Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

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

Back
Research Article

A Series of Furan-based Hydrazones: Design, Synthesis, and Evaluation of Antimicrobial Activity, Cytotoxicity and Genotoxicity

Author(s): Mehlika Dilek Altintop*, Belgin Sever, Özlem Atli Eklioğlu, Merve Baysal, Rasime Demirel and Ahmet Özdemir

Volume 17, Issue 3, 2020

Page: [312 - 322] Pages: 11

DOI: 10.2174/1570180816666190325163948

Abstract

Background: Hydrazones, frequently occurring motifs in many bioactive molecules, have attracted a great deal of interest as potent antimicrobial agents.

Objective: The aim of this work was to design and synthesize new hydrazone-based antimicrobial agents.

Methods: 4-[2-((5-Arylfuran-2-yl)methylene)hydrazinyl]benzonitrile derivatives (1-10) were obtained via the reaction of 4-cyanophenylhydrazine hydrochloride with 5-arylfurfurals. Compounds 1-10 were evaluated for their antimicrobial effects using a broth microdilution method. Their cytotoxic effects on NIH/3T3 mouse embryonic fibroblast cell line were determined using XTT assay. The most effective antimicrobial agents were investigated for their genotoxic effects using Ames MPF assay. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were also performed using Schrödinger’s Maestro molecular modeling package.

Results: The antifungal effects of the compounds were more significant than their antibacterial effects. Compound 5 bearing 3-nitrophenyl moiety was the most potent antifungal agent against Candida albicans, Trichoderma harzianum and Fusarium species, whereas compound 10 bearing 4- chloro-2-nitrophenyl moiety was the most effective antifungal agent on Aspergillus ochraceus. According to XTT and Ames MPF assays, these compounds were neither cytotoxic nor genotoxic at the concentrations tested. Docking studies suggested that these compounds showed good affinity to the active site of lanosterol 14α-demethylase (CYP51) (PDB code: 5V5Z) and interacted with the key residues such as Hem601 and Cys470. Based on in silico ADME studies, the compounds are expected to have high oral bioavailability.

Conclusion: According to the in vitro and in silico studies, compounds 5 and 10 stand out as potential orally bioavailable antifungal agents for further studies.

Keywords: Antimicrobial activity, cytotoxicity, furan, genotoxicity, hydrazone, molecular docking.

« Previous Next »
Graphical Abstract

[1]
Kaczor, A.A.; Polski, A.; Sobótka-Polska, K.; Pachuta-Stec, A.; Makarska-Bialokoz, M.; Pitucha, M. Novel antibacterial compounds and their drug targets - successes and challenges. Curr. Med. Chem., 2017, 24(18), 1948-1982.
[http://dx.doi.org/10.2174/0929867323666161213102127] [PMID: 27978802]
[2]
Simões, N.G.; Bettencourt, A.F.; Monge, N.; Ribeiro, I.A.C. Novel antibacterial agents: An emergent need to win the battle against infections. Mini Rev. Med. Chem., 2017, 17(14), 1364-1376.
[http://dx.doi.org/10.2174/1389557516666160907151454] [PMID: 27629996]
[3]
Gonzalez-Lara, M.F.; Sifuentes-Osornio, J.; Ostrosky-Zeichner, L. Drugs in clinical development for fungal infections. Drugs, 2017, 77(14), 1505-1518.
[http://dx.doi.org/10.1007/s40265-017-0805-2] [PMID: 28840541]
[4]
Liu, N.; Tu, J.; Dong, G.; Wang, Y.; Sheng, C. Emerging new targets for the treatment of resistant fungal infections. J. Med. Chem., 2018, 61(13), 5484-5511.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01413] [PMID: 29294275]
[5]
Mathew, B.; Suresh, J.; Ahsan, M.J.; Mathew, G.E.; Usman, D.; Subramanyan, P.N.; Safna, K.F.; Maddela, S. Hydrazones as a privileged structural linker in antitubercular agents: A review. Infect. Disord. Drug Targets, 2015, 15(2), 76-88.
[http://dx.doi.org/10.2174/1871526515666150724104411] [PMID: 26205803]
[6]
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.
[http://dx.doi.org/10.2174/092986712798918789] [PMID: 22204327]
[7]
Popiołek, Ł. Hydrazide-hydrazones as potential antimicrobial agents: Overview of the literature since 2010. Med. Chem. Res., 2017, 26(2), 287-301.
[http://dx.doi.org/10.1007/s00044-016-1756-y] [PMID: 28163562]
[8]
Kumar, P.; Narasimhan, B. Hydrazides/hydrazones as antimicrobial and anticancer agents in the new millennium. Mini Rev. Med. Chem., 2013, 13(7), 971-987.
[http://dx.doi.org/10.2174/1389557511313070003] [PMID: 23621689]
[9]
Rollas, S.; Küçükgüzel, S.G. Biological activities of hydrazone derivatives. Molecules, 2007, 12(8), 1910-1939.
[http://dx.doi.org/10.3390/12081910] [PMID: 17960096]
[10]
Masunari, A.; Tavares, L.C. A new class of nifuroxazide analogues: synthesis of 5-nitrothiophene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus. Bioorg. Med. Chem., 2007, 15(12), 4229-4236.
[http://dx.doi.org/10.1016/j.bmc.2007.03.068] [PMID: 17419064]
[11]
Guay, D.R. An update on the role of nitrofurans in the management of urinary tract infections. Drugs, 2001, 61(3), 353-364.
[http://dx.doi.org/10.2165/00003495-200161030-00004] [PMID: 11293646]
[12]
Altıntop, M.D.; Özdemir, A.; Turan-Zitouni, G.; Ilgın, S.; Atlı, Ö.; Demirci, F.; Kaplancıklı, Z.A. Synthesis and in vitro evaluation of new nitro-substituted thiazolyl hydrazone derivatives as anticandidal and anticancer agents. Molecules, 2014, 19(9), 14809-14820.
[http://dx.doi.org/10.3390/molecules190914809] [PMID: 25232704]
[13]
Altıntop, M.D.; Özdemir, A.; Turan-Zitouni, G.; Ilgın, S.; Atlı, Ö.; İşcan, G.; Kaplancıklı, Z.A. Synthesis and biological evaluation of some hydrazone derivatives as new anticandidal and anticancer agents. Eur. J. Med. Chem., 2012, 58, 299-307.
[http://dx.doi.org/10.1016/j.ejmech.2012.10.011] [PMID: 23142671]
[14]
Kaplancikli, Z.A.; Altintop, M.D.; Ozdemir, A.; Turan-Zitouni, G.; Goger, G.; Demirci, F. Synthesis and in vitro evaluation of some hydrazone derivatives as potential antibacterial agents. Lett. Drug Des. Discov., 2014, 11, 355-362.
[http://dx.doi.org/10.2174/15701808113109990030]
[15]
Özdemir, A.; Altıntop, M.D.; Sever, B.; Cantürk, Z.; Kaplancıklı, Z.A. Synthesis and evaluation of tetrazole-based hydrazone derivatives bearing a pyridine moiety as antimicrobial agents. Lett. Drug Des. Discov., 2015, 12, 687-693.
[http://dx.doi.org/10.2174/1570180812666150309235217]
[16]
Szulawska-Mroczek, A.; Szumilak, M.; Szczesio, M.; Olczak, A.; Nazarski, R.B.; Lewgowd, W.; Czyz, M.; Stanczak, A. Synthesis and biological evaluation of new bischromone derivatives with antiproliferative activity. Arch. Pharm. (Weinheim), 2013, 346(1), 34-43.
[http://dx.doi.org/10.1002/ardp.201200220] [PMID: 23109220]
[17]
Altıntop, M.D.; Kaplancıklı, Z.A.; Ciftçi, G.A.; Demirel, R. Synthesis and biological evaluation of thiazoline derivatives as new antimicrobial and anticancer agents. Eur. J. Med. Chem., 2014, 74, 264-277.
[http://dx.doi.org/10.1016/j.ejmech.2013.12.060] [PMID: 24480358]
[18]
Altıntop, M.D.; Atlı, Ö.; Ilgın, S.; Demirel, R.; Özdemir, A.; Kaplancıklı, Z.A. Synthesis and biological evaluation of new naphthalene substituted thiosemicarbazone derivatives as potent antifungal and anticancer agents. Eur. J. Med. Chem., 2016, 108, 406-414.
[http://dx.doi.org/10.1016/j.ejmech.2015.11.041] [PMID: 26706351]
[19]
Altıntop, M.D.; Özdemir, A.; Atlı, Ö.; Cantürk, Z.; Baysal, M.; Kaplancıklı, Z.A. Synthesis and evaluation of new thiazole derivatives as potential antimicrobial agents. Lett. Drug Des. Discov., 2016, 13, 903-911.
[http://dx.doi.org/10.2174/1570180813666160226001021]
[20]
Flückiger-Isler, S.; Kamber, M. Direct comparison of the Ames microplate format (MPF) test in liquid medium with the standard Ames pre-incubation assay on agar plates by use of equivocal to weakly positive test compounds. Mutat. Res., 2012, 747(1), 36-45.
[http://dx.doi.org/10.1016/j.mrgentox.2012.03.014] [PMID: 22579797]
[21]
Van Den Driessche, G.; Fourches, D. Adverse drug reactions triggered by the common HLA-B*57:01 variant: A molecular docking study. J. Cheminform., 2017, 9, 13.
[http://dx.doi.org/10.1186/s13321-017-0202-6] [PMID: 28303164]
[22]
Sheehan, D.J.; Hitchcock, C.A.; Sibley, C.M. Current and emerging azole antifungal agents. Clin. Microbiol. Rev., 1999, 12(1), 40-79.
[http://dx.doi.org/10.1128/CMR.12.1.40] [PMID: 9880474]
[23]
Sagatova, A.A.; Keniya, M.V.; Wilson, R.K.; Monk, B.C.; Tyndall, J.D. Structural insights into binding of the antifungal drug fluconazole to Saccharomyces cerevisiae lanosterol 14α-demethylase. Antimicrob. Agents Chemother., 2015, 59(8), 4982-4989.
[http://dx.doi.org/10.1128/AAC.00925-15] [PMID: 26055382]

Rights & Permissions Print Cite
Article Metrics
31
4
© 2024 Bentham Science Publishers | Privacy Policy