Synthesis and evaluation of pantothenic acid analogues as potential inhibitors of malaria parasites and bacteria

[摘要] ENGLISH ABSTRACT: A lot of progress has been made in the development and utilization of antimalarial and antibacterial drugs. However, reports of increasing resistance to these antimicrobial agents are threatening to reduce their overall efficacy. In view of this, the need for new antimicrobials is of the paramount importance. Since pantothenate promotes the growth of microbes, analogues of this compound that may act as antimetabolites have been synthesized and tested for their inhibitory properties against microbial growth.N-substituted pantothenamides is a class of pantothenate analogues previously synthesized in our group that have shown good antibacterial activities, as well as promising inhibition of the proliferation of malaria parasites. In this study the chemical and structural diversity of these analogues were expanded by preparing N-substituted pantothenamides in which a methyl functionality was introduced on either the α- or ß-carbon of the ß-alanine moiety of pantothenate. These compounds were synthesized and purified in parallel, resulting in the production of 40 N-substituted α- and ß-methylpantothenamides which were investigated as potential antibacterial and antimalarial agents.The growth inhibitory activities of these compounds were first investigated on S. aureus, since in the previous study it was shown that N-substituted pantothenamides demonstrated remarkable inhibitory activities against this microbe. Next, the impact of these compounds on the proliferation of malaria parasites was also investigated to determine if the introduction of the methyl group could improve on the poor inhibition exhibited by the first series of pantothenamides tested against this organism.Finally pantoyltauramides, sulfonamide analogues of the pantothenamides, were also synthesized and tested for their inhibitory activities against proliferation of malaria parasites P. falciparum in vitro. The results show that additional functionalization of pantothenic acid may prove to be a viable strategy for improving the inhibitory activity of these antimetabolites.

[发布机构] Stellenbosch University