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Cladosporin was identified as a selective and potent <jats:italic>Pf<\/jats:italic>KRS inhibitor but lacks metabolic stability. Here, we report chemical synthesis, biological evaluation and structural characterization of analogues where the tetrahydropyran (THP) frame of cladosporin is replaced with the piperidine ring bearing functional group variations. Thermal binding, enzymatic, kinetic and parasitic assays complemented with X\u2010ray crystallography reveal compounds that are moderate in potency. Co\u2010crystals of <jats:bold>Cla\u2212B<\/jats:bold> and <jats:bold>Cla\u2212C<\/jats:bold> with <jats:italic>Pf<\/jats:italic>KRS reveal key atomic configurations that allow drug binding to and inhibition of the enzyme. Collectively these piperidine ring scaffold inhibitors lay a framework for further structural editing and functional modifications of the cladosporin scaffold to obtain a potent lead.<\/jats:p>","DOI":"10.1002\/cbic.202100212","type":"journal-article","created":{"date-parts":[[2021,5,9]],"date-time":"2021-05-09T22:24:30Z","timestamp":1620599070000},"page":"2468-2477","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Inhibition of <i>Plasmodium falciparum<\/i> Lysyl\u2010tRNA Synthetase via a Piperidine\u2010Ring Scaffold Inspired Cladosporin Analogues"],"prefix":"10.1002","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5966-8756","authenticated-orcid":false,"given":"Palak","family":"Babbar","sequence":"first","affiliation":[{"name":"Molecular Medicine \u2013 Structural Parasitology Group International Centre for Genetic Engineering and Biotechnology (ICGEB)  Aruna Asaf Ali Marg New Delhi 110067 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