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Design, synthesis, and structural analysis of cladosporin-based inhibitors of malaria parasites

DOI: 10.1021/acsinfecdis.1c00092 DOI Help

Authors: Palak Babbar (International Centre for Genetic Engineering and Biotechnology (ICGEB); Jamia Hamdard) , Pronay Das (CSIR−National Chemical Laboratory; Academy of Scientific and Innovative Research (AcSIR)) , Yogavel Manickam (International Centre for Genetic Engineering and Biotechnology (ICGEB)) , Yash Mankad (CSIR−National Chemical Laboratory) , Swati Yadav (CSIR−National Chemical Laboratory) , Suhel Parvez (Jamia Hamdard) , Amit Sharma (International Centre for Genetic Engineering and Biotechnology (ICGEB); ICMR−National Institute of Malaria Research) , D. Srinivasa Reddy (CSIR−Indian Institute of Integrative Medicine; Academy of Scientific and Innovative Research (AcSIR))
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Acs Infectious Diseases

State: Published (Approved)
Published: April 2021

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 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.

Journal Keywords: antimalaria; cladosporin; co-crystal; drug development; medicinal chemistry; structure−activity relationship

Diamond Keywords: Malaria

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 21/04/2021 08:52

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Disease in the Developing World Drug Discovery Infectious Diseases Structural biology Chemistry Biochemistry Parasitology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)