几种新型苯并三嗪类化合物的合成、分子对接及生物学评价

S. E. Rayes, I. Ali, Walid Fathalla, Mostafa A A Mahmoud
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摘要

甲基2-(4-氧苯并三嗪-3(4H)-酰基)烷酸酯4a-c被证明是制备一些具有生物学意义的含苯并三嗪酮环体系化合物的重要中间体。采用一锅法将甲酰苯甲酸甲酯直接重氮化,再加入氨基酸酯盐酸盐制得4a-c酯。在杂环酰胺与亲电试剂化学选择性反应的基础上,以苯并三嗪-4(3H) 1为原料,与氯乙酸甲酯进行烷基化反应,合成了2-(4氧苯并三嗪-3(4H)-酯)乙酸甲酯4a。以4a-b为原料,通过叠氮偶联法制备了一系列n-烷基-2-(4-氧苯并三嗪-3(4H)-基)烷酰胺7-8(A -h)和2-(2-(4 -氧苯并三嗪-3(4H)-基)烷酰胺9-10(A -d)二肽。酯4a-b转化为相应的肼,然后与醛缩合;4-甲氧基苯甲醛、4-二甲氨基苯甲醛和阿拉伯糖得到相应的腙衍生物11-13。用MOE 2008-10软件作为激动剂对合成的化合物进行分子对接;大肠杆菌Fab-H受体和维生素D受体分别进行抗菌和抗癌评价。与目标大肠杆菌Fab-H受体结合最明显的是化合物7a、11a、11b、10a、10c和12b。另一方面,与目标维生素D受体结合最明显的是化合物3、9c、11a和10d。体外对大肠杆菌、金黄色葡萄球菌和沙门氏菌的抑菌活性进行了测试,所有化合物对大肠杆菌的抑菌活性均为有效阳性,抑菌带约为1.1 cm,而对金黄色葡萄球菌和沙门氏菌均无活性,并对人肝癌细胞系(HepG2)癌细胞进行了体外细胞毒活性测试。许多化合物显示出较低的IC50值,特别是3(6.525μM)和11a (10.97 μM),而标准药物阿霉素(5.8 μM)具有较强的细胞毒活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Synthesis, Molecular Docking and Biological Evaluation of Some New Benzotriazines
Methyl 2-(4-oxobenzotriazin-3(4H)-yl) alkanoates4a-c proved to be important intermediates for the preparation of some biologically interesting compounds containing the benzotriazinone ring system. Esters 4a-c were prepared by direct diazotization of methyl anthranilate followed by addition of amino acid esters hydrochloride in a one-pot strategy. An equivocal synthesis of methyl 2-(4oxobenzotriazin-3(4H)-yl) acetate 4a was achieved by alkylation of benzotriazin-4(3H)one with methyl chloroacetate on the basis of chemoselective reaction of heterocyclic amide with electrophiles. A series of N-alkyl-2-(4-oxobenzotriazin-3(4H)-yl) alkanamides7-8(a-h) and methyl 2-(2-(4oxobenzotriazin-3(4H)-yl)alkanamido)alkanoates (dipeptides) 9-10(a-d) were prepared via azide coupling from 4a-b. Esters 4a-b were converted into the corresponding hydrazides followed by condensation with aldehydes; 4-methoxybenzaldehyde, 4-dimethylamino benzaldehyde and arabinose to afford the corresponding hydrazone derivatives11-13. All the synthesized compounds were subjected to the molecular docking using MOE 2008-10 software as agonist for; E. coli Fab-H receptor and Vitamin D receptor for antibacterial and anticancer evaluation, respectively. The most pronounced strong binding affinity towards the target E. coli Fab-H receptor were compounds 7a, 11a, 11b,10a,10cand 12b. On the other hand, the most pronounced strong binding affinity towards the target Vitamin D receptor were compounds 3, 9c, 11a and 10d. The in vitro antibacterial activity of highest binding affinity docked compounds were tested against E. coli, Staphylococcus aureus and Salmonella spp. All the tested compounds gave effective positive results against E. coli with inhibitory zone of about 1.1 cm, while were inactive against Staphylococcus aureus and Salmonella spp. The in vitro cytotoxic activity of the highest binding affinity docked compounds were tested against human liver carcinoma cell line (HepG2) cancer cell lines. Many compounds showed potent cytotoxic activity with low IC50 values, especially for 3(6.525μM) and 11a (10.97 μM), while for standard drug doxorubicin (5.8 μM).
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