Antimycobacterial Agents. Novel Diarylpyrrole Derivatives of BM212 Endowed with High Activity toward Mycobacterium tuberculosis and Low Cytotoxicity
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- 作者：Mariangela Biava ; Giulio Cesare Porretta ; Giovanna Poce ; Sibilla Supino ; Delia Deidda ; Raffaello Pompei ; Paola Molicotti ; Fabrizio Manetti ; Maurizio Botta
- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：August 10, 2006
- 年：2006
- 卷：49
- 期：16
- 页码：4946 - 4952
- 全文大小：145K
- 年卷期：v.49,no.16(August 10, 2006)
- ISSN：1520-4804
文摘
On the basis of suggestions derived either from a pharmacophoric model for antitubercular agents or froma structure-activity relationship analysis of many pyrroles previously described by us, we report here thedesign 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 positions1 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 mycobacterialstrains 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 aMIC of 0.4 
g/mL (better than BM212 and streptomycin) and a very high protection index (160), betterthan BM212, isoniazid, and streptomycin (6, 128, and 128, respectively). Finally, molecular modeling studieswere performed to rationalize the activity of the new compounds in terms of both superposition onto apharmacophoric model for antitubercular compounds and their hydrophobic character.
g/mL (better than BM212 and streptomycin) and a very high protection index (160), betterthan BM212, isoniazid, and streptomycin (6, 128, and 128, respectively). Finally, molecular modeling studieswere performed to rationalize the activity of the new compounds in terms of both superposition onto apharmacophoric model for antitubercular compounds and their hydrophobic character.