Synthesis of Novel Chiral Sulfonamide‐Bearing 1,2,4‐Triazole‐3‐thione Analogs Derived fromD‐andL‐Phenylalanine Esters as Potential Anti‐Influenza Agents

Abstract

Novel enantiopure 1,2,4-trizole-3-thiones containing a benzensulfonamide moiety were synthesized via multistep reaction sequence starting with D-phenylalanine methyl ester and L-phenylalanine ethyl ester as a source of chirality. The chemical structures of all compounds were characterized by elemental analysis, UV, IR, (1) H NMR, (13) C NMR, 2D NMR (HETCOR), and mass spectral data. All compounds were tested in vitro antiviral activity against a broad variety of DNA and RNA viruses and in vitro cytostatic activity against murine leukemia (L1210), human T-lymphocyte (CEM) and human cervix carcinoma (HeLa) cell lines. Although enantiopure 1,2,4-triazole-3-thione analogs in (R) configuration emerged as promising anti-influenza A H1N1 subtype in Madin Darby canine kidney cell cultures (MDCK), their enantiomers exhibited no activity. Especially compounds , , , , and (EC50 : 6.5, 6.1, 2.4, 1.6, 1.7 μM, respectively) had excellent activity against influenza A H1N1 subtype compared to the reference drug ribavirin (EC50 : 8.0 μM). Several compounds have been found to inhibit proliferation of L1210, CEM and HeLa cell cultures with IC50 in the 12-53 μM range. Compound and in (R) configuration were the most active compounds (IC50 : 12-22 μM for and IC50 : 19-23 μM for ). Chirality 28:495-513, 2016. © 2016 Wiley Periodicals, Inc.

Recent Advances in 1,2,4‐Triazole Scaffolds as Antiviral Agents

“…Compounds (56-60) had excellent activity against influenza A, H1 N1 subtype, especially compounds 59, 60, that are much stronger than the ribavirin (RBV) reference drug, although none of them had any activity against H3 N2 subtype (influenza A) or influenza B virus. [71] Further optimization of such compounds in (R) enantiomeric may lead to potent anti-influenza A, the H1 N1 strain, agents. Figure 19) was identified to be the most potent and highly selective against HIV-1 and HIV-2 with EC 50 values of 23.9 μg/mL and 9.90 μg/ mL, respectively.…”

“…Zhan et al synthesized a set of 1,2,4-triazolacetamide analogs and their anti-HIV activity was examined by assessing their ability to inhibit the replication of human immunodeficiency virus type; HIV-1 (IIIB) and HIV-2 (ROD) in MT-4 cells. Compounds (69)(70)(71)(72)(73)(74) (Figure 23) were the most active, exhibiting moderate to strong activity against HIV-1 strain IIIB with EC 50 values ranging from 2.78 to 6.21 μM, which are much better than dideoxyinosine (DDI). Amongst them, compound 72 was recognized as the most promising lead with favorable inhibitory activity against the wild-type HIV-1 reverse transcriptase (RT) against HIV-1(IIIB), as well as displayed the highest inhibitory activity against the HIV-1 K103 N strain.…”

“…The antiviral activity assay indicated that enantiopure 1,2,4‐triazole‐3‐thione analogs in ( R ) configuration with electron‐releasing substituents were identified as a promising anti‐influenza A (H1 N1), while their enantiomers in ( S ) configuration did not exert any activity. Compounds ( 56‐60 ) had excellent activity against influenza A, H1 N1 subtype, especially compounds 59, 60 , that are much stronger than the ribavirin (RBV) reference drug, although none of them had any activity against H3 N2 subtype (influenza A) or influenza B virus . Further optimization of such compounds in ( R ) enantiomeric may lead to potent anti‐influenza A, the H1 N1 strain, agents.…”

Syntheses and Biological Activities of 1,4-Pentadien-3-oneDerivatives Containing Thioether Triazole Moiety

“…三氮唑杂环作为一种重要的五元含氮化合物, 在 医 药 和 农 药 等 领 域 都 有 着 广 泛 的 应 用 , 如 抗 癌 [14,15] 、抗细菌 [16,17] 、抗病毒 [18] 、抗真菌 [19] 和杀虫 [20] 等, 在商品药物中三氮唑杂环类杀菌剂有: 多效唑 (Paclobutrazol) 、 丙 环 唑 (Propiconazole) 和 亚 胺 唑 (Imibenconazole) 等 [21] . 闫 柏 任 等 [22] 合 成 一 系 列 含 1,2,4-三唑曼尼希碱的喹唑啉酮类衍生物, 生物活性测 试结果表明: 大部分化合物在 200 μg/mL 浓度下, 对柑 橘溃疡病菌和水稻白叶枯病菌表现出较好的抑制活性.…”

Synthesis and Antimicrobial Activities of Novel 1,2,4-Triazole-acyl-hydrazone Derivatives Containing the Quinazolin-4-one Moiety

“…鉴于目前致病菌害耐药性不断增 强而导致现有杀菌剂防效不断降低的严峻形势 [7,8] , 开 发新型高效农用杀菌剂已成为近年来农药化学的一个 研究热点. 1,2,4-三唑类化合物是一类重要的五元含氮杂环化 合物, 在医药和农药等领域有着广泛的应用, 如抗细 菌 [9] 、抗真菌 [10] 、抗癌 [11] 和抗病毒 [12] 等, 商品化的 1,2,4-三 唑 类 杀 菌 剂 有 丙 环 唑 ( P r o p i c o n a z o l e ) 、 亚 胺 唑 (Imibenconazole)和多效唑(Paclobutrazol)(图 1). 此外, 酰腙类化合物由于分子结构中含有活性亚结构基团 (CONHN＝CH)也表现出良好的抗菌 [13] 和杀虫 [14] 等活 性 , 商品化药剂 有醌肟腙( Benqu inox)和呋喃 唑酮 (Furazolidone).…”