Vrablova Lucia, Gonec Tomas, Kauerova Tereza, Oravec Michal, Jendrzejewska Izabela, Kollar Peter, Cizek Alois, Jampilek Josef
Department of Analytical Chemistry, Faculty of Natural Sciences, Comenius University, Ilkovicova 6, 842 15 Bratislava, Slovakia.
Department of Chemical Drugs, Faculty of Pharmacy, Masaryk University, Palackeho tr. 1946/1, 612 00 Brno, Czech Republic.
ADMET DMPK. 2025 Feb 8;13(1):2642. doi: 10.5599/admet.2642. eCollection 2025.
Many new compounds are being prepared to overcome the problem of increasing microbial resistance and the increasing number of infections.
This study includes a series of twenty-seven mono-, di- and trisubstituted 2-hydroxynaphthalene-1-carboxanilides designed as multitarget agents. The compounds are substituted with methoxy, methyl, and nitro groups, as well as additionally with chlorine, bromine, and trifluoromethyl at various positions. All the compounds were evaluated for antibacterial activities against Gram-positive and Gram-negative bacteria and mycobacteria. Cytotoxicity on human cells was also tested.
Three compounds showed activity comparable to clinically used drugs. -(3,5-Dimethylphenyl)-2-hydroxynaphthalene-1-carboxamide () showed only antistaphylococcal activity (minimum inhibitory concentration (MIC) = 54.9 μM); 2-hydroxy--[2-methyl-5-(trifluoromethyl)phenyl]naphthalene-1-carboxamide () and 2-hydroxy--[4-nitro-3-(trifluoromethyl)phenyl]naphthalene-1-carboxamide () were active across the entire spectrum of tested bacteria/mycobacteria, both against the sensitive set and against resistant isolates (MICs range 0.3 to 92.6 μM). Compound was even active against E. coli (MIC = 23.2 μM). The active agents showed no cytotoxicity up to a concentration of 30 μM.
Compounds with trifluoromethyl in the -anilide position, experimental lipophilicity expressed as log (logarithm of the capacity factor) in the range of 0.31 to 0.34 and calculated electron σ parameter for the anilide substituent higher than 0.59 were effective. The investigated compounds meet the definition of Michael acceptors. Based on ADME screening, the investigated compounds , and should have suitable physicochemical parameters for good bioavailability in the organism. Therefore, these are promising agents for further study.
为克服微生物耐药性增加和感染数量增多的问题，人们正在制备许多新化合物。
本研究包括一系列27种单取代、二取代和三取代的2-羟基萘-1-甲酰苯胺，它们被设计为多靶点药物。这些化合物在不同位置被甲氧基、甲基和硝基取代，以及额外被氯、溴和三氟甲基取代。所有化合物均针对革兰氏阳性菌、革兰氏阴性菌和分枝杆菌进行了抗菌活性评估。还测试了其对人细胞的细胞毒性。
三种化合物显示出与临床使用药物相当的活性。-（3,5-二甲基苯基）-2-羟基萘-1-甲酰胺（）仅显示抗葡萄球菌活性（最低抑菌浓度（MIC）=54.9μM）；2-羟基- - [2-甲基-5-（三氟甲基）苯基]萘-1-甲酰胺（）和2-羟基- - [4-硝基-3-（三氟甲基）苯基]萘-1-甲酰胺（）对整个测试细菌/分枝杆菌谱均有活性，对敏感菌株和耐药菌株均有效（MIC范围为0.3至92.6μM）。化合物甚至对大肠杆菌有活性（MIC = 23.2μM）。这些活性剂在浓度高达30μM时未显示细胞毒性。
在甲酰苯胺位置含有三氟甲基、实验亲脂性以容量因子对数（log ）表示在0.31至0.34范围内且计算得出的甲酰苯胺取代基电子σ参数高于0.59的化合物是有效的。所研究的化合物符合迈克尔受体的定义。基于药物代谢动力学（ADME）筛选，所研究的化合物、和应具有适合在生物体内良好生物利用度的理化参数。因此，这些是有前景的进一步研究药物。
