Investigation of 5-Nitrofuran Derivatives:  Synthesis, Antibacterial Activity, and Quantitative Structure−Activity Relationships

• Published in: Journal of medicinal chemistry 2001-10, Vol.44 (22), p.3673-3681
• Main Authors: Pires, José Ricardo, Saito, Cristina, Gomes, Suely L, Giesbrecht, Astréa M, Amaral, Antonia T-do
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Caulobacter crescentus - drug effects; Chromatography, High Pressure Liquid; Inhibitory Concentration 50; Medical sciences; Microbial Sensitivity Tests; Nitrofurans - chemical synthesis; Nitrofurans - chemistry; Nitrofurans - pharmacology; Oxidation-Reduction; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; Staphylococcus aureus - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0101693

Three sets of antibacterial nitrofuran derivatives [set I, 5-R-substituted (Z)-2-(5-nitrofuran-2-ylmethylene)-3(2H)-benzofuranones (R = OCH3, H, CH3, C2H5, nC3H7, Cl, Br, CN, and NO2) and their 2-hydroxyphenyl and 2-acetoxyphenyl analogues; set II, 5-R-substituted (E)-1-(2-hydroxyphenyl)-3-(5-nitrofuryl)-2-propen-1-ones (R = H, CH3, C2H5, Cl, and NO2); and set III, 5-R-substituted (E)-1-(2-acetoxyphenyl)-3-(5-nitrofuryl)-2-propen-1-ones (R = H, CH3; C2H5, Cl, and NO2)] were prepared and tested against a Gram-positive (Staphylococcus aureus, strain ATCC-25923) and a Gram-negative bacterium (Caulobacter crescentus, strain NA 1000). QSAR equations derived for the IC50 values against both bacteria show negative contributions of two terms:  an electronic one, expressed either by σ, the Hammett substituent constant, or by E, the cyclic voltametric reduction potential. Another term described by an indicator variable, I abs, is assigned the value of 0 for set I compounds and the value of 1 for sets II and III. No important contribution of the hydrophobic factor was found. For the three sets, the QSAR regressions suggest that the same structural features describe the activities for both bacteria and that, although reduction is a necessary step, it should not be the determining one. These results agree with those found for the QSAR of 5-nitroimidazole analogues.