidinones under mild conditions. Tetrahedron Lett., 2005, 52(1), 80-84.
(f) Hajipour, A.R.; Khazdooz, L.; Zarei, A. Bronsted acidic ionic liquid-catalyzed one-pot synthesis of 3, 4-dihydropyrimidin-2 (1 H)-ones and thiones under solvent-free conditions. Synth. Commun., 2002, 41, 2200-2208.
(g) Liberto, N.A.; de Paiva Silva, S.; de Fatima, A.; Fernandes, S.A. Beta-Cyclodextrin-assisted synthesis of Biginelli adducts under solvent-free conditions. Tetrahedron, 2013, 69(38), 8245-8249.

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