Identification of a potential lead structure for designing new antimicrobials to treat infections caused by Staphylococcus epidermidis-resistant strains.
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.
Pinheiro
Luiz C S
LC
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.
Abreu
Paula A
PA
Afonso
Ilidio F
IF
Leal
Bruno
B
Corrêa
Luiz C D
LC
Borges
Júlio C
JC
Marques
Isakelly P
IP
Lourenço
André L
AL
Sathler
Plinio
P
dos Santos
Andre L
AL
Medeiros
Cid A
CA
Cabral
Lúcio M
LM
Júnior
Maurício L O
ML
Romeiro
Gilberto A
GA
Ferreira
Vitor F
VF
Rodrigues
Carlos R
CR
Castro
Helena C
HC
Bernardino
Alice M R
AM
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
D000900:Anti-Bacterial Agents; D011725:Pyridines