The Centers for Disease Control (CDC) reported that 2.8 million antibiotic resistance infections occurred in the United States in 2019, and more than 35,000 people died as a result. The discovery of novel antibiotics working through unique mechanisms is an important goal toward mitigating the threat antibiotic resistant bacteria present. Dihydrofolate reductase (DHFR) inhibition is an underexploited antibiotic target, with only one approved antibiotic working through this mechanism. A functionalized dihydropyrimidine called emmacin was reported to exert antibacterial activity through uncompetitive inhibition of DHFR, and we are exploring this compound class using a combination of medicinal chemistry, bacteriology, and biochemistry approaches. Despite the unique uncompetitive antibacterial mechanism this compound utilizes on underexploited DHFR, only four comparable compound derivatives have been described in the literature. Toward fully investigating the structure activity relationships (SAR) of these functionalized dihydropyrimidines, analogs have been synthesized that evaluate the (1) sterics of an ethyl group, (2) halogenation pattern of an arene ring, and (3) importance of a phenol for potential hydrogen bonding or dipole-dipole interactions. The biological implications of these modifications were evaluated with antibacterial microdilution assays and DHFR enzyme kinetics assays.

Synthesis and biological evaluation of functionalized dihydropyrimidines as allosteric dihydrofolate reductase inhibitors with antibacterial activity

ACS Fall 2021

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