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Design, Synthesis, Structure-Activity Relationship and Docking Studies of Novel Functionalized Arylvinyl-1,2,4-Trioxanes as Potent Antiplasmodial as well as Anticancer Agents.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-05-11 , DOI: 10.1002/cmdc.202000045 Mohit K Tiwari 1 , Paolo Coghi 2 , Prakhar Agrawal 3 , Bharti Rajesh K Shyamlal 1 , Li Jun Yang 4 , Lalit Yadav 1 , Yuzhong Peng 2 , Richa Sharma 1 , Dharmendra K Yadav 5 , Dinkar Sahal 3 , Vincent Kam Wai Wong 4 , Sandeep Chaudhary 1
ChemMedChem ( IF 3.6 ) Pub Date : 2020-05-11 , DOI: 10.1002/cmdc.202000045 Mohit K Tiwari 1 , Paolo Coghi 2 , Prakhar Agrawal 3 , Bharti Rajesh K Shyamlal 1 , Li Jun Yang 4 , Lalit Yadav 1 , Yuzhong Peng 2 , Richa Sharma 1 , Dharmendra K Yadav 5 , Dinkar Sahal 3 , Vincent Kam Wai Wong 4 , Sandeep Chaudhary 1
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A novel series of synthetic functionalized arylvinyl‐1,2,4‐trioxanes (8 a –p ) has been prepared and assessed for their in vitro antiplasmodial activity against the chloroquine‐resistant Pf INDO strain of Plasmodium falciparum by using a SYBR green‐I fluorescence assay. Compounds 8 g (IC50=0.051 μM; SI=589.41) and 8 m (IC50=0.059 μM; SI=55.93) showed 11‐fold and >9‐fold more potent antiplasmodial activity, respectively, as compared to chloroquine (IC50=0.546 μM; SI=36.63). Different in silico docking studies performed on many target proteins revealed that the most active arylvinyl‐1,2,4‐trioxanes (8 g and 8 m ) showed dihydrofolate reductase (DHFR) binding affinities on a par with those of chloroquine and artesunate. The in vitro cytotoxic potentials of 8 a –p were also evaluated against human lung (A549) and liver (HepG2) cancer cell lines along with immortalized normal lung (BEAS‐2B) and liver (LO2) cell lines. Following screening, five derivatives viz. 8 a , 8 h , 8 l , 8 m and 8 o (IC50=1.65–31.7 μM; SI=1.08–10.96) were found to show potent cytotoxic activity against (A549) lung cancer cell lines, with selectivity superior to that of the reference compounds artemisinin (IC50=100 μM), chloroquine (IC50=100 μM) and artesunic acid (IC50=9.85 μM; SI=0.76). In fact, the most active 4‐naphthyl‐substituted analogue 8 l (IC50=1.65 μM; SI >10) exhibited >60 times more cytotoxicity than the standard reference, artemisinin, against A549 lung cancer cell lines. In silico docking studies of the most active anticancer compounds, 8 l and 8 m , against EGFR were found to validate the wet lab results. In summary, a new series of functionalized aryl‐vinyl‐1,2,4‐trioxanes (8 a –p ) has been shown to display dual potency as promising antiplasmodial and anticancer agents.
中文翻译：
新型功能化芳基乙烯基1,2,4-三恶烷作为有效的抗疟原虫药和抗癌药的设计，合成，结构活性关系和对接研究。
制备了一系列新的合成的功能化芳基乙烯基1,2,4-三恶烷（8 a – p），并使用SYBR green-I评估了它们对恶性疟原虫耐氯喹Pf INDO菌株的体外抗疟原虫活性。荧光测定。与氯喹（IC）相比，化合物8 g（IC 50 = 0.051μM; SI = 589.41）和8 m（IC 50 = 0.059μM ; SI = 55.93）分别显示出更强的抗血浆活性11倍和> 9倍50 = 0.546μM； SI = 36.63）。不同的计算机对许多靶蛋白的对接研究表明，活性最高的芳基乙烯基1,2,4-三恶烷（8 g和8 m）显示出二氢叶酸还原酶（DHFR）的结合亲和力与氯喹和青蒿琥酯的亲和力相当。在体外的细胞毒性潜力8 - p也针对人肺（A549）和肝（HepG2细胞）肿瘤细胞系评价与永生化的正常肺（BEAS-2B）和肝（LO2）细胞系一起。筛选后，得到五种衍生物。8 a，8 h，8 l，8 m和8 o（IC 50= 1.65–31.7μM；SI = 1.08–10.96）被发现对（A549）肺癌细胞系具有强大的细胞毒活性，其选择性优于参考化合物青蒿素（IC 50 = 100μM），氯喹（IC 50 = 100μM）和青蒿琥酯（IC 50＝9.85μM； SI ＝ 0.76）。事实上，最活跃的4-萘基取代类似物8 l（IC 50 = 1.65μM； SI> 10）对标准品青蒿素对A549肺癌细胞系的细胞毒性高出60倍以上。在计算机对接研究中，最活跃的抗癌化合物分别为8 l和8 m发现针对EGFR的，可以验证湿实验室的结果。总而言之，一系列新功能化的芳基-乙烯基1,2,4-三恶烷（8 a – p）已显示出作为有前途的抗血浆和抗癌药的双重功效。
更新日期：2020-07-03
中文翻译：
新型功能化芳基乙烯基1,2,4-三恶烷作为有效的抗疟原虫药和抗癌药的设计，合成，结构活性关系和对接研究。
制备了一系列新的合成的功能化芳基乙烯基1,2,4-三恶烷（8 a – p），并使用SYBR green-I评估了它们对恶性疟原虫耐氯喹Pf INDO菌株的体外抗疟原虫活性。荧光测定。与氯喹（IC）相比，化合物8 g（IC 50 = 0.051μM; SI = 589.41）和8 m（IC 50 = 0.059μM ; SI = 55.93）分别显示出更强的抗血浆活性11倍和> 9倍50 = 0.546μM； SI = 36.63）。不同的计算机对许多靶蛋白的对接研究表明，活性最高的芳基乙烯基1,2,4-三恶烷（8 g和8 m）显示出二氢叶酸还原酶（DHFR）的结合亲和力与氯喹和青蒿琥酯的亲和力相当。在体外的细胞毒性潜力8 - p也针对人肺（A549）和肝（HepG2细胞）肿瘤细胞系评价与永生化的正常肺（BEAS-2B）和肝（LO2）细胞系一起。筛选后，得到五种衍生物。8 a，8 h，8 l，8 m和8 o（IC 50= 1.65–31.7μM；SI = 1.08–10.96）被发现对（A549）肺癌细胞系具有强大的细胞毒活性，其选择性优于参考化合物青蒿素（IC 50 = 100μM），氯喹（IC 50 = 100μM）和青蒿琥酯（IC 50＝9.85μM； SI ＝ 0.76）。事实上，最活跃的4-萘基取代类似物8 l（IC 50 = 1.65μM； SI> 10）对标准品青蒿素对A549肺癌细胞系的细胞毒性高出60倍以上。在计算机对接研究中，最活跃的抗癌化合物分别为8 l和8 m发现针对EGFR的，可以验证湿实验室的结果。总而言之，一系列新功能化的芳基-乙烯基1,2,4-三恶烷（8 a – p）已显示出作为有前途的抗血浆和抗癌药的双重功效。
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