Synthesis of nitro(benzo)thiazole acetamides and in vitro antiprotozoal effect against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis.
We synthesized four 5-nitrothiazole (1-4) and four 6-nitrobenzothiazole acetamides (5-8) using an easy two step synthetic route. All compounds were tested in vitro against amitochondriate parasites Giardia intestinalis and Trichomonas vaginalis, showing excellent antiprotozoal effects. IC₅₀'s of the most potent compounds range from nanomolar to low micromolar order, being more active than their drugs of choice. Compound 1 (IC₅₀=122 nM), was 44-times more active than Metronidazole, and 10-fold more effective than Nitazoxanide against G. intestinalis and showed good trichomonicidal activity (IC₅₀=2.24 μM). This compound did not display in vitro cytotoxicity against VERO cells. The in vitro inhibitory effect of compounds 1-8 and Nitazoxanide against G. intestinalis fructose-1,6-biphosphate aldolase (GiFBPA) was evaluated as potential drug target, showing a clear inhibitory effect over the enzyme activity. Molecular docking of compounds 1, 4 and Nitazoxanide into the ligand binding pocket of GiFBPA, revealed contacts with the active site residues of the enzyme. Ligand efficiency metrics of 1 revealed optimal combinations of physicochemical and antiprotozoal properties, better than Nitazoxanide.
['Navarrete-Vázquez|Gabriel|G|', 'Chávez-Silva|Fabiola|F|', 'Colín-Lozano|Blanca|B|', 'Estrada-Soto|Samuel|S|', 'Hidalgo-Figueroa|Sergio|S|', 'Guerrero-Álvarez|Jorge|J|', 'Méndez|Sara T|ST|', 'Reyes-Vivas|Horacio|H|', 'Oria-Hernández|Jesús|J|', 'Canul-Canché|Jaqueline|J|', 'Ortiz-Andrade|Rolffy|R|', 'Moo-Puc|Rosa|R|']
D000081:Acetamides D000818:Animals D000981:Antiprotozoal Agents D052160:Benzothiazoles D002470:Cell Survival D002522:Chlorocebus aethiops D004305:Dose-Response Relationship, Drug D004791:Enzyme Inhibitors D005634:Fructose-Bisphosphate Aldolase D016829:Giardia lamblia D056004:Molecular Dynamics Simulation D015394:Molecular Structure D009574:Nitro Compounds D021261:Parasitic Sensitivity Tests D013329:Structure-Activity Relationship D013844:Thiazoles D014246:Trichomonas vaginalis D014709:Vero Cells
Giardia Nitazoxanide Aldolase Docking