Synthesis and Antimicrobial Evaluation of New 1,2,4-Triazolo[1,5- a]pyrimidine-Based Derivatives as Dual Inhibitors of Bacterial DNA Gyrase and DHFR

Lamya H Al-Wahaibi; Safwat M Rabea; Mohamed A Mahmoud; Bahaa G M Youssif; Stefan Bräse; Salah A Abdel-Aziz

doi:10.1021/acsomega.4c08365

Synthesis and Antimicrobial Evaluation of New 1,2,4-Triazolo[1,5- a]pyrimidine-Based Derivatives as Dual Inhibitors of Bacterial DNA Gyrase and DHFR

ACS Omega. 2024 Nov 11;9(47):47261-47273. doi: 10.1021/acsomega.4c08365. eCollection 2024 Nov 26.

Authors

Lamya H Al-Wahaibi¹, Safwat M Rabea², Mohamed A Mahmoud³, Bahaa G M Youssif³, Stefan Bräse⁴, Salah A Abdel-Aziz^{5

6}

Affiliations

¹ Department of Chemistry, College of Sciences, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia.
² Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
³ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
⁴ Institute of Biological and Chemical Systems, IBCS-FMS, Karlsruhe Institute of Technology, Karlsruhe 76131, Germany.
⁵ Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Boys), Al-Azhar University, Assiut 71524, Egypt.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, Minia 61519, Egypt.

Abstract

A series of 1,2,4-triazolo[1,5-a]pyrimidine-based derivatives were developed and prepared by reacting chalcones 8a-p with 3-phenyl-1,2,4-triazole-5-amine (5). The novel compounds were analyzed using several spectroscopic techniques, and their antimicrobial efficacies against six pathogens (Gram-negative, Gram-positive, and fungi) were tested. Most of the tested compounds exhibited significant antimicrobial activity compared to ciprofloxacin and fluconazole. Four compounds (9d, 9n, 9o, and 9p) showed promising results. Their minimal inhibitory concentration (MIC) values were between 16 and 102 μM, similar to ciprofloxacin's 10-90 μM values. MIC values against the tested fungal species were between 15.50 and 26.30 μM, higher than fluconazole's 11.50-17.50 μM values. Compounds 9n and 9o, in particular, showed excellent bactericidal activity. Compounds 9n and 9o, the most effective antibacterial agents, were further evaluated for their inhibitory effects on bacterial DNA gyrase and DHFR enzymes as possible molecular targets. The results indicated that 9n and 9o demonstrated a similar level of activity against DNA gyrase and DHFR when compared to the reference drugs ciprofloxacin and trimethoprim. We conducted molecular docking to investigate the binding mechanism and evaluate the reactivity of the intriguing compounds. Compounds 9n and 9o demonstrated favorable binding interactions with the essential amino acids necessary for the inhibition of E. coli DNA gyrase and DHFR enzymes.