四氢苯并[4,5]噻吩并[2,3-d]嘧啶衍生物的设计、合成、晶体结构和抗疟原虫评价,RSC Medicinal Chemistry

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四氢苯并[4,5]噻吩并[2,3-d]嘧啶衍生物的设计、合成、晶体结构和抗疟原虫评价
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-5-18 , DOI: 10.1039/d1md00038a
Kavita Pal ₁ , Md Kausar Raza ₂ , Jenny Legac ₃ , Md Ataur Rahman ₄ , Shoaib Manzoor ₁ , Philip J Rosenthal ₃ , Nasimul Hoda ₁

Affiliation

有效的化疗对于控制疟疾至关重要。然而，恶性疟原虫对现有抗疟药物的耐药性破坏了控制并最终根除该疾病的努力。在本研究中，一系列 2-((取代)(4-(5,6,7,8-四氢苯并[4,5]噻吩并[2,3 - d ]嘧啶-4-基)哌嗪-1-基)甲基)-6-取代的苯酚衍生物使用 Petasis 反应制备，以评估它们对恶性疟原虫的活性。^{通过 H 1} NMR、C ¹³ NMR、质谱的研究证明了合成化合物 ( F1–F16 ) 的发展。化合物F1和F2还通过单晶 X 射线衍射分析在结构上进行了验证。评估了所有化合物对恶性疟原虫的 W2 菌株（耐氯喹）的体外抗疟原虫评估， IC ₅₀值范围为 0.74-6.4 μM。两种化合物F4和F16对恶性疟原虫W2 菌株表现出显着的活性，浓度分别为 0.75 和 0.74 μM。还评估了化合物（F3-F6和F16 ）对两种癌细胞系人肺 (A549) 和宫颈 (HeLa) 细胞的体外细胞毒性，这证明了非细胞毒性和显着的选择性指数。此外，计算机ADME 分析和物理化学特性预测具有非常低毒性作用的药物样特性。因此，所有这些结果表明四氢苯并[4,5]噻吩并[2,3- d ]嘧啶支架可以作为开发抗疟药物的模型。

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Design, synthesis, crystal structure and anti-plasmodial evaluation of tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives

Effective chemotherapy is essential for controlling malaria. However, resistance of Plasmodium falciparum to existing antimalarial drugs has undermined attempts to control and eventually eradicate the disease. In this study, a series of 2-((substituted)(4-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)methyl)-6-substitutedphenol derivatives were prepared using Petasis reaction with a view to evaluate their activities against P. falciparum. The development of synthesized compounds (F1–F16) was justified through the study of H¹ NMR, C¹³ NMR, mass spectra. Compound F1 and F2 were also structurally validated by single crystal X-ray diffraction analysis. All the compounds were evaluated for their in vitro antiplasmodial assessment against the W2 strain (chloroquine-resistant) of P. falciparum IC₅₀ values ranging from 0.74–6.4 μM. Two compounds, F4 and F16 exhibited significant activity against W2 strain of P. falciparum with 0.75 and 0.74 μM. The compounds (F3–F6 and F16) were also evaluated for in vitro cytotoxicity against two cancer cell lines, human lung (A549) and cervical (HeLa) cells, which demonstrated non-cytotoxicity with significant selectivity indices. In addition, in silico ADME profiling and physiochemical properties predicts drug-like properties with a very low toxic effect. Thus, all these results indicate that tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine scaffolds may serve as models for the development of antimalarial agents.

更新日期：2021-05-18

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