Matei Lilia, Bleotu Coralia, Baciu Ion, Diaconu Carmen Cristina, Hanganu Anamaria, Banu Otilia, Ionita Petre, Paun Anca, Tatibouët Arnaud, Zarafu Irina
Stefan S Nicolau Institute of Virology, Romanian Academy, Bucharest, Romania; Faculty of Chemistry, University of Bucharest, Romania.
Stefan S Nicolau Institute of Virology, Romanian Academy, Bucharest, Romania.
Bioorg Med Chem. 2015 Feb 1;23(3):401-10. doi: 10.1016/j.bmc.2014.12.038. Epub 2014 Dec 26.
A series of several new isoniazid derivatives, isonicotinic acid 2-(2-hydroxy-8-substituted-tricyclo[7.3.1.0(2.7)]tridec-13-ylidene)-hydrazides, were synthesized and fully characterized. These new isoniazid derivatives were studied regarding their antibacterial activity and cytotoxicity, as well as their influences on some metabolizing enzymes. The best anti-mycobacterial activity was observed in the case of compounds containing alkyl side chains in the 8 position of tricyclo[7.3.1.0(2.7)]tridec-13-ylidene group. On contrary, the antimicrobial activity of these new compounds against various non-tuberculosis strains showed the best activity to be with the phenyl side chain of compound 6. It proved also to be the most toxic, inducing apoptosis and blocking the cell cycle in G0/G1 phase. The cell cycle was blocked in G0/G1 phase also by compound 3, but this compound did not show any toxicity. All compounds induced the expression of NAT1 and NAT2 genes in HT-29 cell line, and the expression of CYP1A1 in HT-29 and HCT-8 cell lines. The expression level of CYP3A4 was increased by compounds 1, 6 and 7 in HCT-8 cells. These results indicated that the activation of other metabolizing pathways, apart from those of isoniazid, take place. It might also point out the possibility of an increased isoniazid acetylation ratio by co-administration with new compounds in slow acetylators.
合成并全面表征了一系列几种新的异烟肼衍生物，即异烟酸2-(2-羟基-8-取代-三环[7.3.1.0(2.7)]十三碳-13-亚基)-酰肼。对这些新的异烟肼衍生物进行了抗菌活性、细胞毒性以及它们对某些代谢酶影响的研究。在三环[7.3.1.0(2.7)]十三碳-13-亚基基团的8位含有烷基侧链的化合物中观察到了最佳的抗分枝杆菌活性。相反，这些新化合物对各种非结核菌株的抗菌活性显示，化合物6的苯基侧链具有最佳活性。它也被证明是毒性最大的，可诱导细胞凋亡并使细胞周期阻滞在G0/G1期。化合物3也使细胞周期阻滞在G0/G1期，但该化合物没有显示出任何毒性。所有化合物均诱导HT-29细胞系中NAT1和NAT2基因的表达，以及HT-29和HCT-8细胞系中CYP1A1的表达。化合物1、6和7使HCT-8细胞中CYP3A4的表达水平升高。这些结果表明，除了异烟肼的代谢途径外，其他代谢途径也被激活。这也可能指出在慢乙酰化者中与新化合物共同给药时异烟肼乙酰化率增加的可能性。
