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Ongarora D.S.B.,University of Cape Town | Gut J.,University of California at San Francisco | Rosenthal P.J.,University of California at San Francisco | Masimirembwa C.M.,Harare Institute of Technology | Chibale K.,University of Cape Town
Bioorganic and Medicinal Chemistry Letters

The synthesis and evaluation of antiplasmodial activity of benzothiazole, benzimidazole, benzoxazole and pyridine analogues of amodiaquine is hereby reported. Benzothiazole and benzoxazole analogues with a protonatable tertiary nitrogen atom possessed excellent activity against the W2 and K1 chloroquine resistant strains of Plasmodium falciparum, with IC50s ranging from 7 to 22 nM. © 2012 Elsevier Ltd. All rights reserved. Source

Awortwe C.,Stellenbosch University | Bouic P.J.,Synexa Life science | Bouic P.J.,Stellenbosch University | Masimirembwa C.M.,Harare Institute of Technology | Rosenkranz B.,Stellenbosch University
Drug Metabolism Letters

The purpose of this study was to evaluate the potential risk of common herbal medicines used by HIV-infected patients in Africa for herb-drug interactions (HDI). High throughput screening assays consisting of recombinant Cytochrome P450 enzymes (CYPs) and fluorescent probes, and parallel artificial membrane permeability assays (PAMPA) were used. The potential of herbal medicines to cause HDI was ranked according to FDA guidelines for reversible inhibition and categorization of time dependent inhibition was based on the normalized ratio. CYPs 1A2 and 3A4 were most inhibited by the herbal extracts. H. hemerocallidea (IC50 = 0.63 μg/mL and 58 μg/mL) and E. purpurea (IC50 = 20 μg/mL and 12 μg/mL) were the potent inhibitors of CYPs 1A2 and 3A4 respectively. L. frutescens and H. hemerocallidea showed clear time dependent inhibition on CYP3A4. Furthermore, the inhibitory effect of both H. hemerocallidea and L. frutescens before and after PAMPA were identical. The results indicate potential HDI of H. hemerocallidea, L. frutescens and E. purpurea with substrates of the affected enzymes if maximum in vivo concentration is achieved. © 2013 Bentham Science Publishers. Source

Ziuku S.,Harare Institute of Technology | Seyitini L.,Great Zimbabwe University | Mapurisa B.,Great Zimbabwe University | Chikodzi D.,Great Zimbabwe University | van Kuijk K.,VU University Amsterdam
Energy for Sustainable Development

This study seeks to assess the potential of utilizing Concentrated Solar Power for electricity generation in Zimbabwe. Data from 26 meteorological stations which are widely distributed around the country was used to map the distribution of solar radiation. Geographic information systems were employed to locate sites with potential for installing concentrating solar power plants. Areas with good potential were identified by using the following assessment factors: direct normal irradiance (DNI), proximity to transmission lines and water bodies, flatness of the area and the vulnerability of vegetation and wild life. After considering all the assessment factors, a total area of 250000km2 was found to be suitable. If only 10% of the suitable land area is used and the technology with the least efficiency (8-10%) is adopted, about 71.4GW can be generated. The projected power generation is about thirty times the current power demand of the country. © 2014 Elsevier Ltd. Source

Ericsson T.,Gothenburg University | Masimirembwa C.,Harare Institute of Technology | Abelo A.,Gothenburg University | Ashton M.,Gothenburg University
Drug Metabolism Letters

Artemisinin-based combination therapy (ACT) is the recommended treatment of uncomplicated P.falciparum malaria by the World Health Organisation (WHO). Some artemisinin compounds and anti-retroviral drugs have been shown to be metabolized by CYP2B6. In the African clinical settings, the likelihood of co-administration of ACTs and antiretroviral drugs is higher than elsewhere, posing the risk of drug-drug interactions (DDIs). This study aimed to investigate whether artemisinin compounds inhibit CYP2B6 activity in vitro using recombinant CYP2B6 (rCYP2B6) and human liver microsomes (HLM). Values for IC50 and Ki were determined by kinetic analyses using non-linear regression. In vitro to in vivo extrapolations of the likelihood of DDIs where done using a static [I]/Ki approach. Artemisinin and artemether were shown to inhibit CYP2B6 in vitro through a partial mixed type of inhibition, while dihydroartemisinin did not inhibit the enzymatic activity. IC50 values for artemisinin were 9.5 and 9.1 μM for rCYP2B6 and HLM, respectively, after 30 min of incubation. Corresponding values for artemether were 7.5 and 5.4 μM. Artemisinin did not show any time-dependency or requirement of NADPH in its mechanism, indicating a reversible mode of inhibition. Based on the [I]/Ki approach using rCYP2B6, the risk of DDIs for artemisinin was indicated to be medium to high, while artemether had a low risk. The findings indicate a potential but moderate risk of DDIs in the co-administration of artemisinin or artemether with efavirenz in the co-treatment of malaria and HIV/AIDS. © 2013 Bentham Science Publishers. Source

Njuguna N.M.,University of Cape Town | Masimirembwa C.,Harare Institute of Technology | Chibale K.,University of Cape Town
Journal of Natural Products

Toxicity of natural products arising from their metabolic biotransformation into reactive chemical intermediates is an important reason for high attrition rates in early drug discovery efforts. Screening promising natural products for their likelihood to form such metabolites is therefore an important step in identifying potential liabilities in the drug development process. However, such screening is complicated by the need to have test methods that are sensitive, reliable, accurate, efficient, and cost-effective enough to allow for routine identification and characterization of the reactive metabolites. These metabolites are typically formed in minute quantities, usually through minor metabolic pathways, and, due to their highly reactive and therefore transient chemical nature, pose considerable analytical challenges in attempts to determine their properties. Understanding the formation of reactive metabolites may be used as the basis for synthetic chemical modification of parent natural products aimed at bypassing such harmful bioactivation. This paper highlights the general principles and protocols commonly used to predict and study the formation of reactive metabolites in vitro and how the data obtained from such studies can be used in the development of safer drugs from natural products. © 2012 The American Chemical Society and American Society of Pharmacognosy. Source

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