Synthesis and Antifungal Potential of Some Novel Benzimidazole-1,3,4-Oxadiazole Compounds.

Ahmet Çağrı Karaburun,Begüm Nurpelin Sağlık,Zafer Asım Kaplancıklı,Derya Osmaniye,Betül Kaya Çavuşoğlu,Ulviye Acar Çevik,Ali Savaş Koparal,Yusuf Özkay,Özlem Atlı,Serkan Levent

doi:10.3390/molecules24010191

Ahmet Çağrı Karaburun, Begüm Nurpelin Sağlık + Show 8 more

Open Access

https://doi.org/10.3390/molecules24010191

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Abstract

Discovery of novel anticandidal agents with clarified mechanisms of action, could be a rationalist approach against diverse pathogenic fungal strains due to the rise of resistance to existing drugs. In support to this hypothesis, in this paper, a series of benzimidazole-oxadiazole compounds were synthesized and subjected to antifungal activity evaluation. In vitro activity assays indicated that some of the compounds exhibited moderate to potent antifungal activities against tested Candida species when compared positive control amphotericin B and ketoconazole. The most active compounds 4h and 4p were evaluated in terms of inhibitory activity upon ergosterol biosynthesis by an LC-MS-MS method and it was determined that they inhibited ergosterol synthesis concentration dependently. Docking studies examining interactions between most active compounds and lanosterol 14-α-demethylase also supported the in vitro results.

Highlights

The treatment of fungal infections continues to be a thought-provoking problem worldwide
The reaction sequences followed for the synthesis of the final compounds 4a–4n are outlined in Scheme 1
The ring closure reaction of the corresponding hydrazide 2 with carbon disulfide in the presence of sodium hydroxide resulted in the formation of 5-(4-(1H-benzimidazol-2-yl)phenyl)-1,3,4-oxadiazole-2-thiol (3), which was reacted with suitable substituted phenacyl bromides to obtain the target compounds

Summary

Introduction

The treatment of fungal infections continues to be a thought-provoking problem worldwide. Such infections vary in severity from superficial to complex fungal infections and most commonly affect immunocompromised patients [1]. In the past the affected patients have used numerous antibiotics and synthetic drugs, mostly without precautions, which has led to antifungal resistance to prescribed agents, the high morbidity and mortality caused by fungi are still increasing serious threat [2]. Since current antifungals do not meet the growing requirements of managing with life threatening infections, medicinal chemists are highlighting the need for the search of novel antifungal drugs. Protein, sterols and cell wall are known targets of the current agents in antifungal therapy [3]. The introduction of polyene antifungals, such as amphotericin B, became a milestone in clinic, infusional toxicity, nephrotoxicity and electrolyte imbalances limited its usage [4,5]

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