Semi-synthetic analogues of cryptolepine as a potential source of sustainable drugs for the treatment of malaria, human African trypanosomiasis, and cancer

Show simple item record Abacha, Yabalu Z. Forkuo, Arnold Donkor Gbedema, Stephen Y. Mittal, Nimisha Ottilie, Sabine Rocamora, Frances Winzeler, Elizabeth A. Van Schalkwyk, Donelly A. Kelly, John M. Taylor, Martin C. Reader, Janette Birkholtz, Lyn-Marie Lisgarten, David R. Cockcroft, Jeremy K. Lisgarten, John N. Palmer, Rex A. Talbert, Rosemary C. Shnyder, Steven D. Wright, Colin W. 2022-09-05T08:00:25Z 2022-09-05T08:00:25Z 2022-04
dc.description.abstract The prospect of eradicating malaria continues to be challenging in the face of increasing parasite resistance to antimalarial drugs so that novel antimalarials active against asexual, sexual, and liver-stage malaria parasites are urgently needed. In addition, new antimalarials need to be affordable and available to those most in need and, bearing in mind climate change, should ideally be sustainable. The West African climbing shrub Cryptolepis sanguinolenta is used traditionally for the treatment of malaria; its principal alkaloid, cryptolepine (1), has been shown to have antimalarial properties, and the synthetic analogue 2,7-dibromocryptolepine (2) is of interest as a lead toward new antimalarial agents. Cryptolepine (1) was isolated using a two-step Soxhlet extraction of C. sanguinolenta roots, followed by crystallization (yield 0.8% calculated as a base with respect to the dried roots). Semi-synthetic 7-bromo- (3), 7, 9-dibromo- (4), 7-iodo- (5), and 7, 9-dibromocryptolepine (6) were obtained in excellent yields by reaction of 1 with N-bromo- or N-iodosuccinimide in trifluoroacetic acid as a solvent. All compounds were active against Plasmodia in vitro, but 6 showed the most selective profile with respect to Hep G2 cells: P. falciparum (chloroquine-resistant strain K1), IC50 = 0.25 µM, SI = 113; late stage, gametocytes, IC50 = 2.2 µM, SI = 13; liver stage, P. berghei sporozoites IC50 = 6.13 µM, SI = 4.6. Compounds 3–6 were also active against the emerging zoonotic species P. knowlesi with 5 being the most potent (IC50 = 0.11 µM). In addition, 3–6 potently inhibited T. brucei in vitro at nM concentrations and good selectivity with 6 again being the most selective (IC50 = 59 nM, SI = 478). These compounds were also cytotoxic to wild-type ovarian cancer cells as well as adriamycin-resistant and, except for 5, cisplatin-resistant ovarian cancer cells. In an acute oral toxicity test in mice, 3–6 did not exhibit toxic effects at doses of up to 100 mg/kg/dose × 3 consecutive days. This study demonstrates that C. sanguinolenta may be utilized as a sustainable source of novel compounds that may lead to the development of novel agents for the treatment of malaria, African trypanosomiasis, and cancer. en_US
dc.description.department Biochemistry en_US
dc.description.department Genetics en_US
dc.description.department Microbiology and Plant Pathology en_US
dc.description.department UP Centre for Sustainable Malaria Control (UP CSMC) en_US
dc.description.librarian hj2022 en_US
dc.description.sponsorship UK Medical Research Council (MRC) and a Medicines for Malaria Venture Grant. en_US
dc.description.uri en_US
dc.identifier.citation Abacha, Y.Z., Forkuo, A.D., Gbedema, S.Y., Mittal, N., Ottilie, S., Rocamora, F., Winzeler, E.A., Van Schalkwyk, D.A., Kelly, J.M., Taylor, M.C., Reader, J., Birkholtz, L.-M., Lisgarten, D.R., Cockcroft, J.K., Lisgarten, J.N., Palmer, R.A., Talbert, R.C., Shnyder, S.D. and Wright, C.W. (2022) Semi-Synthetic Analogues of Cryptolepine as a Potential Source of Sustainable Drugs for the Treatment of Malaria, Human African Trypanosomiasis, and Cancer. Frontiers in Pharmacology 13:875647. doi: 10.3389/fphar.2022.875647. en_US
dc.identifier.issn 1663-9812 (online)
dc.identifier.issn 10.3389/fphar.2022.875647
dc.language.iso en en_US
dc.publisher Frontiers Media en_US
dc.rights © 2022 Abacha, Forkuo, Gbedema, Mittal, Ottilie, Rocamora, Winzeler, van Schalkwyk, Kelly, Taylor, Reader, Birkholtz, Lisgarten, Cockcroft, Lisgarten, Palmer, Talbert, Shnyder and Wright. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). en_US
dc.subject Sustainable pharmaceuticals en_US
dc.subject Halogenation of cryptolepine en_US
dc.subject Plasmodium falciparum en_US
dc.subject Plasmodium knowlesi en_US
dc.subject Trypanosoma brucei en_US
dc.subject Ovarian cancer en_US
dc.title Semi-synthetic analogues of cryptolepine as a potential source of sustainable drugs for the treatment of malaria, human African trypanosomiasis, and cancer en_US
dc.type Article en_US

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