title: Identification of a potential lead structure for designing new antimicrobials to treat infections caused by Staphylococcus epidermidis-resistant strains.
abstract: Bacterial infections are a significant cause of morbidity and mortality among critically ill patients. The increase of antibiotic resistance in bacteria from human microbiota-such as Staphylococcus epidermidis, an important nosocomial pathogen that affects immunocompromised patients or those with indwelling devices-increased the desire for new antibiotics. In this study we designed, synthesized, and determined the antimicrobial activity of 27 thieno[2,3-b]pyridines (1, 2, 2a-2m, 3, 3a-3m) derivatives against a drug-resistant clinical S. epidermidis strain. In addition, we performed a structure-activity relationship analysis using a molecular modeling approach, and discuss the drug absorption, distribution, metabolism, excretion, and toxicity profile and Lipinski's "rule of five," which are tools to assess the relationship between structures and drug-like properties of active compounds. Our results showed that compound 3b (5-(1H-tetrazol-5-yl)-4-(3;-methylphenylamino)thieno[2,3-b]pyridine) was as active as oxacillin and chloramphenicol but with lower theoretical toxicity risks and a better drug likeness and drug score potential than chloramphenicol. All molecular modeling and biological results reinforced the promising profile of 3b for further experimental investigation and development of new antibacterial drugs.
authors.affiliation: Instituto de Química, Departamento de Química Orgânica, Programa de Pós-Graduação em Química Orgânica, Universidade Federal Fluminense, Campus do Valonguinho, CEP 24020-150, Niteroi, RJ, Brazil.
authors.forename: Luiz C S
authors.initials: LC
authors.lastname: Pinheiro
authors.forename: Paula A
authors.initials: PA
authors.lastname: Abreu
authors.forename: Ilidio F
authors.initials: IF
authors.lastname: Afonso
authors.forename: Bruno
authors.initials: B
authors.lastname: Leal
authors.forename: Luiz C D
authors.initials: LC
authors.lastname: Corrêa
authors.forename: Júlio C
authors.initials: JC
authors.lastname: Borges
authors.forename: Isakelly P
authors.initials: IP
authors.lastname: Marques
authors.forename: André L
authors.initials: AL
authors.lastname: Lourenço
authors.forename: Plinio
authors.initials: P
authors.lastname: Sathler
authors.forename: Andre L
authors.initials: AL
authors.lastname: dos Santos
authors.forename: Cid A
authors.initials: CA
authors.lastname: Medeiros
authors.forename: Lúcio M
authors.initials: LM
authors.lastname: Cabral
authors.forename: Maurício L O
authors.initials: ML
authors.lastname: Júnior
authors.forename: Gilberto A
authors.initials: GA
authors.lastname: Romeiro
authors.forename: Vitor F
authors.initials: VF
authors.lastname: Ferreira
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Rodrigues
authors.forename: Helena C
authors.initials: HC
authors.lastname: Castro
authors.forename: Alice M R
authors.initials: AM
authors.lastname: Bernardino
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013212:Staphylococcus epidermidis / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D011725:Pyridines