Affiliation:
1. Unit for Environmental Sciences and Management North‐West University Potchefstroom South Africa
2. Centre of Excellence for Pharmaceutical Sciences (PHARMACEN) North‐West University Potchefstroom South Africa
3. Department of Zoology and Entomology University of the Free State Phuthaditjhaba South Africa
4. OIE Reference Laboratory for Surra, National Research Center for Protozoan Diseases Obihiro University of Agriculture and Veterinary Medicine Obihiro Hokkaido Japan
Abstract
AbstractHuman African trypanosomosis (HAT) which is also known as sleeping sickness is caused by Trypanosoma brucei gambiense that is endemic in western and central Africa and T. b. rhodesiense that is endemic in eastern and southern Africa. Drugs used for treatment against HAT first stage have limited effectiveness, and the second stage drugs have been reported to be toxic, expensive, and have time‐consuming administration, and parasitic resistance has developed against these drugs. The aim of this study was to evaluate the anti‐trypanosomal activity of nitrofurantoin‐triazole hybrids against T. b. gambiense and T. b. rhodesiense parasites in vitro. This study screened 19 synthesized nitrofurantoin‐triazole (NFT) hybrids on two strains of human trypanosomes, and cytotoxicity was evaluated on Madin‐Darby bovine kidney (MDBK) cells. The findings in this study showed that an increase in the chain length and the number of carbon atoms in some n‐alkyl hybrids influenced the increase in anti‐trypanosomal activity against T. b. gambiense and T. b. rhodesiense. The short‐chain n‐alkyl hybrids showed decreased activity compared to the long‐chain n‐alkyl hybrids, with increased activity against both T. b. gambiense and T. b. rhodesiense. Incorporation of additional electron‐donating substituents in some NFT hybrids showed increased anti‐trypanosomal activity than to electron‐withdrawing substituents in NFT hybrids. All 19 NFT hybrids tested displayed better anti‐trypanosomal activity against T. b. gambiense than T. b. rhodesiense. The NFT hybrid no. 16 was among the best performing hybrids against both T. b. gambiense (0.08 ± 0.04 μM) and T. b.rhodesiense (0.11 ± 0.06 μM), and its activity might be influenced by the introduction of fluorine in the para‐position on the benzyl ring. Remarkably, the NFT hybrids in this study displayed weak to moderate cytotoxicity on MDBK cells. All of the NFT hybrids in this study had selectivity index values ranging from 18 to greater than 915, meaning that they were up to 10–100 times fold selective in their anti‐trypanosomal activity. The synthesized NFT hybrids showed strong selectivity >10 to T. b. gambiense and T. b. rhodesiense, which indicates that they qualify from the initial selection criteria for potential hit drugs.
Funder
Japan Society for the Promotion of Science
National Research Foundation
Subject
Pharmacology (medical),Pharmacology