Purpose: Continuous efforts into the discovery and development of new antimalarials are required to face the emerging resistance of the parasite to available treatments. Thus, new effective drugs, ideally able to inhibit the Plasmodium life-cycle stages that cause the disease as well as those responsible for its transmission, are needed. Eight compounds from the Medicines for Malaria Venture (MMV) Malaria Box, potentially interfering with the parasite polyamine biosynthesis were selected and assessed in vitro for activity against malaria transmissible stages, namely mature gametocytes and early sporogonic stages. Methods: Compound activity against asexual blood stages of chloroquine-sensitive 3D7 and chloroquine-resistant W2 strains of Plasmodium falciparum was tested measuring the parasite lactate dehydrogenase activity. The gametocytocidal effect was determined against the P. falciparum 3D7elo1-pfs16-CBG99 strain with a luminescent method. The murine P. berghei CTRP.GFP strain was employed to assess compounds activities against early sporogonic stage development in an in vitro assay simulating mosquito midgut conditions. Results: Among the eight tested molecules, MMV000642, MMV000662 and MMV006429, containing a 1,2,3,4-tetrahydroisoquinoline-4-carboxamide chemical skeleton substituted at N-2, C-3 and C-4, displayed multi-stage activity. Activity against asexual blood stages of both strains was confirmed with values of IC50 (50% inhibitory concentration) in the range of 0.07–0.13 µM. They were also active against mature stage V gametocytes with IC50 values below 5 µM (range: 3.43–4.42 µM). These molecules exhibited moderate effects on early sporogonic stage development, displaying IC50 values between 20 and 40 µM. Conclusion: Given the multi-stage, transmission-blocking profiles of MMV000642, MMV000662, MMV006429, and their chemical characteristics, these compounds can be considered worthy for further optimisation toward a TCP5 or TCP6 target product profile proposed by MMV for transmission-blocking antimalarials.
In vitro multistage malaria transmission blocking activity of selected malaria box compounds / H.M. Malebo, S. D'alessandro, Y.A. Ebstie, H. Sore, A.R.T. Guedoung, S.J. Katani, S. Parapini, D. Taramelli, A. Habluetzel. - In: DRUG DESIGN, DEVELOPMENT AND THERAPY. - ISSN 1177-8881. - 14(2020 Apr 28), pp. 1593-1607.
|Titolo:||In vitro multistage malaria transmission blocking activity of selected malaria box compounds|
D'ALESSANDRO, SARAH (Secondo) [Investigation]
PARAPINI, SILVIA [Investigation] (Corresponding)
TARAMELLI, DONATELLA [Supervision]
|Parole Chiave:||Malaria elimination; Multi-stage antimalarials; Plasmodium; Transmission blocking drugs|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
Settore MED/07 - Microbiologia e Microbiologia Clinica
Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio
|Progetto:||Towards multi-stage drugs to fight poverty related and neglected parasitic diseases: synthetic and natural compounds directed against Leishmania, Plasmodium and Schistosoma life stages and assessment of their mechanisms of action.|
|Data di pubblicazione:||28-apr-2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.2147/DDDT.S242883|
|Appare nelle tipologie:||01 - Articolo su periodico|