02283nas a2200193 4500008004100000022001400041245015800055210006900213260000800282300001400290490000700304520154900311100002101860700001601881700002101897700002101918700002201939856012801961 2020 eng d a0022-326300aDFT/NMR approach for the configuration assignment of groups of stereoisomers by the combination and comparison of experimental and predicted sets of data0 aDFTNMR approach for the configuration assignment of groups of st cMAR a3297-33060 v853 a

Quantum mechanical/nuclear magnetic resonance (NMR) approaches are widely used for the configuration assignment of organic compounds generally comparing one cluster of experimentally determined data (e.g., C-13 NMR chemical shifts) with those predicted for all possible theoretical stereoisomers. More than one set of experimental data, each related to a specific stereoisomer, may occur in some cases, and the accurate stereoassignments can be obtained by combining the experimental and computed data. We introduce here a straightforward methodology based on the simultaneous analysis, combination, and comparison of all sets of experimental/calculated C-13 chemical shifts for aiding the correct configuration assignment of groups of stereoisomers. The comparison of the differences between the calculated/experimental chemical shifts instead of the shifts themselves led to the advantage of avoiding errors arising from calibration procedures, reducing systematic errors, and highlighting the most diagnostic differences between calculated and experimental data. This methodology was applied on a tetrad of synthesized cladosporin stereoisomers (cladologs) and further corroborated on a tetrad of pochonicine stereoisomers, obtaining the correct correspondences between experimental and calculated sets of data. The new MAE(Delta Delta delta) parameter, useful for indicating the best fit between sets of experimental and calculated data, is here introduced for facilitating the stereochemical assignment of groups of stereoisomers.

1 aLauro, Gianluigi1 aDas, Pronay1 aRiccio, Raffaele1 aReddy, Srinivasa1 aBifulco, Giuseppe uhttps://library.ncl.res.in/content/dftnmr-approach-configuration-assignment-groups-stereoisomers-combination-and-comparison04015nas 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