Abstract
A small series of 5-nitro-2-aminothiazole-based amides containing arylpiperazine-, biphenyl- or aryloxyphenyl groups in their core were synthesized and evaluated as antitrypanosomatid agents. All tested compounds were active or moderately active against Trypanosoma cruzi amastigotes in infected L6 cells and Trypanosoma brucei brucei, four of eleven compounds were moderately active against Leishmania donovani axenic parasites while none were deemed active against T. brucei rhodesiense. For the most active/moderately active compounds a moderate selectivity against each parasite was observed. There was good correlation between lipophilicity (clogP value) and antileishmanial activity or toxicity against L6 cells. Similarly, good correlation existed between clogP values and IC50 values against T. cruzi in structurally related subgroups of compounds. Three compounds were more potent as antichagasic agents than benznidazole but were not activated by the type I nitrorectusase (NTR).
Highlights
American trypanosomiasis (Chagas disease), human African trypanosomiasis (HAT or sleeping sickness) and leishmaniasis are considered neglected tropical diseases (NTD) and represent a severe global health problem [1,2]
African trypanosomiasis is endemic in Abbreviations: NTD, Neglected tropical diseases; T. brucei, Trypanosoma brucei; HAT, human African trypanosomiasis; T. cruzi, Trypanosoma cruzi; Bnz, benznidazole (N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide); Nfx, nifurtimox (4-(5nitrofurfurylindenamino)-3-methylthio-morpholine-1,1-dioxide); NTR, type I nitroreductase; TbNTR, T. brucei NTR; CYP51, sterol 14a-demethylase enzyme; TcCYP51, T. cruzi CYP51; IC50, concentration for 50% growth inhibition; SI, selectivity index; SAR, structure-activity relationships
We have shown that several chemical classes of 3-nitro-1H1,2,4-triazole-based compounds exhibit excellent antichagasic activity both in vitro and in vivo [18e25]
Summary
American trypanosomiasis (Chagas disease), human African trypanosomiasis (HAT or sleeping sickness) and leishmaniasis are considered neglected tropical diseases (NTD) and represent a severe global health problem [1,2]. African trypanosomiasis is endemic in Abbreviations: NTD, Neglected tropical diseases; T. brucei, Trypanosoma brucei; HAT, human African trypanosomiasis; T. cruzi, Trypanosoma cruzi; Bnz, benznidazole (N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide); Nfx, nifurtimox (4-(5nitrofurfurylindenamino)-3-methylthio-morpholine-1,1-dioxide); NTR, type I nitroreductase; TbNTR, T. brucei NTR; CYP51, sterol 14a-demethylase enzyme; TcCYP51, T. cruzi CYP51; IC50, concentration for 50% growth inhibition; SI, selectivity index; SAR, structure-activity relationships. Leishmaniasis, caused by more than 20 Leishmania species, occurs throughout tropical and sub-tropical regions and is spreading worldwide as an HIV co-infection [5]. Treatment of these NTD is currently based on a series of problematic drugs. We have synthesized and evaluated in vitro a small series of 5-nitro-2-aminothiazole-based compounds bearing moieties that were previously proven effective in the trypanocidal activity of 3-nitrotriazole-based agents
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