title: Synthesis and biological evaluation of benzimidazole-5-carbohydrazide derivatives as antimalarial, cytotoxic and antitubercular agents.
abstract: A series of N'-substituted-2-(5-nitrofuran or 5-nitrothiophen-2-yl)-3H-benzo[d]imidazole-5-carbohydrazide derivatives were synthesized and investigated for their abilities to inhibit β-hematin formation, hemoglobin hydrolysis and in vivo for their antimalarial efficacy in rodent Plasmodium berghei. Selected analogues were screened for their antitubercular activity against sensitive MTB H(37)Rv and multidrug-resistant MDR-MTB strains, and cytotoxic activity against a panel of human tumor cell lines and two nontumourogenic cell lines. Compounds 3a, 5a, f, 6g were the most promising as inhibitors of β-hematin formation, however, their effect as inhibitors of hemoglobin hydrolysis were marginal. The most active compounds to emerge from the in vitro and in vivo murine studies were 3a and 6i, suggesting an antimalarial activity via inhibition of β-hematin formation and are as efficient as chloroquine. The cytotoxic and antitubercular activities of the present compounds were not comparable with those of the standard drugs employed. But, however, compound 5b showed better antitubercular activity compared to rifampin against multidrug-resistant MDR-MTB strains. Compounds 3a, 6i and 5b showed a good safety index.
authors.affiliation: Laboratorio de Síntesis Orgánica, Universidad Central de Venezuela, Aptdo. 47206, Los Chaguaramos, 1041-A Caracas, Venezuela.
authors.forename: José
authors.initials: J
authors.lastname: Camacho
authors.forename: Arthur
authors.initials: A
authors.lastname: Barazarte
authors.forename: Neira
authors.initials: N
authors.lastname: Gamboa
authors.forename: Juan
authors.initials: J
authors.lastname: Rodrigues
authors.forename: Rosario
authors.initials: R
authors.lastname: Rojas
authors.forename: Abraham
authors.initials: A
authors.lastname: Vaisberg
authors.forename: Robert
authors.initials: R
authors.lastname: Gilman
authors.forename: Jaime
authors.initials: J
authors.lastname: Charris
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001562:Benzimidazoles / Q000737:chemistry*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D006427:Hemin / Q000037:antagonists & inhibitors / Q000378:metabolism; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D006868:Hydrolysis; D051379:Mice; D010961:Plasmodium / Q000187:drug effects
chemical_list: D000962:Antimalarials; D000995:Antitubercular Agents; D001562:Benzimidazoles; D006454:Hemoglobins; D006834:Hydrazines; D006427:Hemin; C031000:benzimidazole; C019289:carbohydrazide