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Multi-targeted dihydrazones as potent biotherapeutics
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2018-09-01 , DOI: 10.1016/j.bioorg.2018.08.024
Chen Li , M.B. Sridhara , K.P. Rakesh , H.K. Vivek , H.M. Manukumar , C.S. Shantharam , Hua-Li Qin

Hydrazone compounds were considered as a useful moiety in drug design development. Therefore, these studies were aimed at the synthesis of new dihydrazones and were screened for their in vitro H+/K+-ATPase and anti-inflammatory activities. The results revealed that compounds 9 (22 ± 0.62 µg/mL), 10 (26 ± 0.91 µg/mL), 15 (24 ± 0.44 µg/mL), 16 (28 ± 0.63 µg/mL), 17 (12 ± 0.38 µg/mL), 18 (14 ± 0.47 µg/mL), 19 (26 ± 0.54 µg/mL), 20 (16 ± 0.41 µg/mL), 25 (06 ± 0.68 µg/mL) and 26 (08 ± 0.43 µg/mL) showed excellent H+/K+-ATPase activity and their IC50 value were lower than the standard drug Omerazole (48 ± 0.12 µg/mL). Compounds 5 (28 ± 0.65 µg/mL), 6 (24 ± 0.61 µg/mL), 7 (28 ± 0.64 µg/mL), 8 (26 ± 0.45 µg/mL), 11 (30 ± 0.74 µg/mL), 12 (28 ± 0.40 µg/mL), 13 (32 ± 0.24 µg/mL), 14 (30 ± 0.55 µg/mL) and 21 (08 ± 0.47 µg/mL), 22 (12 ± 0.47 µg/mL), 23 (10 ± 0.51 µg/mL) and 24 (14 ± 0.84 µg/mL) showed better anti-inflammatory activity compared to standard indomethacin (44 ± 0.15 µg/mL). The structure activity relationship (SAR) showed that, electron donating groups (OH, OCH3) favored the H+/K+-ATPase and antioxidants activity, whereas, electron withdrawing groups (F, Cl, Br and NO2) favored the anti-inflammatory activity. Furthermore, molecular docking study was performed to investigate the binding interactions of the most active analogs with the active site of H+/K+-ATPase enzyme. Compounds 25 (G-score = −9.063) and 26 (G-score = −8.977) showed the highest docking G-scores for H+/K+-ATPase inhibition activity.



中文翻译:

多目标二hydr唑类作为有效的生物治疗剂

dra化合物被认为是药物设计开发中的有用部分。因此,这些研究的目的是合成新的二hydr,并筛选它们的体外H + / K + -ATPase和抗炎活性。结果显示,化合物9( 22±0.62μg/ mL),10( 26±0.91μg/ mL),15( 24±0.44μg/ mL),16( 28±0.63μg/ mL),17( 12±0.38)微克/毫升),18( 14±0.47微克/毫升),19( 26±0.54微克/毫升),20( 16±0.41微克/毫升),25( 06±0.68微克/毫升)和26(08±0.43 µg / mL)表现出优异的H + / K + -ATPase活性,其IC 50值低于标准药物奥美拉唑(48±0.12 µg / mL)。化合物5( 28±0.65μg/ mL),6( 24±0.61μg/ mL),7( 28±0.64μg/ mL),8( 26±0.45μg/ mL),11( 30±0.74μg/ mL),12( 28±0.40微克/毫升),13( 32±0.24微克/毫升),14( 30±0.55微克/毫升)和21( 08±0.47微克/毫升),22( 12±0.47微克/毫升),23( 10±0.51 µg / mL)和24(与标准消炎痛(44±0.15 µg / mL)相比,14±0.84 µg / mL)显示出更好的抗炎活性。结构活性关系(SAR)表明,供电子基团(OH,OCH 3)有利于H + / K + -ATPase和抗氧化剂的活性,而吸电子基团(F,Cl,Br和NO 2)有利于抗电子活性。-炎症活动。此外,进行了分子对接研究以研究最活跃的类似物与H + / K + -ATPase酶的活性位点的结合相互作用。化合物25(G分数= −9.063)和26( G分数= −8.977)对H +的对接G分数最高/ K + -ATPase抑制活性。

更新日期:2018-09-01
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