title: Antimycobacterial agents. Novel diarylpyrrole derivatives of BM212 endowed with high activity toward Mycobacterium tuberculosis and low cytotoxicity.
abstract: On the basis of suggestions derived either from a pharmacophoric model for antitubercular agents or from a structure-activity relationship analysis of many pyrroles previously described by us, we report here the design and synthesis of new analogues of 1,5-(4-chlorophenyl)-2-methyl-3-(4-methylpiperazin-1-yl)methyl-1H-pyrrole (BM212). Various substituents with different substitution patterns were added to both positions 1 and 5 of the pyrrole nucleus to evaluate their influence on the activity toward Mycobacterium tuberculosis (MTB) and atypical mycobacteria. Biological data showed that, although some nontuberculosis mycobacterial strains were found to be sensitive, MIC values were higher than those found toward MTB. The best compound (1-(4-fluorophenyl)-2-methyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole, 5) possessed a MIC of 0.4 microg/mL (better than BM212 and streptomycin) and a very high protection index (160), better than BM212, isoniazid, and streptomycin (6, 128, and 128, respectively). Finally, molecular modeling studies were performed to rationalize the activity of the new compounds in terms of both superposition onto a pharmacophoric model for antitubercular compounds and their hydrophobic character.
authors.affiliation: Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università La Sapienza, P. le A. Moro 5, 00185 Rome, Italy. mariangela.biava@uniroma1.it
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
authors.forename: Giulio Cesare
authors.initials: GC
authors.lastname: Porretta
authors.forename: Giovanna
authors.initials: G
authors.lastname: Poce
authors.forename: Sibilla
authors.initials: S
authors.lastname: Supino
authors.forename: Delia
authors.initials: D
authors.lastname: Deidda
authors.forename: Raffaello
authors.initials: R
authors.lastname: Pompei
authors.forename: Paola
authors.initials: P
authors.lastname: Molicotti
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002522:Chlorocebus aethiops; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D021281:Quantitative Structure-Activity Relationship; D014709:Vero Cells
chemical_list: C513369:1-(4-fluorophenyl)-2-methyl-3-(thiomorpholin-4-yl)methyl-5-(4-methylphenyl)-1H-pyrrole; D000995:Antitubercular Agents; D009025:Morpholines; D010879:Piperazines; D011758:Pyrroles; C115651:BM 212