A Class of Pantothenic Acid Analogs Inhibits Plasmodium falciparum Pantothenate Kinase and Represses the Proliferation of Malaria Parasites

Abstract

The growth and proliferation of the human malaria parasite Plasmodium falciparum are dependent on the parasite's ability to obtain essential nutrients. One nutrient for which the parasite has an absolute requirement is the water-soluble vitamin pantothenic acid (vitamin B 5 ). In this study, a series of pantothenic acid analogs which retain the 2,4-dihydroxy-3,3-dimethylbutyramide core of pantothenic acid but deviate in structure from one another and from pantothenic acid in the nature of the substituent attached to the amide nitrogen were synthesized using an efficient single-step synthetic route. Eight of 10 analogs tested inhibited the proliferation of intraerythrocytic P. falciparum parasites in vitro, doing so with 50% inhibitory concentrations between 15 and 200 M. The compounds were generally selective, inhibiting the proliferation of a human cell line (the Jurkat cell line) only at concentrations severalfold higher than those required for inhibition of parasite growth. It was demonstrated that compounds in this series inhibited the phosphorylation of pantothenic acid by pantothenate kinase, the first step in the parasite's biosynthesis of the essential enzyme cofactor coenzyme A, doing so competitively, with K i values in the nanomolar range.

Feedback Inhibition of Pantothenate Kinase Regulates Pantothenol Uptake by the Malaria Parasite

“…Pantothenol is a competitive inhibitor of the phosphorylation of pantothenate by PfPanK (3). Recently, additional pantothenate analogs have been synthesized and shown to inhibit P. falciparum proliferation at concentrations severalfold lower than those required to inhibit the proliferation of a human cell line (17). Like pantothenol, these compounds inhibit parasite proliferation via a mechanism that entails competition with pantothenate.…”

“…Inhibitors of the conversion of pantothenate to CoA are being investigated both as antimalarial (3,(15)(16)(17) and antibacterial (12)(13)(14) agents. Pantothenol, a pantothenate analog and a common ingredient of multivitamin supplements, shampoos, and cosmetics, is one such candidate that has been shown recently to inhibit P. falciparum growth in vitro and to inhibit the in vivo proliferation of the mouse parasite Plasmodium vinckei vinckei.…”

“…substrate affinity) (5). The value of this pathway as an antimalarial target was validated by the discovery that the widely used provitamin pantothenol (which differs from pantothenate only in the replacement of the terminal carboxyl group with a hydroxyl group) as well as a range of other pantothenate analogs (16,17) inhibit the growth of P. falciparum in vitro via a mechanism that involves competitive inhibition of pantothenate phosphorylation by PfPanK (3).…”

Thiolactomycin-based β-Ketoacyl-AcpM Synthase A (KasA) Inhibitors

“…2) was synthesized using a published protocol (22,23). Details of the synthesis and analytical data are given in supplemental Fig.…”

Stereochemical modification of geminal dialkyl substituents on pantothenamides alters antimicrobial activity

“…For example, the provitamin pantothenol as well as a range of other pantothenate analogues have been shown to repress the proliferation of the malarial parasite Plasmodium falciparum. [11][12][13][14][15] A synthetic route for accessing geminal dialkyl-substituted pantothenamide derivatives was recently reported by some of us. 16 In this study, several compounds were synthesized and evaluated for antibacterial properties which revealed that larger substituents were not well tolerated at the gem-dimethyl position.…”