title: Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors.
abstract: We are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure-activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity.
authors.affiliation: Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); and Pharmaceutical and Medicinal Chemistry, Saarland University , Campus E8.1, 66123 Saarbrücken, Germany.
authors.forename: Walid A M
authors.initials: WA
authors.lastname: Elgaher
authors.affiliation: Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, UMR 7213 CNRS, Université de Strasbourg, 74 Route du Rhin, 67401 Illkirch, France.
authors.forename: Kamal K
authors.initials: KK
authors.lastname: Sharma
authors.affiliation: Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); and Pharmaceutical and Medicinal Chemistry, Saarland University , Campus E8.1, 66123 Saarbrücken, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Haupenthal
authors.affiliation: Department of Medical Biotechnologies, University of Siena , Viale Mario Bracci 16, 53100 Siena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Saladini
authors.affiliation: Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, UMR 7213 CNRS, Université de Strasbourg, 74 Route du Rhin, 67401 Illkirch, France.
authors.forename: Manuel
authors.initials: M
authors.lastname: Pires
authors.affiliation: Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, UMR 7213 CNRS, Université de Strasbourg, 74 Route du Rhin, 67401 Illkirch, France.
authors.forename: Eleonore
authors.initials: E
authors.lastname: Real
authors.affiliation: Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, UMR 7213 CNRS, Université de Strasbourg, 74 Route du Rhin, 67401 Illkirch, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Mély
authors.affiliation: Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS); and Pharmaceutical and Medicinal Chemistry, Saarland University , Campus E8.1, 66123 Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006678:HIV / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C514200:2-ureidothiophene-3-carboxylate; D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D013876:Thiophenes; D012194:RNA-Directed DNA Polymerase; D012321:DNA-Directed RNA Polymerases