title: Synthesis, antimicrobial activity and molecular modeling studies of halogenated 4-[1H-imidazol-1-yl(phenyl)methyl]-1,5-diphenyl-1H-pyrazoles.
abstract: During the course of our studies in the azole antifungals area, we synthesized a number of 1,5-disubstituted 4-[1H-imidazol-1-yl(phenyl)methyl]-1H-pyrazoles, analogues of bifonazole. 1,5-Diphenyl-1H-pyrazole 3 showed weak antimycotic and antibacterial activities in vitro against Candida albicans, Cryptococcus neoformans and Staphylococcus aureus. In order to increase these properties, given that the halo substitution was found to be capable of enhancing antifungal effects, we prepared a series of fluoro and chloro derivatives of 3. The microbiological evaluation carried out on newly synthesized compounds included in vitro assays for antifungal, antibacterial and antimycobacterial activities. Among the tested compounds, some dichloro and trichloro-derivatives showed interesting antimicrobial properties. In particular, compounds 10j,k,l produced inhibitory effects against pathogen representatives of yeast (C. albicans, C. neoformans) and Gram positive bacteria (S. aureus) similar or superior to those of bifonazole. In addition, their activity against Mycobacterium tuberculosis was superior to that of clotrimazole and econazole, which were used as reference drugs. The replacement, in these compounds, of chlorine with fluorine atoms led to inactive derivatives. Docking studies were carried out on the most active compounds, in order to rationalize the pharmacological results.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, 16132 Genova, Italy. menozzi@unige.it
authors.forename: Giulia
authors.initials: G
authors.lastname: Menozzi
authors.forename: Luisa
authors.initials: L
authors.lastname: Merello
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Luisa
authors.initials: L
authors.lastname: Mosti
authors.forename: Francesco
authors.initials: F
authors.lastname: Bondavalli
authors.forename: Roberta
authors.initials: R
authors.lastname: Loddo
authors.forename: Chiara
authors.initials: C
authors.lastname: Murgioni
authors.forename: Valeria
authors.initials: V
authors.lastname: Mascia
authors.forename: Paolo
authors.initials: P
authors.lastname: La Colla
authors.forename: Elena
authors.initials: E
authors.lastname: Tamburini
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000737:chemistry; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D006846:Hydrocarbons, Halogenated; D007093:Imidazoles; D011720:Pyrazoles; C036596:bifonazole