Yes / 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.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/18930 |
| Date | 26 April 2022 |
| Creators | Abacha, Yabalu 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, Steven, Wright, Colin W. |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Article, Published version |
| Rights | © 2022 The Authors. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms., CC-BY |
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