Evaluation of Antimicrobial Activity of Some Hybrids of Pyrimidine-Azole Derivatives along with Molecular docking study

Document Type : Original Article


1 Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

2 Department of Medical Mycology and Parasitology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

3 Basic Researches in Infectious Diseases Center, Shiraz University of Medical Sciences, Shiraz, Iran

4 Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran



Despite extensive research on antimicrobial drugs, efforts to find suitable alternatives to older drugs have not been very successful yet, due to microbial resistance. Heterocycles including azole and pyrimidine derivatives were used to design antimicrobial activity in this research, 12 novel pyrimidine-azole derivatives (3a-3l) that were previously synthesized were screened for their antibacterial and antifungal activities by using CLSI standard method. In this study, we used four species of bacteria, seven species of fungi, and five species of yeast. Molecular docking studies were also performed to investigate their binding mode and orientation toward lanosterol 14-α- demethylase (CYP51), as a plausible mechanism of azole antifungal compounds. The biological results showed that none of the compounds had antibacterial and antifungal effects compared to the control drugs. The molecular docking study showed that the compounds had a low binding affinity in the active site of the lanosterol 14-α- demethylase target, which confirmed the weak antifungal and antibacterial activities of these compounds.


Leila Emami (Google Scholar)

Razieh Sabet (Google Scholar)


1.    Masiá Canuto M, Gutiérrez Rodero F. Antifungal drug resistance to azoles and polyenes. Lancet Infect Dis. 2002 Sep;2(9):550-63. doi: 10.1016/s1473-3099(02)00371-7. PMID: 12206971.
2.    Arastehfar A, Gabaldón T, Garcia-Rubio R, Jenks JD, Hoenigl M, Salzer HJF, et al. Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium. Antibiotics (Basel). 2020 Dec 8;9(12):877. doi: 10.3390/antibiotics9120877. PMID: 33302565; PMCID: PMC7764418.
3.    Sui YF, Li D, Wang J, Bheemanaboina RRY, Ansari MF, Gan LL, et al. Design and biological evaluation of a novel type of potential multi-targeting antimicrobial sulfanilamide hybrids in combination of pyrimidine and azoles. Bioorg Med Chem Lett. 2020 Mar 15;30(6):126982. doi: 10.1016/j.bmcl.2020.126982. Epub 2020 Jan 20. PMID: 32001137.
4.    Eze CC, Ezeokonkwo AM, Ugwu ID, Eze UF, Onyeyilim EL, Attah IS, et al. Azole-Pyrimidine Hybrid Anticancer Agents: A Review of Molecular Structure, Structure Activity Relationship, and Molecular Docking. Anticancer Agents Med Chem. 2022 Aug 4;22(16):2822-2851. doi: 10.2174/1871520622666220318090147. PMID: 35306990.
5.    Bheemanaboina RRY, Wang J, Hu YY, Meng JP, Guan Z, Zhou CH. A facile reaction to access novel structural sulfonyl-hybridized imidazolyl ethanols as potential DNA-targeting antibacterial agents. Bioorg Med Chem Lett. 2021 Sep 1;47:128198. doi: 10.1016/j.bmcl.2021.128198. Epub 2021 Jun 10. PMID: 34119615.
6.    Shafiei M, Peyton L, Hashemzadeh M, Foroumadi A. History of the development of antifungal azoles: A review on structures, SAR, and mechanism of action. Bioorg Chem. 2020 Nov;104:104240. doi: 10.1016/j.bioorg.2020.104240. Epub 2020 Aug 28. PMID: 32906036.
7.    Beck KR, Telisman L, van Koppen CJ, Thompson GR 3rd, Odermatt A. Molecular mechanisms of posaconazole- and itraconazole-induced pseudohyperaldosteronism and assessment of other systemically used azole antifungals. J Steroid Biochem Mol Biol. 2020 May;199:105605. doi: 10.1016/j.jsbmb.2020.105605. Epub 2020 Jan 23. PMID: 31982514.
8.    Amr Ael-G, Sayed HH, Abdulla MM. Synthesis and reactions of some new substituted pyridine and pyrimidine derivatives as analgesic, anticonvulsant and antiparkinsonian agents. Arch Pharm (Weinheim). 2005 Sep;338(9):433-40. doi: 10.1002/ardp.200500982. PMID: 16134091.
9.    Alam O, Mullick P, Verma SP, Gilani SJ, Khan SA, Siddiqui N, et al. Synthesis, anticonvulsant and toxicity screening of newer pyrimidine semicarbazone derivatives. Eur J Med Chem. 2010 Jun;45(6):2467-72. doi: 10.1016/j.ejmech.2010.02.031. Epub 2010 Feb 18. PMID: 20211511.
10.    Cieplik J, Stolarczyk M, Pluta J, Gubrynowicz O, Bryndal I, Lis T, et al. Synthesis and antibacterial properties of pyrimidine derivatives. Acta Pol Pharm. 2011 Jan-Feb;68(1):57-65. PMID: 21485702.
11.    Zhuang J, Ma S. Recent Development of Pyrimidine-Containing Antimicrobial Agents. ChemMedChem. 2020 Oct 19;15(20):1875-1886. doi: 10.1002/cmdc.202000378. Epub 2020 Sep 11. PMID: 32797654.
12.    Wu W, Lan W, Wu C, Fei Q. Synthesis and Antifungal Activity of Pyrimidine Derivatives Containing an Amide Moiety. Front Chem. 2021 Jul 12;9:695628. doi: 10.3389/fchem.2021.695628. PMID: 34322475; PMCID: PMC8311460.
13.    Khan S, Kale M, Siddiqui F, Nema N. Novel pyrimidine-benzimidazole hybrids with antibacterial and antifungal properties and potential inhibition of SARS-CoV-2 main protease and spike glycoprotein. Digit Chin Med. 2021;4(2):102-19.
14.    Basha J, Goudgaon NM. A comprehensive review on pyrimidine analogs-versatile scaffold with medicinal and biological potential. J Mol Struct. 2021;1246:131168.
15.    Vaou N, Stavropoulou E, Voidarou C, Tsigalou C, Bezirtzoglou E. Towards Advances in Medicinal Plant Antimicrobial Activity: A Review Study on Challenges and Future Perspectives. Microorganisms. 2021 Sep 27;9(10):2041. doi: 10.3390/microorganisms9102041. PMID: 34683362; PMCID: PMC8541629.
16.    Desai NC, Vaghani HV, Jethawa AM, Khedkar VM. In silico molecular docking studies of oxadiazole and pyrimidine bearing heterocyclic compounds as potential antimicrobial agents. Arch Pharm (Weinheim). 2021 Oct;354(10):e2100134. doi: 10.1002/ardp.202100134. Epub 2021 Jun 24. PMID: 34169569.
17.    Desai D, Shende P. Drug-free cyclodextrin-based nanosponges for antimicrobial activity. J Pharm Innov. 2021;16:258-68.
18.    He GX, Xue LW. Synthesis, Structures, and Antibacterial Activities of Hydrazone Compounds Derived from 4-Dimethylaminobenzohydrazide. Acta Chim Slov. 2021 Sep;68(3):567-574. PMID: 34897529.
19.    Barzegar F. Design, synthesis and docking studies of pyrimidine-azole hybrid derivatives (I) as anti-fungal and anti-bacterial agent [Thesis]. Shiraz: Shiraz University of Medical Sciences, Faculty of Pharmacy; 1400.
20.    Madadelahi ardekani Sedighe, Design, synthesis and docking studies of pyrimidine-azole hybrid derivatives (II) as anti-fungal and anti-bacterial agent [Thesis]. Shiraz: Shiraz University of Medical Sciences, Faculty of Pharmacy; 1401.
21.    Onar HÇ, Kara EM, Ceyhan D, Erçağ E. Molecular Docking Studies and Microbial Activities of Mono-, Di-and Tri-Substituted Simple Coumarins. European Journal of Advanced Chemistry Research. 2023;4(1):22-30.
22.    Zare F, Solhjoo A, Sadeghpour H, Sakhteman A, Dehshahri A. Structure-based virtual screening, molecular docking, molecular dynamics simulation and MM/PBSA calculations towards identification of steroidal and non-steroidal selective glucocorticoid receptor modulators. J Biomol Struct Dyn. 2023 Sep-Oct;41(16):7640-7650. doi: 10.1080/07391102.2022.2123392. Epub 2022 Sep 22. PMID: 36134594.
23.    Siva S, Li C, Cui H, Meenatchi V, Lin L. Encapsulation of essential oil components with methyl-β-cyclodextrin using ultrasonication: Solubility, characterization, DPPH and antibacterial assay. Ultrason Sonochem. 2020 Jun;64:104997. doi: 10.1016/j.ultsonch.2020.104997. Epub 2020 Feb 7. PMID: 32058914.
24.    Aljamali D, Mahmood N, Jawad SF. Preparation, spectral characterization, thermal study, and antifungal assay of (Formazane-Mefenamic acid)-Derivatives. Egypt J Chem. 2022;65(2):449-57.