Antimycobacterial agents. Novel diarylpyrrole derivatives of BM212 endowed with high activity toward Mycobacterium tuberculosis and low cytotoxicity.
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.
Biava
Mariangela
M
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
Porretta
Giulio Cesare
GC
Poce
Giovanna
G
Supino
Sibilla
S
Deidda
Delia
D
Pompei
Raffaello
R
Molicotti
Paola
P
Manetti
Fabrizio
F
Botta
Maurizio
M
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
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