Faculdade de Ciências Farmacêuticas, Departamento de Alimentos e Medicamentos, Universidade Federal de Alfenas, MG, 37130-001, Brazil.
Departamento de Análises Clínicas e Toxicológicas, Universidade Federal de Santa Maria, RS, 9710590, Brazil.
Microb Pathog. 2023 Nov;184:106369. doi: 10.1016/j.micpath.2023.106369. Epub 2023 Sep 30.
Historically, the piperazine moiety has been demonstrated to possess pharmacophoric properties, and has subsequently been incorporated in many drugs that have antitumor, antimalarial, antiviral, antibacterial and antifungal properties. Derivatives of eugenol and dihydroeugenol have also been reported as being bioactive compounds. This study reports the synthesis of a range of eugenol/dihydroeugenol - piperazine derivatives which have been tested as antimicrobial compounds against Gram positive, Gram negative and rapid-growing mycobacteria (RGM). The rationale employed in the design of the structural pattern of these new derivatives, provides useful insights into the structure-activity relationships (SAR) of the series. Antimicrobial activity tests were extremely encouraging, with the majority of the synthesised compounds being more active than eugenol and dihydroeugenol starting materials. The antimicrobial potential was most notable against the Gram-negative species K. pneumoniae and P. aeruginosa, but there was also significant performance against the Gram-positive strains S. epidermidis and S. aureus and the Rapidly Growing Mycobacteria (RGM) strains tested. Tests using the synthesised compounds against multidrug-resistance clinical (MDR) isolates also showed high activity. The biofilm inhibition tests using M. fortuitum showed that all evaluated derivatives were able to inhibit biofilm formation even at low concentrations. In terms of structural-activity relationships; the results generated by this study demonstrate that the compounds with bulky substituents on the piperazine subunit were much more active than those with less bulky groups, or no groups. Importantly, the derivatives with a sulfonamide side chain were the most potent compounds. A further observation was that those compounds with a para-substituted benzenesulfonamide ring stand out, regardless of whether this substituent is a donor or an electron-withdrawing group.
从历史上看，哌嗪部分被证明具有药效性质，随后被纳入许多具有抗肿瘤、抗疟疾、抗病毒、抗菌和抗真菌特性的药物中。丁香酚和二氢丁香酚的衍生物也被报道为具有生物活性的化合物。本研究报告了一系列丁香酚/二氢丁香酚-哌嗪衍生物的合成，这些衍生物已被测试为抗革兰氏阳性、革兰氏阴性和快速生长分枝杆菌（RGM）的抗菌化合物。在设计这些新衍生物的结构模式时所采用的原理，为该系列的结构-活性关系（SAR）提供了有用的见解。抗菌活性测试结果非常令人鼓舞，大多数合成化合物比丁香酚和二氢丁香酚起始材料更具活性。抗菌潜力在革兰氏阴性物种 K. pneumoniae 和 P. aeruginosa 中最为显著，但对革兰氏阳性菌株 S. epidermidis 和 S. aureus 以及测试的快速生长分枝杆菌（RGM）菌株也有显著表现。对合成化合物针对多药耐药临床（MDR）分离株的测试也显示出高活性。使用 M. fortuitum 进行的生物膜抑制测试表明，所有评估的衍生物即使在低浓度下也能够抑制生物膜形成。就结构-活性关系而言；本研究的结果表明，哌嗪亚基上带有大取代基的化合物比带有较小取代基或没有取代基的化合物活性更高。重要的是，带有磺酰胺侧链的衍生物是最有效的化合物。另一个观察结果是，那些带有对位取代苯磺酰胺环的化合物引人注目，无论这个取代基是供电子体还是吸电子体。
