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Synthesis, In Vitro Anti-HIV Activity, Cytotoxicity, and Computational Studies of Some New Steroids and Their Pyrazoline and Oxime Analogues
Russian Journal of Bioorganic Chemistry ( IF 1.1 ) Pub Date : 2020-10-23 , DOI: 10.1134/s1068162020050039
Wasfi A. Al-Masoudi , Najim A. Al-Masoudi , Bahjat A. Saeed , Rainer Winter , Christophe Pannecouque

Abstract

There is an urgent need for the design and development of new and safer drugs for the treatment of HIV infection, active against the currently resistant viral strains by development of new non-nucleoside reverse transcriptase inhibitors (NNRTIs). A series of pregnenolone analogues, 3-((aryl)-1-(5-pregnen-3β-ol-17-yl)prop-2-en-1-ones, were synthesized. Further, treatment of 3-((4-bromo-, 4-trifluoromethyl, or 4-methylphenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-ones with thiosemicarbazide in ethanolic KOH or hydrazine hydrate in HOAc gave 5-(4-bromo-, 4-trifluoromethyl, or 4-methylphenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline, respectively. Analogously, treatment of 3-((4-bromophenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one with hydroxylamine afforded the Z/E isomers of 3-(4-bromophenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one oxime. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 3-(thiophene-2-yl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline were the most active in inhibiting HIV-1 and HIV-2 with IC50 = 60.5 μM (SI > 2, against HIV-2 and SI < I against HIV-1), and > 0.29 μM (SI < I), respectively, suggesting to be new leads in the development of antiviral agents. QSAR of 3-((aryl)-1-(5-pregnen-3β-ol-17-yl)prop-2-en-1-ones and 5-(substituted phenyl)-3-(5-preg-5-3β-ol-17-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamides has been studied. The conformational analysis of 5-(4-trifluoromethylphenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline-1-carbothioamide and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline as well as the molecular docking study of the latter compound have been investigated.



中文翻译:

一些新型类固醇及其吡唑啉和肟的类似物的合成,体外抗HIV活性,细胞毒性和计算研究

摘要

迫切需要设计和开发用于治疗HIV感染的新的更安全的药物,该药物通过开发新的非核苷类逆转录酶抑制剂(NNRTIs)来对抗目前耐药的病毒株。合成了一系列孕烯醇酮类似物3-((芳基)-1-(5-pregnen-3β-ol-17-yl)prop-2-en-1-ones。进一步处理3-((4 -溴,4-,三氟甲基或4-甲基苯基)-1-(preg-5-en-3β-ol-17-基)丙-2-烯-1-酮与硫代氨基脲在乙醇KOH中或在肼中的水合肼得到5-(4-溴-,4-三氟甲基或4-甲基苯基)-3-(preg-5-en-3β-ol-17-yl)-4,5-二氢-1 H-吡唑啉-1-碳硫酰胺和1- O-乙酰基-(5-(4-溴苯基)-3-(preg-5-en-3β-ol-17-yl)-4,5-二氢-1 H-吡唑啉。类似地,用羟胺处理3-((4-溴苯基)-1-(preg-5-en-3β-ol-17-基)丙-2-烯-1-酮得到3-的Z / E异构体。 (4-溴苯基)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one肟。测定了新化合物对MT-中的HIV-1和HIV-2的作用。 4细胞。化合物3-(噻吩-2-基)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one和1- O-乙酰基-(5- (4-溴苯基)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1 H-吡唑啉在抑制HIV-1和HIV-2方面的活性最强,IC 50分别为60.5μM(针对HIV-2的SI> 2和针对HIV-1的SI <I)和> 0.29μM(SI <I),表明这是抗病毒药物开发的新线索。3-((芳基)-1-(5-孕-3β-ol-17-基)丙-2-烯-1-酮和5-(取代的苯基)-3-(5-preg-5-研究了3β-ol-17-yl)-4,5-dihydro-1 H-吡唑-1-碳硫酰胺5-(4-三氟甲基苯基)-3-(preg-5-en-3β-的构象分析ol-17-基)-4,5-二氢-1 H-吡唑啉-1-碳硫酰胺和1- O-乙酰基-(5-(4-溴苯基)-3-(preg-5-en-3β-ol-已经研究了17-基)-4,5-二氢-1 H-吡唑啉以及后者化合物的分子对接研究。

更新日期:2020-10-30
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