TY - JOUR T1 - Design, synthesis, and structural analysis of cladosporin-based inhibitors of malaria parasites JF - ACS Infectious Diseases Y1 - 2021 A1 - Babbar, Palak A1 - Das, Pronay A1 - Manickam, Yogavel A1 - Mankad, Yash A1 - Yadav, Swati A1 - Parvez, Suhel A1 - Sharma, Amit A1 - Reddy, Srinivasa AB -

Here we have described a systematic structure activity relationship (SAR) of a set of compounds inspired from cladosporin, a tool compound that targets parasite (Plasmodium falciparum) lysyl tRNA synthetase (KRS). Four sets of analogues, synthesized based on point changes in the chemical scaffold of cladosporin and other logical modifications and hybridizations, were assessed using high throughput enzymatic and parasitic assays along with in vitro pharmacokinetics. Co-crystallization of the most potent compound in our series (CL-2) with PfKRS revealed its structural basis of enzymatic binding and potency. Further, we report that CL-2 has performed better than cladosporin in terms of metabolic stability. It thus represents a new lead for further optimization toward the development of antimalarial drugs. Collectively, along with a lead compound, the series offers insights on how even the slightest chemical modification might play an important role in enhancing or decreasing the potency of a chemical scaffold.

VL - 7 IS - 6 U3 -

Foreign

U4 - 5.084 ER -