Current Topics in Medicinal Chemistry - Volume 24, Issue 26, 2024

In this review, we have summarized antifungal agents containing potent azole analogues.

The provided literature is related to the development and application of azole derivatives and has been accessed from electronic data bases such as Science direct, Google Scholar, and Pubmed using keywords such as “design, synthesis and evaluation”, “azole hybrids”, “diazole hybrids”, “indazole derivatives”, “imidazole derivatives”, “triazole derivatives”, “tetrazole derivatives” and related combinations.

From this review, it was identified that azole derivatives with promising antifungal activity play a vital role in drug discovery and development. The literature revealed that azole derivatives can effectively fight several types of microorganisms, such as Candida albicans, Aspergillus niger, and others. The rational design and structure‒activity relationship of these compounds are discussed in this paper, highlighting their potential as effective therapeutic options against various fungal pathogens. Moreover, this work addresses the challenges and future directions in the development of azole hybrids. The results of docking studies of several of the hybrids that the researchers provided are also summarized.

The current work attempts to review such innovations, which may lead to the preparation of novel therapeutics. More research is required to confirm their safety and effectiveness in clinical practices.

For cell wall biosynthesis, drug-resistant S. aureus uses a special protein called PBP2a, even when antibiotics are present and stop its natural processes from working. To combat this, novel therapies are required to specifically target PBP2a with greater efficacy.

Using computational approaches, we screened nine phenolic compounds from other Bergenia species, including Bergenia ciliata, Begenia ligulata, Bergenia purpurascens, and Bergenia stracheyi, against the PBP2a allosteric site to explore the potential interaction between phenolic compounds and a specific region of PBP2a known as the allosteric site.

Based on interaction patterns and estimated affinity, vitexin has been found to be the most prominent phenolic compound. We performed MD simulations on vitexin and ceftazidime as control molecules based on the docking results. The binding free energy estimates of vitexin 
(-94.48 +/- 17.92 kJ/mol) using MM/PBSA were lower than those of the control (-67.61 +/- 12.29 kJ/mol), which suggests that vitexin may be able to inhibit PBP2a activity in MRSA.

It has been intriguing to observe a correlation between the affinity of the lead vitexin at the allosteric site and the modification of Tyr446, the active site gatekeeper residue in PBP2a. Our findings have implied that lead vitexin can either directly or indirectly decrease PBP2a activity by inducing allosteric site change in conventional medicine.