01881nas a2200265 4500008004100000022001400041245011900055210006900174260000800243300001400251490000700265520098400272100001601256700001801272700002001290700002101310700002601331700002401357700002801381700001701409700002201426700001701448700002101465856012901486 2018 eng d a0022-262300aSpecific stereoisomeric conformations determine the drug potency of cladosporin scaffold against malarial parasite0 aSpecific stereoisomeric conformations determine the drug potency cJUL a5664-56780 v613 a

The dependence of drug potency on diastereomeric configurations is a key facet. Using a novel general divergent synthetic route for a three-chiral center antimalarial natural product cladosporin, we built its complete library of stereoisomers (cladologs) and assessed their inhibitory potential using parasite-, enzyme-, and structure-based assays. We show that potency is manifest via tetrahyropyran ring conformations that are housed in the ribose binding pocket of parasite lysyl tRNA synthetase (KRS). Strikingly, drug potency between top and worst enantiomers varied 500-fold, and structures of KRS-cladolog complexes reveal that alterations at C3 and C10 are detrimental to drug potency whereas changes at C3 are sensed by rotameric flipping of glutamate 332. Given that scores of antimalarial and anti-infective drugs contain chiral centers, this work provides a new foundation for focusing on inhibitor stereochemistry as a facet of antimicrobial drug development.

1 aDas, Pronay1 aBabbar, Palak1 aMalhotra, Nipun1 aSharma, Manmohan1 aJachak, Goraknath, R.1 aGonnade, Rajesh, G.1 aShanmugam, Dhanasekaran1 aHarlos, Karl1 aYogavel, Manickam1 aSharma, Amit1 aReddy, Srinivasa uhttps://library.ncl.res.in/content/specific-stereoisomeric-conformations-determine-drug-potency-cladosporin-scaffold-against04015nas a2200217 4500008004100000245010000041210006900141260000800210300001600218490000600234520328400240100001803524700001603542700002203558700001703580700001703597700001803614700001703632700002103649856012703670 2021 eng d00aDesign, synthesis, and structural analysis of cladosporin-based inhibitors of malaria parasites0 aDesign synthesis and structural analysis of cladosporinbased inh cJUL a1777–17940 v73 a

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.

1 aBabbar, Palak1 aDas, Pronay1 aManickam, Yogavel1 aMankad, Yash1 aYadav, Swati1 aParvez, Suhel1 aSharma, Amit1 aReddy, Srinivasa uhttps://library.ncl.res.in/content/design-synthesis-and-structural-analysis-cladosporin-based-inhibitors-malaria-parasites