Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Design and Synthesis of New Antifungals Based on N-Un-substituted Azoles as 14α Demethylase Inhibitor

Author(s): Asghar Davood*, Aneseh Rahimi, Maryam Iman, Parisa Azerang, Soroush Sardari and Arash Mahboubi

Volume 17, Issue 2, 2021

Published on: 17 February, 2020

Page: [235 - 243] Pages: 9

DOI: 10.2174/1573409916666200217090855

Price: $65

Abstract

Objective: Azole antifungal agents, which are widely used as antifungal antibiotics, inhibit cytochrome P450 sterol 14α-demethylase (CYP51). Nearly all azole antifungal agents are Nsubstituted azoles. In addition, an azolylphenalkyl pharmacophore is uniquely shared by all azole antifungals. Due to the importance of nitrogen atom of azoles (N-3 of imidazole and N-4 of triazole) in coordination with heme in the binding site of the enzyme, here a group of N- un-substituted azoles in which both nitrogen are un-substituted was reported.

Materials and Methods: Designed compounds were synthesized by the reaction of imidazole-4- carboxaldehyde with appropriate arylamines and subsequently reduced to desired amine derivatives. Antifungal activity against Candida albicans and Saccharomyces cervisiae was done using a broth micro-dilution assay. Docking studies were done using AutoDock.

Results: Antimicrobial evaluation revealed that some of these compounds exhibited moderate antimicrobial activities against tested pathogenic fungi, wherein compounds 3, 7, and 8 were potent. Docking studies propose that all of the prepared azoles interacted with 14α-DM, wherein azoleheme coordination played the main role in drug-receptor interaction.

Conclusion: Our results offer some useful references for molecular design performance or modification of this series of compounds as a lead compound to discover new and potent antimicrobial agents.

Keywords: Antifungal, azole, docking, imidazole, 14α demethylase, imidazole-4- carboxaldehyde.

« Previous Next »
Graphical Abstract

[1]
Sheriff, M.J.; Krebs, C.J.; Boonstra, R. The sensitive hare: sublethal effects of predator stress on reproduction in snowshoe hares. J. Anim. Ecol., 2009, 78(6), 1249-1258.
[http://dx.doi.org/10.1111/j.1365-2656.2009.01552.x] [PMID: 19426257]
[2]
Joseph-Horne, T.; Hollomon, D.W. Molecular mechanisms of azole resistance in fungi. FEMS Microbiol. Lett., 1997, 149(2), 141-149.
[http://dx.doi.org/10.1111/j.1574-6968.1997.tb10321.x] [PMID: 9141655]
[3]
[Vanden Bossche H, Dromer F, Improvisi I, Lozano-Chiu M, Rex JH, Sanglards D. Antifungal Drug Resistance in Aspergillus. Med. Mycol., 1998, 36, 119-128.
[4]
Marichal, P. Mechanisms of resistance to azole antifungal compounds. Curr Opin Anti-Infect Invest Drugs., 1999, 1, 318-333.
[5]
Whaley, S.G.; Berkow, E.L.; Rybak, J.M.; Nishimoto, A.T.; Barker, K.S.; Rogers, P.D. Azole antifungal resistance in candida albicans and emerging non-albicans Candida Species. Front. Microbiol., 2017, 7, 2173.
[http://dx.doi.org/10.3389/fmicb.2016.02173] [PMID: 28127295]
[6]
Riat, A.; Plojoux, J.; Gindro, K.; Schrenzel, J.; Sanglard, D. Azole resistance of environmental and clinical aspergillus fumigatus isolates from Switzerland. Antimicrob. Agents Chemother., 2018, 62(4), e02088-e17.
[http://dx.doi.org/10.1128/AAC.02088-17] [PMID: 29437612]
[7]
Verweij, P.E.; Chowdhary, A.; Melchers, W.J.; Meis, J.F. Azole resistance in aspergillus fumigatus: Can we retain the clinical use of Mold-Active antifungal azoles? Clin. Infect. Dis., 2016, 62(3), 362-368.
[http://dx.doi.org/10.1093/cid/civ885] [PMID: 26486705]
[8]
Zoran, T.; Sartori, B.; Sappl, L.; Aigner, M.; Sánchez-Reus, F.; Rezusta, A.; Chowdhary, A.; Taj-Aldeen, S.J.; Arendrup, M.C.; Oliveri, S.; Kontoyiannis, D.P.; Alastruey-Izquierdo, A.; Lagrou, K.; Cascio, G.L.; Meis, J.F.; Buzina, W.; Farina, C.; Drogari-Apiranthitou, M.; Grancini, A.; Tortorano, A.M.; Willinger, B.; Hamprecht, A.; Johnson, E.; Klingspor, L.; Arsic-Arsenijevic, V.; Cornely, O.A.; Meletiadis, J.; Prammer, W.; Tullio, V.; Vehreschild, J.J.; Trovato, L.; Lewis, R.E.; Segal, E.; Rath, P.M.; Hamal, P.; Rodriguez-Iglesias, M.; Roilides, E.; Arikan-Akdagli, S.; Chakrabarti, A.; Colombo, A.L.; Fernández, M.S.; Martin-Gomez, M.T.; Badali, H.; Petrikkos, G.; Klimko, N.; Heimann, S.M.; Uzun, O.; Roudbary, M.; de la Fuente, S.; Houbraken, J.; Risslegger, B.; Lass-Flörl, C.; Lackner, M. Azole-resistance in aspergillus terreus and related Species: An emerging problem or a rare phenomenon? Front. Microbiol., 2018, 9, 516.
[http://dx.doi.org/10.3389/fmicb.2018.00516] [PMID: 29643840]
[9]
Seyedmousavi, S.; Mouton, J.W.; Melchers, W.J.; Verweij, P.E. Posaconazole prophylaxis in experimental azole-resistant invasive pulmonary aspergillosis. Antimicrob. Agents Chemother., 2015, 59(3), 1487-1494.
[http://dx.doi.org/10.1128/AAC.03850-14] [PMID: 25534731]
[10]
Berger, S.; El Chazli, Y.; Babu, A.F.; Coste, A.T. Azole resistance in aspergillus fumigatus: A consequence of antifungal use in agriculture? Front. Microbiol., 2017, 8, 1024.
[http://dx.doi.org/10.3389/fmicb.2017.01024] [PMID: 28638374]
[11]
Iman, M.; Davood, A. Homology modeling of lanosterol 14α-demethylase of Candida albicans and insights into azole binding. Med. Chem. Res., 2014, 23, 2890-2899.
[http://dx.doi.org/10.1007/s00044-013-0769-z]
[12]
Iman, M; Davood, A; Gebbink, BK; Azerang, P Design and antimicrobial evaluation of 1-Methylimidazole derivatives as new antifungal and antibacterial agents 2014, 48, 513-519.
[13]
Pore, V.S.; Agalave, S.G.; Singh, P.; Shukla, P.K.; Kumar, V.; Siddiqi, M.I. Design and synthesis of new fluconazole analogues. Org. Biomol. Chem., 2015, 13(23), 6551-6561.
[http://dx.doi.org/10.1039/C5OB00590F] [PMID: 25975803]
[14]
Saha, A.K.; Liu, L.; Simoneaux, R.L.; Kukla, M.J.; Marichal, P.; Odds, F. Novel antifungals based on 4-substituted imidazole: a combinatorial chemistry approach to lead discovery and optimization. Bioorg. Med. Chem. Lett., 2000, 10(19), 2175-2178.
[http://dx.doi.org/10.1016/S0960-894X(00)00445-5] [PMID: 11012023]
[15]
Saha, A.K.; Liu, L.; Marichal, P.; Odds, F. Novel antifungals based on 4-substituted imidazole: solid-phase synthesis of substituted aryl sulfonamides towards optimization of in vitro activity. Bioorg. Med. Chem. Lett., 2000, 10(24), 2735-2739.
[http://dx.doi.org/10.1016/S0960-894X(00)00551-5] [PMID: 11133080]
[16]
Galley, G.; Goergler, A.; Zbinden, K.G.; Norcross, R.; Stalder, H. Aminomethyl-4-imidazoles US patent 0119535 A1, 2008.
[17]
Abdel-Magid, A.F.; Carson, K.G.; Harris, B.D.; Maryanoff, C.A.; Shah, R.D. Reductive amination of aldehydes and ketones with sodium triacetoxyborohydride. studies on direct and indirect reductive amination procedures. J. Org. Chem., 1996, 61(11), 3849-3862.
[http://dx.doi.org/10.1021/jo960057x] [PMID: 11667239]
[18]
Davood, A; Iman, M. Med. Chem. Res., Docking and QSAR studies of β -phenylethylidenehydrazine derivatives as a Gammaaminobutyric acid aminotransferase inhibitor. 2011, 20, 955-961.
[19]
Davood, A.; Iman, M. Molecular docking and QSAR study on imidazole derivatives as 14/alpha -demethylase inhibitors. Turk. J. Chem., 2013, 37, 119-133.
[20]
Davood, A.; Iman, M.; Nematollahi, A.; Shafiee, A. Docking and QSAR studies of new 1,4-dihydropyridines containing 4(5)-chloro-2-methyl-5(4)-imidazolyl substituent. Med. Chem. Res., 2012, 21(3), 325-332.
[http://dx.doi.org/10.1007/s00044-010-9515-y]
[21]
Davood, A.; Nematollahi, A.; Iman, M.; Shafiee, A. Computational studies of new 1, 4-dihydropyridines containing 4-(5)-chloro-2-ethyl-5-(4)-imidazolyl substituent: QSAR and docking. Med. Chem. Res., 2010, 19, 58-70.
[http://dx.doi.org/10.1007/s00044-009-9171-2]
[22]
Iman, M.; Davood, A.; Nematollahi, A.R.; Dehpoor, A.R.; Shafiee, A. Design and synthesis of new 1,4-dihydropyridines containing 4(5)-chloro-5(4)-imidazolyl substituent as a novel calcium channel blocker. Arch. Pharm. Res., 2011, 34(9), 1417-1426.
[http://dx.doi.org/10.1007/s12272-011-0902-9] [PMID: 21975802]
[23]
Iman, M.; Davood, A.; Dehqani, G.; Lotfinia, M.; Sardari, S.; Azerang, P.; Amini, M. Design, Synthesis and Evaluation of Antitubercular Activity of Novel Dihydropyridine Containing Imidazolyl Substituent. Iran. J. Pharm. Res., 2015, 14(4), 1067-1075.
[PMID: 26664373]
[24]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[25]
Wallace, A.C.; Laskowski, R.A.; Thornton, J.M. LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng., 1995, 8(2), 127-134.
[http://dx.doi.org/10.1093/protein/8.2.127] [PMID: 7630882]
[26]
Wayne, P. Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard. NCCLS document M27-A. National committee for clinical laboratory standards 1997.
[27]
Kirkpatrick, W.R.; McAtee, R.K.; Revankar, S.G.; Fothergill, A.W.; McCarthy, D.I.; Rinaldi, M.G.; Patterson, T.F. Comparative evaluation of National Committee for Clinical Laboratory Standards broth macrodilution and agar dilution screening methods for testing fluconazole susceptibility of Cryptococcus neoformans. J. Clin. Microbiol., 1998, 36(5), 1330-1332.
[http://dx.doi.org/10.1128/JCM.36.5.1330-1332.1998] [PMID: 9574699]

Rights & Permissions Print Cite
Article Metrics
23
2
© 2024 Bentham Science Publishers | Privacy Policy