Antimalarial natural product cladosporin: synthesis of stereoisomeric library, lead optimization, co-crystallization, and biological evaluation and synthesis of related macrocyclic natural products

Abstract

The work incorporated in this thesis is mainly focused on “Medicinal chemistry” and “Total synthesis”. Herein we have developed a unique and divergent synthetic scheme to access all the possible stereoisomers of a potent anti-malarial natural product, cladosporin and assessed their inhibitory potency through parasite-, enzyme- and cell-based assays. Based on the scores from biological assays, we categorized the entire set of stereoisomers in to three different potency classes, two of them (including cladosporin) being the most potent ones. X-ray diffraction study of co-crystals of the stereoisomers with target protein, PfKRS further gave an insight about the structural bases of enzymatic binding of the isomers. This exercise collectively helped us to decipher the role of stereochemical modifications on anti-malarial potency of cladosporin. Natural products are mostly procured in substantial low quantities from natural sources, which often hinders, and sometimes, even eliminates the possibility of in depth biological assessment (mainly in vivo). Hence, we adopted a modified synthetic protocol to access more than two grams of cladosporin in a single batch process. Besides, the scheme adopted herein is amenable to further scale-up. In the later part of this work, we have studied a systematic structure activity relationship (SAR) of a library of analogues, designed and synthesized based on cladosporin scaffold in anti-malarial potency through parasite-, enzyme- and cell-based assays. In this effort, we identified a lead compound (CL-2) having similar potency to that of cladosporin, but with improved drug-like properties (increased metabolic stability and hydrophilicity). Besides, the co-crystal structure of the most active compound (CL-2) with target protein PfKRS reveals new features of enzyme drug interactions. Lastly, we have accomplished the total synthesis of three bio-active twelve membered resorcyclic acid lactones (RAL12) namely (R)-penicimenolide A, (R)-dihydroresorcyclide and (R)-trans-resorcyclide. These natural products bear an interesting structural compliance with cladosporin.