A5023081928- Malaria Research and Control
- Research on Leishmaniasis Studies
- HIV/AIDS drug development and treatment
- Computational Drug Discovery Methods
- Parasites and Host Interactions
- Phytochemical compounds biological activities
- Natural product bioactivities and synthesis
- Microbial Natural Products and Biosynthesis
- Cancer therapeutics and mechanisms
- Parasite Biology and Host Interactions
- Synthesis and biological activity
- Marine Sponges and Natural Products
- Plant biochemistry and biosynthesis
- Biochemical and Molecular Research
- Global Health and Surgery
- Tuberculosis Research and Epidemiology
- Drug Transport and Resistance Mechanisms
- Synthesis and Characterization of Heterocyclic Compounds
- Trypanosoma species research and implications
- Biotechnology and Related Fields
- Plant Diversity and Evolution
- Antibiotics Pharmacokinetics and Efficacy
- Phytochemistry and Bioactivity Studies
- Synthesis and Biological Activity
- Protein Interaction Studies and Fluorescence Analysis
University of Cape Town
2016-2025
Discovery Centre
2024
University of Ghana
2015-2023
South African Medical Research Council
2021-2022
Plasmepsins represent novel antimalarial drug targets. However, plasmepsin-based discovery efforts in the past 2 decades have generally suffered some drawbacks including lack of translatability target inhibition to potent parasite vitro and vivo as well poor selectivity over related human aspartic proteases. Most studies reported this period over-relied on use hemoglobinase plasmepsins I–IV (particularly I II) targets for new inhibitors even though these are known be nonessential at asexual...
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...
The continued emergence of resistance to front-line antimalarial treatments is great concern. Therefore, new compounds that potentially have a novel target in various developmental stages Plasmodium parasites are needed treat patients and halt the spread malaria. Here, several benzimidazole derivatives were screened for activity against symptom-causing intraerythrocytic asexual blood transmissible gametocyte P. falciparum. Submicromolar was obtained 54 stage with 6 potent at IC50 < 100 nM...
Structure-activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potent inhibitors
Molecular hybridization is a drug discovery strategy that involves the rational design of new chemical entities by fusion (usually via covalent linker) two or more drugs, both active compounds and/or pharmacophoric units recognized and derived from known bioactive molecules. The expected outcome this modification to produce hybrid compound with improved affinity efficacy compared parent drugs. Additionally, can result in presenting modified selectivity profiles, different dual modes action,...
New compounds targeting human malaria parasites are critical for effective control and elimination. Here, we pursued the imidazoquinolinone AZD0156 (MMV1580483), a ataxia‐telangiectasia mutated (ATM) kinase inhibitor that completed Phase I clinical trials as an anticancer agent. We validated its in vitro activity against two main forms of Plasmodium falciparum parasite host, viz. asexual blood (symptomatic) stage sexual gametocyte (transmission) stage. Resistance selection, cross‐resistance,...
New compounds targeting human malaria parasites are critical for effective control and elimination. Here, we pursued the imidazoquinolinone AZD0156 (MMV1580483), a ataxia‐telangiectasia mutated (ATM) kinase inhibitor that completed Phase I clinical trials as an anticancer agent. We validated its in vitro activity against two main forms of Plasmodium falciparum parasite host, viz. asexual blood (symptomatic) stage sexual gametocyte (transmission) stage. Resistance selection, cross‐resistance,...
Fusidic acid is a natural product antibiotic used clinically, primarily against staphylococcal infections. It has also exhibited antimycobacterial activity Mycobacterium species, including tuberculosis (Mtb). Novel C-21 fusidic amides were synthesized and evaluated for in drug repositioning approach tuberculosis. The compounds good potency MB7H9/CAS medium albeit showing low to no MB7H9/ADC medium. ethanamides were, generally, the most potent of analogues (MIC90 < 10 μM) lack was supported...
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,...
The marine red algae of the genus Laurencia have been widely studied for their structurally diverse and biologically active secondary metabolites. We report here natural product investigation organic extract a newly identified South African endemic species, alfredensis. A sequence column chromatography, preparative TLC normal phase HPLC resulted in isolation eleven compounds comprising three labdane-type diterpenes (1-3), four polyether triterpenes (4-7), cholestane-type ecdysteroids (8-10)...
Dichapetalum filicaule Breteler (Dichapetalaceae) is a rare species occurring only in Côte d'Ivoire and Ghana. Although research on several of the genus has produced interesting bioactive compounds, particularly Dichapetalins, novel class triterpenoids with antineoplastic properties, there virtually no information ethnobotanical uses chemical constituents D. filicaule.The phytochemical anthelminthic activities were investigated.Chemical petroleum ether, chloroform-acetone, methanol root...
Recent studies on 3,6-diphenylated imidazopyridazines have demonstrated impressive in vitro activity and vivo efficacy mouse models of malaria infection. Herein, we report the synthesis antiplasmodium evaluation a new series amidated analogues demonstrate that these compounds potently inhibit Plasmodium phosphatidylinositol-4-kinase (PI4K) type IIIβ while moderately inhibiting cyclic guanidine monophosphate (cGMP)-dependent protein kinase (PKG) vitro. Using silico docking, predict key...
Praziquantel is the only widely available drug to treat schistosomiasis. With very few candidates currently in development pipeline, there an urgent need discover and develop novel antischistosomal drugs. In this regard, pyrido[1,2-a]benzimidazole (PBI) scaffold has emerged as a promising chemotype hit-to-lead efforts. Here, we report series of PBIs with potent vitro activity (IC50 values 0.08–1.43 μM) against Schistosoma mansoni newly transformed schistosomula adult worms. Moreover, current...
As part of our search for bioactive compounds from the Dichapetalaceae, repeated chromatographic purification roots a hitherto unexamined species, Dichapetalum pallidum, led to isolation newly occurring 7-hydroxydichapetalin P (1) and known dichapetalins A (2) X (3). Also isolated were friedelin-2,3-lactone (4), friedelan-3-one (6), friedelan-3β-ol (7) pomolic (8), as well dipeptide aurantiamide acetate (5). The characterized by direct interpretation their IR, 1D NMR 2D spectral data...
Here we report a new polyhydroxylated triterpene, 2β,6β,21α-trihydroxyfriedelan-3-one (4) isolated from the root and stem bark of Dichapetalum albidum A. Chev (Dichapetalaceae), along with six known triterpenoids (1-3, 5, 6, 8), sitosterol-3β-O-D-glucopyranoside (9), dipeptide (7), tyramine derivative coumaric acid (10). Friedelan-3-one (2) showed an antimicrobial activity (IC50) 11.40 μg/mL against Bacillus cereus, while friedelan-3α-ol (1) gave IC50 13.07 Staphylococcus aureus ampicillin...
Fusidic acid (FA) has previously been shown to be rapidly metabolized in rodents its C-3 epimer, which significantly lower antimycobacterial activity relative FA. This was part hypothesized account for FA's lack of vivo efficacy a mouse model tuberculosis despite potent vitro activity. In the current work, we that alkyl ester prodrugs FA would deliver higher levels drug and prevent rapid metabolism observed upon administration original form. Pharmacokinetic analysis 3-ketofusidic metabolite...
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a major global health concern given the increase in multiple forms of drug-resistant TB. This underscores importance continuous pipeline new anti-TB agents. Drug repurposing has shown promise expanding therapeutic options for TB chemotherapy. Fusidic acid (FA), natural product-derived antibiotic, one such candidate repurposing. The present study aimed to understand mechanism action FA and its selected analogs M. tuberculosis. By...
Over the past 50 years, marine invertebrates, especially sponges, have proven to be a valuable source of new and/or bioactive natural products that potential further developed as lead compounds for pharmaceutical applications. Although benthic invertebrate communities occurring off coast South Africa been explored their biomedicinal potential, product investigation sponges from sub-Antarctic Islands in Southern Ocean presence secondary metabolites has relatively unexplored thus far. We...
ABSTRACT In response to the spread of artemisinin (ART) resistance, ART-based hybrid drugs were developed, and their activity profile was characterized against drug-sensitive drug-resistant Plasmodium falciparum parasites. Two hybrids found display parasite growth reduction, stage-specificity, speed activity, additivity in drug combinations, stability hepatic microsomes similar levels those displayed by dihydroartemisinin (DHA). Conversely, rate chemical homolysis peroxide bonds is slower...