Novel biaryl imines and amines as potential competitive inhibitors of dihydropteroate synthase

Antibiotic-resistant bacteria account for over 2.8 million infections and 35,000 deaths annually in the United States. The evolution of new resistant strains necessitates the continued development of new antimicrobial compounds. A target for further pharmaceutical development is the enzyme dihydropteroate synthase (DHPS), which plays a key role in prokaryotic biosynthesis of folic acid. A class of drugs called sulfonamides, including drugs sulfamethoxazole and sulfatrim, bind and act as competitive substrates to p-aminobenzoic acid (pABA), a substrate of DHPS, but are limited by their numerous side effects on the human body and bacterial resistance mutations that block larger molecules from entering the binding pocket. Here, we report the design, combinatorial synthesis, and antibacterial properties of a library of novel biaryl small molecules to target the binding pocket of DHPS. We hypothesize that the synthesized compounds in this study will have strong antibiotic efficacy because of their structural similarities to dihydropteroate, an intermediate in the biosynthesis of folate by the enzyme DHPS. Compounds were first screened in silico via docking to the binding pocket in DHPS. The antibiotic efficacy of these compounds was then tested on three species of bacteria related to human pathogens through a Kirby Bauer assay. Two hit compounds were discovered as having larger radii of inhibition compared to other compounds from the data of the assay. The larger radii of inhibition indicates that the bacteria tested against were susceptible to the use of the hit compounds. The results of the assay establish a definitive structure-activity relationship for the compounds studied and provide a basis for the future development of antibiotics targeting DHPS.