Metabolism-oriented Lead Optimization of Propargyl- linked DHFR Inhibitors

Dihydrofolate reductase (DHFR), a key enzyme within folate biosynthetic pathway, has been a popular drug target for over six decades. Trimethoprim (TMP) is the only FDA approved antibacterial DHFR inhibitor and remains clinically important. However, acquired resistance by point mutations and natural enzymatic insensitivity limit its use. A library of novel propargyl-linked antifolates targeting DHFR from MSRA, Candida and Klebsiella species was developed. Early lead propargyl-linked antifolates were proven potent antibacterial and antifungal agents. Much effort was placed on evaluating the metabolism properties. A strategy of incorporating crystallographic insight and experimental evaluation of structure-activity relationships (SAR) to guide new compound generation was explored to optimize the drug likeliness while maintaining high antimicrobial potency. Exciting compounds with excellent antibacterial activity (MIC = 0.02 µg/mL against MRSA), moderate metabolic stability (t1/2 = 99 min), low CYP inhibition (IC50> 50 µM against CYP3A4 and CYP2D6) were designed and generated. These studies will lead to identification of promising candidate compounds that would be ready for further translational development