Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Selcuk University, Konya, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Atatürk University, Erzurum, Turkey.
Bioorg Chem. 2019 May;86:316-321. doi: 10.1016/j.bioorg.2019.02.008. Epub 2019 Feb 4.
Recently, inhibition of carbonic anhydrase (hCA) and acetylcholinesterase (AChE) have appeared as a promising approach for pharmacological intervention in a variety of disorders such as glaucoma, epilepsy, obesity, cancer, and Alzheimer's disease. Keeping this in mind, N,N'-bis[(1-aryl-3-heteroaryl)propylidene]hydrazine dihydrochlorides, N1-N11, P1, P4-P8, and R1-R6, were synthesized to investigate their inhibitory activity against hCA I, hCA II, and AChE enzymes. All compounds in N, P, and R-series inhibited hCAs (I and II) and AChE more efficiently than the reference compounds acetazolamide (AZA), and tacrine. According to the activity results, the most effective inhibitory compounds were in R-series with the K values of 203 ± 55-473 ± 67 nM and 200 ± 34-419 ± 94 nM on hCA I, and hCA II, respectively. N,N'-Bis[1-(4-fluorophenyl)-3-(morpholine-4-yl)propylidene]hydrazine dihydrochlorides, N8, in N-series, N,N'-Bis[1-(4-hydroxyphenyl)-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides, P4, in P-series, and N,N'-bis[1-(4-chlorophenyl)-3-(pyrrolidine-1-yl)propylidene]hydrazine dihydrochlorides, R5, in R-series were the most powerful compounds against hCA I with the K values of 438 ± 65 nM, 344 ± 64 nM, and 203 ± 55 nM, respectively. Similarly, N8, P4, and R5 efficiently inhibited hCA II isoenzyme with the K values of 405 ± 60 nM, 327 ± 80 nM, and 200 ± 34 nM, respectively. On the other hand, P-series compounds had notable inhibitory effect against AChE than the reference compound tacrine and the K values were between 66 ± 20 nM and 128 ± 36 nM. N,N'-Bis[1-(4-fluorophenyl)-3-(piperidine-1-yl)propylidene]hydrazine dihydrochlorides, P7, was the most potent compound on AChE with the K value of 66 ± 20 nM. The other most promising compounds, N,N'-bis[1-(4-hydroxyphenyl)-3-(morpholine-4-yl)propylidene]hydrazine dihydrochlorides, N4 in N-series and N,N'-bis[1-(4-hydroxyphenyl)-3-(pyrrolidine-1-yl)propylidene]hydrazine dihydrochlorides, R4 in R-series were againts AChE with the K values of 119 ± 20 nM, 88 ± 14 nM, respectively.
最近，抑制碳酸酐酶（hCA）和乙酰胆碱酯酶（AChE）已成为治疗多种疾病（如青光眼、癫痫、肥胖症、癌症和阿尔茨海默病）的一种有前途的药物干预方法。考虑到这一点，我们合成了 N,N'-双[(1-芳基-3-杂芳基)丙二烯基]肼二盐酸盐（N1-N11、P1、P4-P8 和 R1-R6），以研究它们对 hCA I、hCA II 和 AChE 酶的抑制活性。所有 N、P 和 R 系列化合物对 hCAs（I 和 II）和 AChE 的抑制活性均优于参考化合物乙酰唑胺（AZA）和他克林。根据活性结果，最有效的抑制化合物是 R 系列，其对 hCA I 和 hCA II 的 K 值分别为 203±55-473±67 nM 和 200±34-419±94 nM。在 N 系列中，N,N'-双[1-(4-氟苯基)-3-(吗啉-4-基)丙二烯基]肼二盐酸盐（N8），在 P 系列中，N,N'-双[1-(4-羟基苯基)-3-(哌啶-1-基)丙二烯基]肼二盐酸盐（P4），在 R 系列中，N,N'-双[1-(4-氯苯基)-3-(吡咯烷-1-基)丙二烯基]肼二盐酸盐（R5）是对 hCA I 抑制作用最强的化合物，其 K 值分别为 438±65 nM、344±64 nM 和 203±55 nM。同样，N8、P4 和 R5 对 hCA II 同工酶也具有很强的抑制作用，其 K 值分别为 405±60 nM、327±80 nM 和 200±34 nM。另一方面，与参考化合物他克林相比，P 系列化合物对 AChE 具有显著的抑制作用，K 值在 66±20 nM 和 128±36 nM 之间。N,N'-双[1-(4-氟苯基)-3-(哌啶-1-基)丙二烯基]肼二盐酸盐（P7）是对 AChE 抑制作用最强的化合物，K 值为 66±20 nM。其他最有前途的化合物是 N,N'-双[1-(4-羟基苯基)-3-(吗啉-4-基)丙二烯基]肼二盐酸盐（N4）和 N,N'-双[1-(4-羟基苯基)-3-(吡咯烷-1-基)丙二烯基]肼二盐酸盐（R4），它们对 AChE 的 K 值分别为 119±20 nM 和 88±14 nM。
