Antitrypanosomal activity of 5-nitro-2-aminothiazole-based compounds

Autor: Shane R. Wilkinson, William D. Bloomer, Marcel Kaiser, Maria V. Papadopoulou, Howard S. Rosenzweig, Joanna Szular
Rok vydání: 2016
Předmět:
0301 basic medicine
Chagas disease
NTD
Neglected tropical diseases
T. cruzi
Trypanosoma cruzi
SI
selectivity index
01 natural sciences
Antitrypanosomal agents
Bnz
benznidazole (N-benzyl-2-(2-nitro-1H-imidazol-1-yl)acetamide)
Parasitic Sensitivity Tests
CYP51
sterol 14α-demethylase enzyme
Drug Discovery
MZSRZQZBRGCXDO-UHFFFAOYSA-N
5-Nitro-2-aminothiazoles
Leishmania
biology
Chemistry
Nfx
nifurtimox (4-(5-nitrofurfurylindenamino)-3-methylthio-morpholine-1
1-dioxide)
SAR
structure-activity relationships
General Medicine
Type I nitroreductase
TcCYP51
T. cruzi CYP51
Trypanocidal Agents
Biochemistry
Benznidazole
Lipophilicity
Research Paper
medicine.drug
Trypanosoma
Stereochemistry
Antiprotozoal Agents
Leishmania donovani
Trypanosoma brucei
Cell Line
TbNTR
T. brucei NTR
Structure-Activity Relationship
03 medical and health sciences
HAT
human African trypanosomiasis
parasitic diseases
medicine
Humans
IC50
concentration for 50% growth inhibition
Amastigote
Trypanosoma cruzi
Trypanocidal agent
Pharmacology
Organic Chemistry
biology.organism_classification
Amides
NTR
type I nitroreductase
0104 chemical sciences
Thiazoles
010404 medicinal & biomolecular chemistry
030104 developmental biology
T. brucei
Trypanosoma brucei
Zdroj: European Journal of Medicinal Chemistry
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2016.04.010
Popis: 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).
Graphical abstract
Highlights • Novel 5-nitro-2-aminothiazole-based amides were synthesized and evaluated for antiparasitic activity. • Most derivatives were active or moderately active against Trypanosoma cruzi and Trypanosoma brucei. • Some analogs demonstrated moderate antileishmanial activity in vitro. • Lipophilicity positively affects antichagasic and antileishmanial activity. • These compounds are not activated by Type I nitroreductases.
Databáze: OpenAIRE
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