Abstract
When a benzenesulfonyl moiety (BS) was bound to the N-piperazinyl ring of antibacterial fluoroquinolones (AMFQs) norfloxacin (NOR) or ciprofloxacin (CIP), the resulting benzenesulfonyl-fluoroquinolone (BSFQs) analogs showed an improved in vitro activity against Gram-positive strains. A bioisosterical replacement of the sulfonyl group for a carbonyl group led to the benzenecarboxamide-fluoroquinolones (BCFQs) that showed a similar trend in the antibacterial activity and spectrum. The BSFQs and BCFQs are considered members of the "dual targeting" fluoroquinolones, targeting both DNA gyrase and topoisomerase IV. To disclose the real contribution of the BS/BC moiety in anti-staphylococcal activity, a 3D-QSAR analysis that included calculation of theoretical molecular descriptors and pharmacophore generation was performed. Previous and present QSAR results have confirmed the positive influence on activity of small electron donating p-substituent on the BS or BC moiety. The generated phamacophore model showed that both phenyl and SO2/CO groups are involved in the interaction with receptor. We postulate that the enhanced potency of BSFQs against Staphylococcus aureus compared to CIP and NOR could be caused by the presence of the BS moiety that resulted in enhanced binding to DNA gyrase of Sa. Additionally, their greater ability to enter bacterial cells by diffusion and a reduced susceptibility to FQ-specific efflux pumps could also make a contribution.
Keywords: Benzenesulfonyl group, conformational analysis, fluoroquinolones, pharmacophore, QSAR, Staphylococcus, spectrum, benzenecarboxamide, bioisosterical, topoisomerase
Medicinal Chemistry
Title:SAR Analysis of New Dual Targeting Fluoroquinolones. Implications of the Benzenesulfonyl Group
Volume: 8 Issue: 3
Author(s): Marcelo J. Nieto, Adriana B. Pierini, Nidhi Singh, Christopher R. McCurdy, Ruben H. Manzo and aria R. Mazzieri
Affiliation:
Keywords: Benzenesulfonyl group, conformational analysis, fluoroquinolones, pharmacophore, QSAR, Staphylococcus, spectrum, benzenecarboxamide, bioisosterical, topoisomerase
Abstract: When a benzenesulfonyl moiety (BS) was bound to the N-piperazinyl ring of antibacterial fluoroquinolones (AMFQs) norfloxacin (NOR) or ciprofloxacin (CIP), the resulting benzenesulfonyl-fluoroquinolone (BSFQs) analogs showed an improved in vitro activity against Gram-positive strains. A bioisosterical replacement of the sulfonyl group for a carbonyl group led to the benzenecarboxamide-fluoroquinolones (BCFQs) that showed a similar trend in the antibacterial activity and spectrum. The BSFQs and BCFQs are considered members of the "dual targeting" fluoroquinolones, targeting both DNA gyrase and topoisomerase IV. To disclose the real contribution of the BS/BC moiety in anti-staphylococcal activity, a 3D-QSAR analysis that included calculation of theoretical molecular descriptors and pharmacophore generation was performed. Previous and present QSAR results have confirmed the positive influence on activity of small electron donating p-substituent on the BS or BC moiety. The generated phamacophore model showed that both phenyl and SO2/CO groups are involved in the interaction with receptor. We postulate that the enhanced potency of BSFQs against Staphylococcus aureus compared to CIP and NOR could be caused by the presence of the BS moiety that resulted in enhanced binding to DNA gyrase of Sa. Additionally, their greater ability to enter bacterial cells by diffusion and a reduced susceptibility to FQ-specific efflux pumps could also make a contribution.
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Cite this article as:
J. Nieto Marcelo, B. Pierini Adriana, Singh Nidhi, R. McCurdy Christopher, H. Manzo Ruben and R. Mazzieri aria, SAR Analysis of New Dual Targeting Fluoroquinolones. Implications of the Benzenesulfonyl Group, Medicinal Chemistry 2012; 8 (3) . https://dx.doi.org/10.2174/157340612800786633
DOI https://dx.doi.org/10.2174/157340612800786633 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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