Studies toward the structural optimization of new brazilizone-related trypanocidal 1,3,4-thiadiazole-2-arylhydrazone derivatives

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 1; pp. 413 - 421
• Main Authors: Carvalho, Samir A., Lopes, Francisco A.S., Salomão, Kelly, Romeiro, Nelilma C., Wardell, Solange M.S.V., de Castro, Solange L., da Silva, Edson F., Fraga, Carlos A.M.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 2008; Elsevier Science
• Subjects: 1,3,4-Thiadiazole-2-arylhydrazone; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiparasitic agents; Biological and medical sciences; Chagas’ disease; Chemotherapy; CoMFA model; Crystallography, X-Ray; Hydrazones - chemical synthesis; Hydrazones - chemistry; Hydrazones - pharmacology; Medical sciences; Megazol; Molecular Structure; Parasitic Sensitivity Tests; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; Structure-Activity Relationship; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - pharmacology; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - pharmacology; Trypanosoma - drug effects; Trypanosoma cruzi; Chemotherapy; 1,3,4-Thiadiazole-2-arylhydrazone; CoMFA model; Megazol; Chagas’ disease; Trypanosoma cruzi; Nitro compound; Imidazole derivatives; Five membered ring; Nitrogen heterocycle; Modeling; Antiprotozoal agent; Absorption; Structure activity relation; Molecular model; Comparative molecular field analysis method; Hydrazone; Kinetoplastida; Protozoa; Sulfur nitrogen heterocycle; Benzene derivatives; Prediction; In vitro; Three dimensional model; Phenols; Parasiticide; Chagas' disease
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.09.027

We describe herein a 3D-QSAR model constructed with trypanocidal agents structurally-related to Brazilizone A (
2) and the discovery of the 1,3,4-thiadiazole-2-arylhydrazone derivative (
15), named Brazilizone N, as a novel potent antichagasic lead-candidate.
Megazol is a highly active compound against
Trypanosoma cruzi, and has become a core structure for the design of new trypanocidal agents. Recently, we have identified the new potent trypanocide agent Brazilizone A, which presents an IC
50 twofold more potent than the prototype megazol. This result has encouraged us to further explore structurally-related 1,3,4-thiadiazole-2-arylhydrazone derivatives, in order to get a better understanding of their structural and antiprotozoal activity relationships. Herein we report the synthesis and trypanocidal profile of thirteen new Brazilizone A analogues, which supported the construction of 3D-QSAR models used for its structural optimization.