New Phenylthiazoles: Design, Synthesis, and Biological Evaluation as Antibacterial, Antifungal, and Anti‐COVID‐19 Candidates

Abstract

The combination of antibacterial and antiviral agents is becoming a very important aspect of dealing with resistant bacterial and viral infections. The N‐phenylthiazole scaffold was found to possess significant anti‐MRSA, antifungal, and anti‐COVID‐19 activities as previously published; hence, a slight refinement was proposed to attach various alkyne lipophilic tails to this promising scaffold, to investigate their effects on the antimicrobial activity of the newly synthesized compounds and to provide a valuable structure–activity relationship. Phenylthiazole 4 m exhibited the most potent anti‐MRSA activity with 8 μg/mL MIC value. Compounds 4 k and 4 m demonstrated potent activity against Clostridium difficile with MIC values of 2 μg/mL and moderate activity against Candida albicans with MIC value of 4 μg/mL. When analyzed for their anti‐COVID‐19 inhibitory effect, compound 4 b emerged with IC50=1269 nM and the highest selectivity of 138.86 and this was supported by its binding score of −5.21 kcal mol−1 when docked against SARS‐CoV‐2 M pro. Two H‐bonds were formed, one with His164 and the other with Met49 stabilizing phenylthiazole derivative 4 b, inside the binding pocket. Additionally, it created two arene‐H bonds with Asn142 and Glu166, through the phenylthiazole scaffold and one arene‐H bond with Leu141 via the phenyl ring of the lipophilic tail.

Synthesis of Some New Azole Derivatives as Antibacterial Agents

“…While they showed anti-biofilm activity, the poor permeability of the early phenylthiazoles likely contributed to their narrow spectrum (Eid, Elsebaei et al 2017, Helal, Sayed et al 2019, Mancy, Abutaleb et al 2019, Elsebaie, El-Din et al 2022, Sayed, Abutaleb et al 2023. Consequently, changes to the tail led to the third generation, which showed intracellular effectiveness but required further optimization of the metabolic profile(El-Din, , Omara, Hagras et al 2023, Shahin, Mohamed et al 2023, Elbakry, Harras et al 2024). This study delves deeper into scaffold modifications to elucidate their influence on activity against various microbial organisms and expands our understanding of the structure-activity relationship within this promising class of antibacterial agents.…”