A5015276222- Malaria Research and Control
- Synthesis and biological activity
- Research on Leishmaniasis Studies
- Cancer therapeutics and mechanisms
- Tuberculosis Research and Epidemiology
- Computational Drug Discovery Methods
- Phenothiazines and Benzothiazines Synthesis and Activities
- HIV/AIDS drug development and treatment
- Trypanosoma species research and implications
- Mosquito-borne diseases and control
- Drug Transport and Resistance Mechanisms
- Synthesis and Characterization of Heterocyclic Compounds
- Quinazolinone synthesis and applications
- Mycobacterium research and diagnosis
- Bioactive Compounds and Antitumor Agents
- Genetics, Bioinformatics, and Biomedical Research
- Parasites and Host Interactions
- Pharmacogenetics and Drug Metabolism
- Synthesis and Catalytic Reactions
- Pharmacological Effects of Natural Compounds
- Steroid Chemistry and Biochemistry
- Synthesis of Organic Compounds
- Synthesis and Biological Evaluation
- Crystallization and Solubility Studies
- Click Chemistry and Applications
University of Cape Town
2016-2025
South African Medical Research Council
2014-2024
The 2-aminopyridine MMV048 was the first drug candidate inhibiting Plasmodium phosphatidylinositol 4-kinase (PI4K), a novel target for malaria, to enter clinical development. In an effort identify next generation of PI4K inhibitors, series optimized improve properties such as solubility and antiplasmodial potency across parasite life cycle, leading 2-aminopyrazine UCT943.
High-throughput screening of a library small polar molecules against Mycobacterium tuberculosis led to the identification phthalimide-containing ester hit compound (1), which was optimized for metabolic stability by replacing moiety with methyl oxadiazole bioisostere. A route utilizing polymer-supported reagents designed and executed explore structure-activity relationships respect N-benzyl substituent, leading compounds nanomolar activity. The frontrunner (5h) from these studies well...
The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of parasite and contribution establishment resistance artemisinin (ART)-based therapies. However, because a similarly for host proteasome, key property any antiproteasome therapeutic selectivity. Several parasite-specific inhibitors have recently been reported, however, their selectivity must be improved enable clinical development. Here we describe screening diverse...
A novel 2,8-disubstituted-1,5-naphthyridine hit compound stemming from the open access Medicines for Malaria Venture Pathogen Box formed a basis hit-to-lead medicinal chemistry program. Structure-activity relationship investigations resulted in compounds with potent antiplasmodial activity against both chloroquine sensitive (NF54) and multidrug resistant (K1) strains of human malaria parasite Plasmodium falciparum. In humanized P. falciparum mouse efficacy model, one frontrunner showed vivo...
Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors
Mixed-ligand platinum(II) complexes incorporating bipyridine and acyl-thiourea ligands were synthesized evaluated for their in vitro growth inhibitory activity against the human malaria parasite Plasmodium falciparum (Pf). The substituents at four distinct sites varied to identify structure–activity relationships this series. Most displayed potent PfNF54 with IC50 values nanomolar range favorable cytotoxicity profiles. Five (C1, C11, C12, C15, C17) exhibited both asexual blood sexual...
Mefloquine is an antimalarial drug routinely used for prophylaxis and in the treatment of malaria. Approximately 50% mefloquine metabolism, both vitro vivo, mediated by CYP3A4 with remaining contributions other CYP450 isoforms unaccounted for. This study aimed to determine contribution CYP450s metabolism incorporate this knowledge into a physiologically-based pharmacokinetic model. The data human liver microsomes demonstrated involvement CYP3A4/5 as well previously unreported CYP1A2...
Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to identification of potent, metabolically stable compounds with improved in vivo oral efficacy P. berghei mouse model and additional activity against parasite liver gametocyte stages, making them potential candidates for preclinical development. Inhibition hemozoin formation possibly contributes mechanism action.
Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure–activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to identification potent pyrazolopyridines, which showed good efficacy pharmacokinetics profiles. The lead compounds also proved be very parasite liver gametocyte stages, makes them high interest.
A novel series of pyrido[1,2-a]benzimidazoles bearing Mannich base side chains and their metabolites were synthesized evaluated for in vitro antiplasmodium activity, microsomal metabolic stability, reactive metabolite (RM) formation, vivo antimalarial efficacy a mouse model. Oral administration one the derivatives at 4 × 50 mg/kg reduced parasitemia by 95% Plasmodium berghei-infected mice, with mean survival period 16 days post-treatment. The these is likely consequence active metabolites,...
A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure–activity relationship studies revealed that 1-benzylbenzimidazole analogues possessed submicromolar activities in contrast to 1H-benzimidazole analogues, were only active against (ABS) parasites. Further, former demonstrated microtubule inhibitory activity ABS parasites but more...
Described here is a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis through inhibition DNA gyrase. The SPT class operates via novel mode inhibition, which involves Mg 2+ -independent stabilization the cleavage complex gyrase and thereby not cross-resistant other gyrase-inhibiting antibacterials, including fluoroquinolones.
Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships activity against asexual blood stages of human malaria parasite
Fusidic acid (FA), a natural product fusidane triterpene-based antibiotic with unique structural features, is active in vitro against Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). While possessing good pharmacokinetics man, FA rapidly metabolized rodents, thus complicating proof-of-concept studies this model. Toward repositioning as an anti-TB agent, we herein describe synthesis, activity, and metabolism semisynthesized ester derivatives rat liver microsomes, plasma,...
Abstract Herein we report the screening of a small library aurones and their isosteric counterparts, azaaurones N ‐acetylazaaurones, against Mycobacterium tuberculosis . Aurones were found to be inactive at 20 μ m , whereas ‐acetylazaaurones emerged as most potent compounds, with nine derivatives displaying MIC 99 values ranging from 0.4 2.0 In addition, several active multidrug‐resistant (MDR) extensively drug‐resistant (XDR) clinical M isolates. The antimycobacterial mechanism action these...
Phenotypic whole-cell screening against Mycobacterium tuberculosis (Mtb) in glycerol–alanine–salts supplemented with Tween 80 and iron (GASTE-Fe) media led to the identification of a 2-aminoquinazolinone hit compound, sulfone 1 which was optimized for solubility by replacing moiety sulfoxide 2. The synthesis structure–activity relationship (SAR) studies identified several compounds potent antimycobacterial activity, were metabolically stable noncytotoxic. Compound 2 displayed favorable vitro...
Phenotypic whole cell high-throughput screening of a ∼150,000 diverse set compounds against Mycobacterium tuberculosis (Mtb) in cholesterol-containing media identified 1,3-diarylpyrazolyl-acylsulfonamide 1 as moderately active hit. Structure–activity relationship (SAR) studies demonstrated clear scope to improve potency MIC values <0.5 μM, and plausible pharmacophore model was developed describe the chemical space compounds. Compounds are bactericidal vitro replicating Mtb retained activity...
A BioFocus DPI SoftFocus library of ∼35 000 compounds was screened against Mycobacterium tuberculosis (Mtb) in order to identify novel hits with antitubercular activity. The were evaluated biology triage assays exclude suggested function via frequently encountered promiscuous mechanisms action including inhibition the QcrB subunit cytochrome bc1 complex, disruption cell–wall homeostasis, and DNA damage. Among that passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series...
A novel diazaspiro[3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with sp3-rich scaffold provided an attractive starting point for hit-to-lead medicinal chemistry optimization and biological profiling program. Structure-activity-relationship studies led to identification compounds that showed low nanomolar asexual blood-stage (<50 nM) strong...