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Synthesis, structure elucidation, and antifungal potential of certain new benzodioxole–imidazole molecular hybrids bearing ester functionalities

Authors Al-Wabli RI, Al-Ghamdi AR, Ghabbour HA, Al-Agamy MH, Attia MI

Received 21 December 2018

Accepted for publication 29 January 2019

Published 26 February 2019 Volume 2019:13 Pages 775—789

DOI https://doi.org/10.2147/DDDT.S199135

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 2

Editor who approved publication: Dr Anastasios Lymperopoulos


Reem I Al-Wabli,1 Alwah R Al-Ghamdi,1 Hazem A Ghabbour,2 Mohamed H Al-Agamy,3,4 Mohamed I Attia1,5

1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 2Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; 3Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 4Microbiology and Immunology Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt; 5Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza 12622, Egypt

Background: The incidence of fungal infections is a growing serious global health burden. There is an urgent medical demand to acquire new antifungal drug-like compounds having azole nuclei to get rid of the drawbacks of the currently available azole antifungal agents.
Methods: The target compounds 5a-r were synthesized in a four-step reaction sequence using the appropriate acetophenone derivative as a starting material. The antifungal potential of the title compounds was assessed using DIZ and MIC assays according to the reported standard procedures.
Results: The newly synthesized oximino esters 5a-r were identified with the aid of various spectroscopic approaches. Their assigned chemical structures were confirmed via single-crystal X-ray structure of compound 5o. The molecular structure of compound 5o was crystallized in the triclinic, P-1, a=9.898 (3) Å, b=10.433 (3) Å, c=11.677 (4) Å, α=86.886 (6)°, β=87.071 (7)°, γ=64.385 (6)°, V=1,085.2 (6) Å3, Z=2. The synthesized compounds 5a-r were in vitro evaluated for antifungal potential against four fungal strains. Compounds 5l and 5m bearing a trifluoromethylphenyl moiety showed the best anti-Candida albicans activity with minimum inhibitory concentration (MIC) value of 0.148 µmol/mL, while compound 5b displayed the best activity toward Candida tropicalis with MIC value of 0.289 µmol/mL. Compounds 5o and 5l were the most active congeners against Candida parapsilosis and Aspergillus niger, respectively.
Conclusion: Single-crystal X-ray analysis of compound 5o confirmed without doubt the assigned chemical structures of the title compounds as well as confirmed the (E)-configuration of their oximino group. Compounds 5b, 5l, 5m, and 5o emerged as the most active compounds against the tested fungi and they could be considered as new antifungal lead candidates.

Keywords: crystal structure, imidazole, benzodioxole, ester, antifungal

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