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The emergence of resistance to nearly every therapeutic agent directed against malaria-causing Plasmodium parasites emphasises the dire need for new antimalarials. Despite their high potency and low cytotoxicity in vitro, the clinical use of pantothenamides is hindered by pantetheinase-mediated hydrolysis in human serum. We herein report the chemical synthesis and biological activity of a new series of pantothenamide analogues in which the labile amide group is replaced with an isoxazole ring. In addition, we utilised, for the first time, enzymatic late-stage diversification to generate additional isoxazole-containing pantothenamide-mimics. Thirteen novel isoxazole-containing pantothenamide-mimics were generated, several of which display nanomolar antiplasmodial activity against Plasmodium falciparum and are non-toxic to human cells in vitro. Although the derivatives generated via late-stage diversification are less potent than the parent compounds, the most potent still exerted its activity via a mechanism that interferes with the pantothenate-utilising process and appears to be nontoxic to human cells. This increases the appeal of using late-stage diversification to modify pantothenamide-mimics, potentially leading to compounds with improved antiplasmodial and/or pharmacological properties., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kevin Saliba and Karine Auclair reports financial support was provided by Australian National Health and Medical Research Council. Karine Auclair and Kevin Saliba reports financial support was provided by Canadian Institutes of Health Research. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

A series of novel molecular hybrids based on 4-aminoquinoline-pyrimidine were synthesized and examined for their antimalarial activity. Most of the compounds were found to have potent in vitro antimalarial activity against both CQ-sensitive D6 and CQ-resistant W2 strains of P. falciparum. The active compounds have no considerable cytotoxicity against the mammalian VERO cell lines. Twenty three compounds displayed better antimalarial activity against CQ-resistant strain W2 with IC 50 values in the range 0.0189-0.945 μM, when compared with standard drug chloroquine. The best active compound 7d was studied for heme binding so as to find the primary mode of action of these hybrid molecules. Compound 7d was found to form a stable 1:1 complex with hematin as determined by its Job's plot which suggests that heme may be a probable target of these molecules. Docking studies performed with Pf-DHFR exhibited good binding interactions in the active site. The pharmacokinetic properties of some active compounds were also analysed using ADMET prediction., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

A series of 4-aminoquinoline-piperonyl-pyrimidine hybrids were synthesized with the aim of identifying compounds with enhanced antimalarial activity. All the synthesized molecules were evaluated in vitro against cultured Plasmodium falciparum W2 and D6 strains and exhibited potent antiplasmodial activities with IC 50 values in the range of 0.02-5.16 μM. Out of the 22 synthesised hybrids, 12 were found to be better (up to eight-fold more active) than chloroquine (CQ), particularly against the CQ-resistant W2 strain of P. falciparum with no significant cytotoxicity towards the mammalian cells. Mechanistic studies reveal that these compounds bind with heme and computational docking studies showed good docking interactions within the active site of Pf-DHFR., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)