Structure-Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials

John A. Gilleran, Kutub Ashraf, Melvin Delvillar, Tyler Eck, Raheel Fondekar, Edward B. Miller, Ashley Hutchinson, Aiping Dong, Alma Seitova, Mariana Laureano De Souza, David Augeri, Levon Halabelian, John Siekierka, David P. Rotella, John Gordon, Wayne E. Childers, Mark C. Grier, Bart L. Staker, Jacques Y. Roberge, Purnima Bhanot

Research output: Contribution to journalArticlepeer-review

Abstract

Controlling malaria requires new drugs against Plasmodium falciparum. The P. falciparum cGMP-dependent protein kinase (PfPKG) is a validated target whose inhibitors could block multiple steps of the parasite’s life cycle. We defined the structure-activity relationship (SAR) of a pyrrole series for PfPKG inhibition. Key pharmacophores were modified to enable full exploration of chemical diversity and to gain knowledge about an ideal core scaffold. In vitro potency against recombinant PfPKG and human PKG were used to determine compound selectivity for the parasite enzyme. P. berghei sporozoites and P. falciparum asexual blood stages were used to assay multistage antiparasitic activity. Cellular specificity of compounds was evaluated using transgenic parasites expressing PfPKG carrying a substituted “gatekeeper” residue. The structure of PfPKG bound to an inhibitor was solved, and modeling using this structure together with computational tools was utilized to understand SAR and establish a rational strategy for subsequent lead optimization.

Original languageEnglish
Pages (from-to)3467-3503
Number of pages37
JournalJournal of Medicinal Chemistry
Volume67
Issue number5
DOIs
StatePublished - 14 Mar 2024

Fingerprint

Dive into the research topics of 'Structure-Activity Relationship of a Pyrrole Based Series of PfPKG Inhibitors as Anti-Malarials'. Together they form a unique fingerprint.

Cite this