Our current medicinal chemistry programme on anti-infective (anti-malarial, anti-tuberculosis, anti-HIV/AIDS), anti-hypertension and anti-cancer agents has three main objectives:
 

(i) to develop target-directed inhibitors

(ii) to develop single agents that provide target-directed inhibition of multiple disease-causing organisms or cells

(iii) to develop single agents that provide maximal anti-infective and anti-cancer activity by acting against multiple targets.

More recently, we have initiated a major research programme aimed at integrating African natural products and biodiversity research into modern drug discovery paradigms. This project is partly under the auspices of the Medical Research Council (MRC) Drug Discovery and Development Research Unit (http://www.mrc.ac.za/drug/drug.htm). Specifically we are creating a technology platform that will allow the exploration of the potential of African natural products and general biodiversity to feed into modern paradigms of drug discovery in the form of a virtual database and actual physical collection of purified and characterized African natural products. We are pursuing virtual (in silico) screening of African natural product libraries against novel and validated molecular targets of infectious diseases. As part of a programme to diversify and enrich the collection of purified African natural products, we have set up a biotransformation platform for combinatorial biocatalysis mediated by a panel of recombinant bacterial and human cytochrome P450s.

KC’s earlier work has included asymmetric synthesis utilizing sulfur and organolanthanide chemistry as well as the total synthesis of natural and designed biologically relevant molecules.

[1] K. Chibale, N. Greeves, L. Lyford and E.J. Pease. New Homochiral Binaphthol-Modified Organolanthanide Reagents for the Enantioselective Addition to Aldehydes. Tetrahedron: Asymmetry 1993, 4, 2407-2410.
[2] K. Chibale and S. Warren. Kinetic Resolution in Asymmetric Anti Aldol Reactions of Branched and Straight Chain Racemic 2-Phenylsulfanyl Aldehydes: Asymmetric Synthesis of Cyclic Ethers and Lactones by Phenylsulfanyl Migration. J. Chem. Soc., Perkin Trans.1, 1996, 1935-1940.
[3] K.C. Nicolaou, J.I. Trujillo and K. Chibale. Design, Synthesis and Biological Evaluation of Carbohydrate-Based Mimetics of cRGDFV. Tetrahedron 1997, 53, 8751-8778.
[4] Synthesis and Structure Activity Relationships of Parasiticidal Thiosemicarbazone Cysteine Protease Inhibitors against P.falciparum, T. brucei and T. cruzi. D. Greenbaum, Z. Mackey, E. Hansell, P. Doyle, J. Gut, C. R. Caffrey, J. Lehman, P. J. Rosenthal, J. H. McKerrow, and K. Chibale. J. Med. Chem. 2004, 47, 3212-3219.
[5] The new permeability pathways: targets and selective routes for the development of new antimalarial agents. H. M. Staines, J. C. Ellory and K. Chibale. Combinatorial Chemistry and High Throughput Screening 2005, 8, 81-88.
[6] Economic drug discovery and rational medicinal chemistry for tropical diseases. K. Chibale. Pure & Applied Chemistry 2005, 77, 1957-1964.
[7] Arylpiperazines displaying preferential potency against chloroquine-resistant strains of the malaria parasite Plasmodium falciparum. C.-A. Molyneaux, M. Krugliak, H. Ginsburg, and K. Chibale Biochemical Pharmacology. 2005, 71, 61-68.
[8] Novel Ketomethylene Inhibitors of Angiotensin-I Converting Enzyme (ACE): Inhibition and Molecular Modelling. P. Redelinghuys, A. T. Nchinda, K. Chibale and E. D. Sturrock Biological Chemistry, 2006, 387, 461-466.
[9] Novel approaches to antimalarial drug discovery. C. Biot and K. Chibale, Infectious Disorders- Drug Targets-, 2006, 6, 173-204.
[10] Application of Multi-Component Reactions to Antimalarial Drug Discovery. Part 2. New Antiplasmodial and Antitrypanosomal 4- Aminoquinoline γ– and δ Lactams via a “Catch and Release” Protocol. C. C. Musonda, J. Gut, P. J. Rosenthal V. Yardley, R. C. Carvalho de Souza and K. Chibale. Bioorg. Med. Chem. 2006, 14, 5605-5615.
[11] Purification of human malaria parasite hypoxanthine guanine xanthine phosphoribosyltransferase (HGXPRT) using immobilized Reactive Red 120. B. Mbewe, K. Chibale and D. B. McIntosh. Protein Expression and Purification 2007, 52, 153-158.
[12] Antiplasmodial hirsutinolides from Vernonia staehelinoides and their utilization towards a novel simplified pharmacophore. P. Pillay, R. Vleggaar, V. J. Maharaj, P. J. Smith, C. A. Lategan,. F. Chouteau and K. Chibale. Phytochemistry 2007, 68, 1200-1205.
[13] Chemoselectivity and unusual internal acetal formation in the synthesis of a glycosidation precursor. A. T. Stevens, J. R. Bull and K. Chibale. Synlett 2007, 3175-3179.
[14] Effect of varying the anionic component of a copper (I) catalyst on homologation of arylacetylenes to allenes by the Mannich reaction. V. Kumar, A. Chipeleme and K. Chibale. Eur. J. Org. Chem. 2008, 43-46.
[15] Studies in Iridoid Synthesis. Chemoselective Transformations of Cis-1,2,4,6-Tetrahydrophthalic Anhydride. A. T. Stevens, J. R. Bull and K. Chibale. Org. Biomol. Chem., 2008, 6, 586-595.
[16] Novel web-based tools combining chemistry informatics, biology and social networks for drug discovery. M. Hohman, K. Gregory, K. Chibale, P.J. Smith, S. Ekins and B. Bunin. Drug Discovery Today, 2009,14, 261-70.
[17] Synthesis of novel anti-2-alkoxy-3-amino-3-arylpropan-1-ols and cis-5-alkoxy-4aryl-1,3-oxazinanes with antimalarial activity. M. D’hooghe, P. J. Smith, S. Dekeukeleire, K. Mollet, K. Chibale and N. De Kimpe J. Med. Chem. 2009, 52, 4058-4062.