Identification of novel pyrazole and benzimidazole based derivatives as PBP2a inhibitors: Design, synthesis, and biological evaluation

Shalaby, Menna-Allah W.; Dokla, Eman M.E.; Serya, Rabah A. T.; Abouzid, Khaled A. M.

doi:10.21608/aps.2019.16625.1010

Identification of novel pyrazole and benzimidazole based derivatives as PBP2a inhibitors: Design, synthesis, and biological evaluation

Document Type : Original Article

Authors

¹ Pharmaceutical Chemistry Department Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt.

² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt

³ Dean Faculty of Pharmacy, Sadat University in Egypt, Professor of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo 11566, Egypt

10.21608/aps.2019.16625.1010

Abstract

The antibiotic resistance of methicillin-resistant Staphylococcus aureus (MRSA) is attributable to the expression of the high molecular mass transpeptidase enzyme, penicillin-binding protein 2a (PBP2a), an enzyme that catalyzes the cross-linking reaction step in the cell wall biosynthesis in the face of the challenge by β-lactam antibiotics. In the current study, ten pyrazole and benzimidazole based-compounds were designed, synthesized, and evaluated as anti-MRSA agents. These derivatives were screened for their antibacterial activity against two Staphylococcus (S.) aureus strains; methicillin-sensitive Staphylococcus aureus (MSSA) ATTC6538 and MRSA USA300 strains. Three of the tested compounds (XII, XIII, and XIV) exhibited moderate bactericidal activity against MSSA, MRSA, and vancomycin-resistant Staphylococcus aureus (VRSA) strains. Docking of these compounds into the allosteric site of PBP2a showed comparable binding modes to that of the lead quinazolinone PBP2a inhibitors suggesting a similar mode of action. The present study presents a promising candidate for further optimization as a potential PBP2a inhibitor targeting MRSA infection.

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