- Specific Stereoisomeric Conformations Determine the Drug Potency of Cladosporin Scaffold against Malarial Parasite
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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.
- Das, Pronay,Babbar, Palak,Malhotra, Nipun,Sharma, Manmohan,Jachak, Goraknath R.,Gonnade, Rajesh G.,Shanmugam, Dhanasekaran,Harlos, Karl,Yogavel, Manickam,Sharma, Amit,Reddy, D. Srinivasa
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- Scalable synthesis of cladosporin
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Cladosporin, a secondary metabolite isolated from fungal sources like Cladosporium cladosporioides and Aspergillus flavus was found to exhibit selective nano-molar activity against malarial parasite Plasmodium falciparum by inhibiting parasitic protein biosynthesis. In addition, this natural product has a broad range of bioactivities including, antiparasitic, antifungal, antibacterial as well as plant growth inhibition. However, it has limited availability from the natural sources for further development. Herein, we report a modified and improved synthetic route which led us to produce this potent natural product in a gram scale. Conversion of the undesired diastereomer to desired one via Mitsunobu inversion of secondary alcohol and carbon monoxide insertion reaction towards the construction of isocoumarin unit are the key features of the present synthesis.
- Das, Pronay,Mankad, Yash,Reddy, D. Srinivasa
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p. 831 - 833
(2019/02/25)
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- Asymmetric total synthesis of cladosporin and isocladosporin
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The first asymmetric total syntheses of cladosporin and isocladosporin were accomplished in 8 steps with 8% overall yield and 10 steps with 26% overall yield, respectively. The relative configuration of isocladosporin was determined via this total synthes
- Zheng, Huaiji,Zhao, Changgui,Fang, Bowen,Jing, Peng,Yang, Juan,Xie, Xingang,She, Xuegong
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p. 5656 - 5663
(2012/09/07)
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