Harnessing the superiority of pyrimidines, pyrazoles and thiazoles: Design and synthesis of naphthyl amide-based scaffolds as potent antimicrobial agents

Abstract

Microbial resistance poses a significant global health challenge, with nearly 700,000 annual deaths and a projected economic burden of $100 trillion by 2050. Herein, a novel series of naphthalene-based pyrazole, thiazole and pyrimidine-one/thione scaffolds were designed and synthesized from the reaction of N-naphthylen-1-yl-3-oxo-3-phenylpropionamide (1) with phenyl isothiocyanate that gives the mercapto-derivative, which reacted with different amine and halo carbonyl compounds to afford the target pyrazole 5, pyrimidines 7a,b and thiazoles 10–13 scaffolds. Their structures were verified utilizing IR, ¹H NMR, ¹³C NMR, MS and elemental analysis. The new compounds were evaluated as antimicrobials against four bacterial strains and two fungal strains. The results demonstrated various inhibitory effects on bacterial and fungal growth, with excellent MICs compared to the reference drugs chloramphenicol and clotrimazole. Among the examined compounds, the pyrimidinone derivative 7b and thiazole derivative 13 highlighted a broad-spectrum activity against both Gram-positive and Gram-negative bacteria and fungi, suggesting their potential as antibacterial and antifungal inhibitors. Additionally, compound 7b demonstrated superior broad-spectrum antimicrobial activity, with MIC values of 0.625–10 mg/mL. In addition, In-silico molecular modeling studies were conducted. vROCS exhibited that the tested compounds are likely to share a similar 3D spatial arrangement of atoms. Also, FRED docking results displayed an excellent fitting of 7b to the binding pocket of DNA gyrase and CYP51 with FRED Chemgauss4 scores of -12.50 and -10.98, respectively. Moreover, 7b met the Pfizer ADMET criteria. Overall, these findings suggest that 7b possesses promising broad-spectrum antimicrobial properties that warrant further investigation for clinical applications.