2021
DOI: 10.1021/acsinfecdis.1c00092
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Design, Synthesis, and Structural Analysis of Cladosporin-Based Inhibitors of Malaria Parasites

Abstract: 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 compoun… Show more

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Cited by 8 publications
(22 citation statements)
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“…While working on our group’s ongoing research project on the medicinal chemistry of potent antimalarial natural product cladosporin, we have planned a strategy to access the isochromenone scaffold. Among various methods known for this particular transformation involving Brønsted acid and Lewis acid (Pd, Au, Hg, Ir, Pt, Ag, Fe, Cu, Re, and BF 3 ·Et 2 O) catalysis (entry a, Scheme ), Au­(III)-catalyzed (HAuCl 4 ) cyclization was chosen for our study due to its renowned alkynophilic nature and mild reaction parameters (entry b, Scheme ).…”
Section: Resultsmentioning
confidence: 99%
“…While working on our group’s ongoing research project on the medicinal chemistry of potent antimalarial natural product cladosporin, we have planned a strategy to access the isochromenone scaffold. Among various methods known for this particular transformation involving Brønsted acid and Lewis acid (Pd, Au, Hg, Ir, Pt, Ag, Fe, Cu, Re, and BF 3 ·Et 2 O) catalysis (entry a, Scheme ), Au­(III)-catalyzed (HAuCl 4 ) cyclization was chosen for our study due to its renowned alkynophilic nature and mild reaction parameters (entry b, Scheme ).…”
Section: Resultsmentioning
confidence: 99%
“…33 The authors studied structural and functional variations in the mTHP moiety, the aromatic dihydroisocoumarin ring as well as in the methylene functionality of the linker (Figure 3e). 33 The CLD-2 analog bound to the PfKRS enzyme (PDB: 6M0T) similar to the parent CLD molecule with an exception in the linker region, where the hydroxyl group resulted in the formation of a hydrogen bond with the side chain Glu500. 33 This emphasizes the need to explore stereo-chemical or functional modifications and their role in potency of CLD.…”
Section: Three-dimensional Structures Of Pfkrssmentioning
confidence: 99%
“…33 The CLD-2 analog bound to the PfKRS enzyme (PDB: 6M0T) similar to the parent CLD molecule with an exception in the linker region, where the hydroxyl group resulted in the formation of a hydrogen bond with the side chain Glu500. 33 This emphasizes the need to explore stereo-chemical or functional modifications and their role in potency of CLD. In summary, a wealth of information on the structural basis of inhibitor binding to PfKRS cyto has been generated to date.…”
Section: Three-dimensional Structures Of Pfkrssmentioning
confidence: 99%
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