Mabkhot Yahia Nasser, Alatibi Fatima, El-Sayed Nahed Nasser E, Al-Showiman Salim, Kheder Nabila Abdelshafy, Wadood Abdul, Rauf Abdur, Bawazeer Saud, Hadda Taibi Ben
Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh-11451, Saudi Arabia.
National Organization for Drug Control and Research, Agouza, Giza 35521, Egypt.
Molecules. 2016 Feb 17;21(2):222. doi: 10.3390/molecules21020222.
Tetrasubstituted 2-acetylthiophene derivative 5 was synthesized and then condensed with various nitrogen nucleophiles such as 5-amino-1,2,4-triazole, 2-aminobenzimidazole, aniline or p-chloroaniline to afford the corresponding iminothiophene derivatives 6-8a,b. Condensation of thiophene 5 with malononitrile as carbon nucleophile afforded compound 9, which underwent nucleophilic addition with DMF-DMA to afford compound 10. The newly synthesized products were characterized by elemental analysis, IR, MS, ¹H-(13)C-NMR and CHN analysis and then evaluated for their antimicrobial activity. Results of the in vitro antibacterial activity showed that thiophene derivative 7 was found to be more potent than the standard drug gentamicin against Pseudomonas aeruginosa. Some of these compounds showed potential antimicrobial activities. Molecular docking and Osiris/Molinspiration analyses show the crucial role and impact of substituents on bioactivity and indicate the unfavorable structural parameters in actual drug design: more substitution with electronic donor group doesn't guarantee more effective bioactivity. This study should greatly help in an intelligent and a controlled pharmacomodulation of antibiotics.
合成了四取代的2-乙酰基噻吩衍生物5，然后将其与各种氮亲核试剂如5-氨基-1,2,4-三唑、2-氨基苯并咪唑、苯胺或对氯苯胺缩合，得到相应的亚氨基噻吩衍生物6-8a,b。噻吩5与作为碳亲核试剂的丙二腈缩合得到化合物9，化合物9与DMF-DMA进行亲核加成得到化合物10。通过元素分析、红外光谱、质谱、¹H-(13)C-NMR和CHN分析对新合成的产物进行了表征，然后评估了它们的抗菌活性。体外抗菌活性结果表明，噻吩衍生物7对铜绿假单胞菌的活性比标准药物庆大霉素更强。其中一些化合物显示出潜在的抗菌活性。分子对接和Osiris/Molinspiration分析表明取代基对生物活性的关键作用和影响，并指出了实际药物设计中不利的结构参数：电子供体基团的更多取代并不保证更有效的生物活性。这项研究应该对智能且可控的抗生素药物调制有很大帮助。
