title: Investigating the antiplasmodial activity of primary sulfonamide compounds identified in open source malaria data.
abstract: In the past decade there has been a significant reduction in deaths due to malaria, in part due to the success of the gold standard antimalarial treatment - artemisinin combination therapies (ACTs). However the potential threat of ACT failure and the lack of a broadly effective malaria vaccine are driving efforts to discover new chemical entities (NCEs) to target this disease. The primary sulfonamide (PS) moiety is a component of several clinical drugs, including those for treatment of kidney disease, glaucoma and epilepsy, however this chemotype has not yet been exploited for malaria. In this study 31 PS compounds sourced from the GlaxoSmithKline (GSK) Tres Cantos antimalarial set (TCAMS) were investigated for their ability to selectively inhibit the in vitro growth of Plasmodium falciparum asexual stage malaria parasites. Of these, 14 compounds were found to have submicromolar activity (IC500.16-0.89 μM) and a modest selectivity index (SI) for the parasite versus human cells (SI > 12 to >43). As the PS moiety is known to inhibit carbonic anhydrase (CA) enzymes from many organisms, the PS compounds were assessed for recombinant P. falciparum CA (PfCA) mediated inhibition of CO2hydration. The PfCA inhibition activity did not correlate with antiplasmodial potency. Furthermore, no significant difference in IC50was observed for P. falciparum versus P. knowlesi (P > 0.05), a Plasmodium species that is not known to contain an annotated PfCA gene. Together these data suggest that the asexual intraerythrocytic stage antiplasmodial activity of the PS compounds examined in this study is likely unrelated to PfCA inhibition.
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Queensland, Australia.
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Fisher
authors.affiliation: Neurofarba Department, Sezione di Scienze Farmaceutiche Nutraceutiche, and Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Sesto Fiorentino, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bua
authors.affiliation: Neurofarba Department, Sezione di Scienze Farmaceutiche Nutraceutiche, and Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Sesto Fiorentino, Florence, Italy; Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, Napoli, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Del Prete
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Queensland, Australia.
authors.forename: Megan S J
authors.initials: MS
authors.lastname: Arnold
authors.affiliation: Istituto di Bioscienze e Biorisorse, CNR, Via Pietro Castellino 111, Napoli, Italy.
authors.forename: Clemente
authors.initials: C
authors.lastname: Capasso
authors.affiliation: Neurofarba Department, Sezione di Scienze Farmaceutiche Nutraceutiche, and Laboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Sesto Fiorentino, Florence, Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Queensland, Australia. Electronic address: K.Andrews@griffith.edu.au.
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Andrews
authors.affiliation: Griffith Institute for Drug Discovery, Griffith University, Queensland, Australia. Electronic address: s.poulsen@griffith.edu.au.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Poulsen
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D016790:Plasmodium knowlesi / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D013449:Sulfonamides / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D002256:Carbonic Anhydrases
keywords: Carbonic anhydrase; Plasmodium falciparum; Plasmodium knowlesi; Primary sulfonamide; TCAMS