ABSTRACT
Human African Trypanosomiasis (HAT), caused by Trypanosoma brucei gambiense and rhodesiense, is a parasitic disease endemic to sub-Saharan Africa. Untreated cases of HAT can be severely debilitating and fatal. Although the number of reported cases has decreased progressively over the last decade, the number of effective and easily administered medications is very limited. In this work, we report the antitrypanosomal activity of a series of potent compounds. A subset of molecules in the series are highly selective for trypanosomes and are metabolically stable. One of the compounds, (E)-N-(4-(methylamino)-4-oxobut-2-en-1-yl)-5-nitrothiophene-2-carboxamide (10), selectively inhibited the growth of T. b. brucei, T. b. gambiense and T. b. rhodesiense, have excellent oral bioavailability and was effective in treating acute infection of HAT in mouse models. Based on its excellent bioavailability, compound 10 and its analogs are candidates for lead optimization and pre-clinical investigations.
Subject(s)
Trypanocidal Agents , Trypanosoma brucei brucei , Trypanosomiasis, African , Animals , Mice , Humans , Trypanosoma brucei rhodesiense , Trypanocidal Agents/pharmacology , Trypanocidal Agents/therapeutic use , Trypanosomiasis, African/drug therapy , Trypanosomiasis, African/parasitology , Trypanosoma brucei gambienseABSTRACT
The number of reported cases of Human African Trypanosmiasis (HAT), caused by kinetoplastid protozoan parasite Trypanosoma brucei, is declining in sub-Saharan Africa. Historically, such declines are generally followed by periods of higher incidence, and one of the lingering public health challenges of HAT is that its drug development pipeline is historically sparse. As a continuation of our work on new antitrypanosomal agents, we found that partially saturated quinoline-based vinyl sulfone compounds selectively inhibit the growth of T. brucei but displayed relatively weak inhibitory activity towards T. brucei's cysteine protease rhodesain. While two nitroaromatic analogues of the quinoline-based vinyl sulfone compounds displayed potent inhibition of T. brucei and rhodesain. The quinoline derivatives and the nitroaromatic-based compounds discovered in this work can serve as leads for ADME-based optimization and pre-clinical investigations.
Subject(s)
Antiprotozoal Agents/pharmacology , Cysteine Proteases/metabolism , Cysteine Proteinase Inhibitors/pharmacology , Sulfones/pharmacology , Trypanosoma brucei brucei/drug effects , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/chemistry , Trypanosoma brucei brucei/growth & development , Trypanosoma brucei brucei/metabolismABSTRACT
Medical evidence has continued to be given and evaluated in Nigerian courts since Nigeria's independence from Britain. The attitudes of the courts have been largely varied against a background of the individual judge's appreciation of forensic science and who should be considered an expert witness. The prosecution and defence lawyers equally display limited knowledge of forensic science. This paper reviews some of the decided cases, the reasons for the verdicts, forensic concerns and recommendations for the improvement of the criminal justice system. There is need to improve the knowledge base of the bar and the bench.
