A5083216093- Malaria Research and Control
- Mosquito-borne diseases and control
- HIV/AIDS drug development and treatment
- Synthesis and Biological Evaluation
- Computational Drug Discovery Methods
- Metal complexes synthesis and properties
- Bacterial Infections and Vaccines
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Drug Transport and Resistance Mechanisms
- Ferrocene Chemistry and Applications
- Quinazolinone synthesis and applications
- Phenothiazines and Benzothiazines Synthesis and Activities
- Neuroinflammation and Neurodegeneration Mechanisms
- Cerebrospinal fluid and hydrocephalus
- Research on Leishmaniasis Studies
- Pharmacological Effects and Toxicity Studies
- HIV Research and Treatment
- Pneumocystis jirovecii pneumonia detection and treatment
- Vector-borne infectious diseases
- Genetic Associations and Epidemiology
- Orthopedic Infections and Treatments
- Schizophrenia research and treatment
- vaccines and immunoinformatics approaches
- Parasites and Host Interactions
University of Cape Town
2015-2024
Wellcome Centre for Infectious Diseases Research in Africa
2019-2020
Groote Schuur Hospital
2016-2020
Chemical analysis has shown that Plasmodium falciparum trophozoites contain 61±2% of the iron within parasitized erythrocytes, which 92±6% is located food vacuole. Of this, 88±9% in form haemozoin. 57Fe-Mössbauer spectroscopy shows haemozoin only detectable species trophozoites. Electron spectroscopic imaging confirms this conclusion.
ABSTRACT Current efforts to reduce the global burden of malaria are threatened by rapid spread throughout Asia Plasmodium falciparum resistance artemisinin-based combination therapies, which includes increasing rates clinical failure with dihydroartemisinin plus piperaquine (PPQ) in Cambodia. Using zinc finger nuclease-based gene editing, we report that addition C101F mutation chloroquine (CQ) resistance-conferring PfCRT Dd2 isoform common can confer PPQ cultured parasites. Resistance was...
The activity of several well-known anti-malarials, including chloroquine (CQ), is attributed to their ability inhibit the formation haemozoin (Hz) in malaria parasite. inert Hz, or pigment, from toxic haem acquired host red blood cell parasite during haemoglobin digestion represents a pathway essential for survival. Inhibition this critical therefore remains desirable target novel anti-malarials. A recent publication described results fractionation assay used directly determine haemoglobin,...
Southeast Asia is an epicenter of multidrug-resistant Plasmodium falciparum strains. Selective pressures on the subcontinent have recurrently produced several allelic variants parasite drug resistance genes, including P. chloroquine transporter (pfcrt). Despite significant reductions in deployment 4-aminoquinoline (CQ), which selected for mutant pfcrt alleles that halted CQ efficacy decades ago, locus continuously evolving. This highlighted by presence a highly mutated allele, Cam734 pfcrt,...
The parasitic disease malaria places almost half of the world’s population at risk infection and is responsible for more than 400,000 deaths each year. first-line treatment, artemisinin combination therapies (ACT) regimen, under threat due to emerging resistance Plasmodium falciparum strains in e.g. Mekong delta. Therefore, development new antimalarial agents crucial order circumvent growing resistance. Chloroquine, long-established drug, still serves as model compound design quinoline...
Abstract Malaria remains a major public health problem. With the loss of antimalarials to resistance, malaria burden will likely continue for decades. New antimalarial scaffolds are crucial avoid cross-resistance. Here, we present first structure based virtual screening using β-haematin crystal as target new inhibitor by applying docking method. The ZINC15 database was searched compounds with high binding affinity surface PyRx Virtual Screening Tool. Top-ranked predicted interact were...
Quinoline antimalarials target hemozoin formation causing a cytotoxic accumulation of ferriprotoporphyrin IX (Fe(III)PPIX). Well-developed SAR models exist for β-hematin inhibition, parasite activity, and cellular mechanisms this compound class, but no comparably detailed investigations other inhibiting chemotypes. Here, benzamide analogues based on previous HTS hits have been purchased or synthesized. Only derivatives containing an electron deficient aromatic ring capable adopting flat...
In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and series triarylimidazoles were identified as active against Plasmodium falciparum. Here, we report the subsequent synthesis testing derivatives with varying substituents on three phenyl rings this series. The results indicated that 2-hydroxy-1,3-dimethoxy substitution pattern ring A is required submicromolar parasite activity. addition, cell-fractionation studies...
With the continued loss of antimalarials to resistance, drug repositioning may have a role in maximising efficiency and accelerating discovery new antimalarial drugs. Bayesian statistics was previously used as tool virtually screen USFDA approved drugs for predicted β-haematin (synthetic haemozoin) inhibition vitro activity. Here, we report experimental evaluation nine highest ranked drugs, confirming accuracy model by showing an overall 93% hit rate. Lapatinib, nilotinib, lomitapide showed...
A diverse series of hemozoin-inhibiting quinolines, benzamides, triarylimidazoles, quinazolines, benzimidazoles, benzoxazoles, and benzothiazoles have been found to lead exchangeable heme levels in cultured Plasmodium falciparum (NF54) that ranged over an order magnitude at the IC50. Surprisingly, less active compounds often exhibited higher than more ones. Quantities intracellular inhibitor measured using inoculum effect a linear correlation with heme, suggesting formation heme–inhibitor...
Abstract The pauci-cellular nature of cerebrospinal (CSF), particularly ventricular CSF, and the rapid cell death following sampling, incumbers use flow cytometric analysis these samples in investigation central nervous system (CNS) pathologies. Developing a method that allows long-term storage batched CSF without compromising integrity is highly desirable clinical research, given often sampled after hours creating logistical difficulties for fresh processing. We examined percentages...
A fluorescent analogue of a previously synthesised N,N-chelated IrIII complex was prepared by coordination the organic ligand to an extrinsic bis(2-phenylpyridine)iridium(III) fluorophore. This cyclometallated in itself displays good, micromolar activity against chloroquine-sensitive NF54 strain Plasmodium falciparum. Live-cell confocal microscopy found negligible localisation within digestive vacuole parasite. eliminated haem detoxification pathway as potential mechanism action. Similarly,...