title: Synthesis and evaluation of the antiplasmodial activity of tryptanthrin derivatives.
abstract: Malaria remains one of the most deadly diseases threatening humankind and is still affecting a significant proportion of the world population, especially in Africa. Chemotherapy is a vital component of the fight against the disease and new antimalarial agents are urgently needed to curb the spread of malaria parasites that are resistant to existing drugs. The natural product tryptanthrin is known for its wide range of activities, including antiplasmodial activity, but its poor solubility has undermined its development as potent antimicrobial and antiprotozoan agent. The aim of this work was to synthesize analogues of tryptanthrin and to evaluate their antiplasmodial activity against the asexual and sexual blood stages of Plasmodium falciparum. Our results suggest that most tryptanthrin analogues retained their antiplasmodial activity against chloroquine-sensitive and chloroquine-resistant malaria parasites in the nanomolar range (30-100 nM). The antiplasmodial activity of the most active compound NT1 (IC50: 30 nM; SI: 155.9) was similar in both strains and close to that of chloroquine (IC50: 20 nM) on the sensitive strain. The antiplasmodial activity was improved with derivatization, thus pointing out the necessity to explore tryptanthrin using medicinal chemistry approaches. Ten (10) of the tested derivatives met the criteria, allowing for advancement to animal testing, i.e., SI > 100 and IC50 < 100 nM. In addition to their activity on the asexual stages, tryptanthrin and two selected derivatives (NT1 and T8) prevented the maturation of gametocytes at their IC90 concentrations, indicating a transmission-blocking potential. Moreover, NT1 was able to impair gametogenesis by reducing the exflagellation of microgametes by 20% at IC90, while tryptanthrin and T8 had no influence on exflagellation. The results of this study confirm that tryptanthrin and its derivatives are potential antimalarial candidates with abilities to kill the intraerythrocytic asexual stages and prevent the formation of sexual stages of the parasite.
authors.affiliation: Institute of Molecular Biotechnology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Liliane Abodo
authors.initials: LA
authors.lastname: Onambele
authors.affiliation: HochschuleWeihenstephan-Triesdorf, Organic-analytical Chemistry, 94315 Straubing, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Riepl
authors.affiliation: Institute of Molecular Biotechnology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Institute of Molecular Biotechnology, RWTH Aachen University, 52074 Aachen, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pradel
authors.affiliation: Department of Paediatric Oncology, Children's Hospital Cologne, 50735 Köln, Germany.
authors.forename: Aram
authors.initials: A
authors.lastname: Prokop
authors.affiliation: Institute of Molecular Biotechnology, RWTH Aachen University, 52074 Aachen, Germany ; Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Makoah Nigel
authors.initials: MN
authors.lastname: Aminake
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D006801:Humans; D015394:Molecular Structure; D010963:Plasmodium falciparum / Q000187:drug effects*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D011799:Quinazolines
keywords: Antiplasmodial; Gametocytes; Malaria; Synthesis; Tryptanthrin derivatives