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

Jana, Collins Edward (2011-12)

Thesis (MSc (Biochemistry))--Stellenbosch University, 2011.

Thesis

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.

AFRIKAANSE OPSOMMING: Alhoewel goeie vordering gemaak is in die ontwikkeling en gebruik van middels teen malaria en bakteriele infeksies, dreig toenemende weerstand teen sulke verbindings om hul algehele doeltreffendheid te verminder. In die lig hiervan, is die behoefte vir 'n nuwe antimikrobiese middels is van die allergrootste belang. Aangesien pantoteensuur die groei van mikrobes bevorder, is strukturele analoe van hierdie verbinding wat kan optree as antimetaboliete gesintetiseer en getoets vir hul inhiberende eienskappe teen mikrobiese groei. N-Gesubstitueerde pantoteenamiede is 'n klas van pantoteensuur-analoe wat voorheen in ons groep gesintetiseer is en goeie antibakteriese aktiwiteite, sowel as belowende inhibisie van die vermeerdering van malaria-parasiete, getoon het. In hierdie studie is die chemiese en strukturele diversiteit van hierdie analoe uitgebrei deur die bereiding van N-gesubstitueerde pantoteenamiede waarby 'n metielgroep funksie op die α- of ß-koolstof van die ß-alanien gedeelte van pantoteensuur aangebring is. Hierdie verbindings is in parallel gesintetiseer en gesuiwer om sodoende 40 gesubstitueerde α- en ß-metielpantoteenamiede te produseer wat gevolglik as moontlike antibakteriese en anti-malaria agente ondersoek is. Die groei-inhiberende aktiwiteite van hierdie verbindings is eers op S. aureus ondersoek, aangesien 'n vorige studie het getoon dat die N-gesubstitueerde pantoteenamiede merkwaardige inhiberende aktiwiteite teen hierdie bakterie toon. Daarna was die impak van hierdie verbindings ook op die vermeerdering van malaria-parasiete ondersoek om te bepaal of die installering van die metielgroep die swak inhibisie wat die eerste reeks van pantoteenamiede teen hierdie organisme getoon het, kon verbeter. Ten slotte is pantoieltauramiede, sulfoonamied-analoe van die pantoteenamiede, ook gesintetiseer en getoets vir hul effek op die in vitro vermeerdering van P. falciparum malaria-parasiete. Die resultate toon dat die funksionalisering van pantoteensuur 'n lewensvatbare strategie vir die verbetering van die inhiberende aktiwiteit van hierdie antimetaboliete kan wees.

Please refer to this item in SUNScholar by using the following persistent URL: http://hdl.handle.net/10019.1/18120
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