Identification of nor-β-lapachone derivatives as potential antibacterial compounds against Enterococcus faecalis clinical strain.
A broad-spectrum antibiotic therapy has led to medical complications and emergence of multiresistant bacteria including Enterococcus faecalis. In this study, we designed, synthesized, and evaluated the antibacterial activity of 13 nor-β-lapachone derivatives against a drug resistant E. faecalis strain. Two triazole substituted compounds (1e = 8 μg/ml and 1c = 16 μg/ml) and the non-substituted derivative (1a = 8 μg/ml) were promising compared to chloramphenicol (12 μg/ml), an antibiotic currently available in the market. We also performed a structure-activity relationship analysis using a molecular modeling approach that pointed the low HOMO energy values; HOMO density concentrated on the nor-β-lapachone ring, lipophilicity, solubility and number HBA as important stereoelectronic features for the antibacterial profile. In addition the triazole compounds presented low theoretical toxicity profile, and drug-score higher than commercial antibiotics also fulfilling the Lipinski "Rule of Five", which pointed them as promising candidates for further studies in infections caused by multiresistant E. faecalis hospital strains.
Lourenço
André L
AL
Instituto de Biologia, Departamento de Biologia Celular e Molecular, Universidade Federal Fluminense, Outeiro São João Batista s/n-Campus Valonguinho, Niterói, RJ, CEP 24020-150, Brazil.
Abreu
Paula A
PA
Leal
Bruno
B
da Silva Júnior
Eufrânio N
EN
Pinto
Antonio V
AV
Pinto
Maria do Carmo F R
Mdo C
Souza
Alessandra M T
AM
Novais
Juliana S
JS
Paiva
Marcela B
MB
Cabral
Lucio M
LM
Rodrigues
Carlos R
CR
Ferreira
Vitor F
VF
Castro
Helena C
HC
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013293:Enterococcus faecalis / Q000187:drug effects* / Q000302:isolation & purification; D016908:Gram-Positive Bacterial Infections / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D009285:Naphthoquinones; C014638:beta-lapachone