Docking, Synthesis and Evaluation of 4-hydroxy-1-phenyl-2(1H)-quinolone Derivatives as Anticancer Agents.

Q3 Pharmacology, Toxicology and Pharmaceutics Current drug discovery technologies Pub Date : 2024-01-01 DOI:10.2174/1570163820666230719110932

Chaitali Prabhu Tendulkar, Prachita Gauns Dessai, Shivlingrao Mamle Desai, Amrita Kadam

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Abstract

Background: The estimated number of cancer cases in India for the year 2022 was found to be 14,61,427. The development of chemotherapeutic agents has reduced the mortality rate, however, they have high toxicity which is a disadvantage. Many researchers have found out that quinolin-2- one possesses anticancer activity, with this background we thought of synthesizing the quinolin-2-one derivatives.

Objective: This study aimed to carry out docking, synthesis, characterization, and evaluation of 2-(2- (4-Hydroxy-2-oxoquinolin-1(2H)-yl)phenyl/ substituted phenyl)-3-(phenylamino) thiazolidon-4-one derivatives (IVa-g) as an anticancer agent.

Method: Diphenylamine and malonic acid treated with phosphoryl chloride gave compound I, which on formylation afforded compound II, which on reaction with various substituted aromatic phenylhydrazine derivatives gave compounds IIIa-g, which on further reaction with thioglycolic acid and anhydrous zinc chloride yielded the compounds IVa-g.

Result: Among all the synthesized novel derivatives, compounds IV a-d showed 50% lysis in the IC₅₀ range of 25-50μg for the A549 cell line, and compounds IVa, and IVb showed 50% lysis in the IC₅₀ range of 25-50μg for the MDA-MB cell line. The compound, 3-((4-fluorophenyl)amino)-2-(2-(4- hydroxy-2-oxoquinolin-1(2H)-yl)phenyl)thiazolidin-4-one (IVg) was found to be the most active against both the cell line, A549 and MDA-MB with IC₅₀ value of 0.0298μmol and 0.0338μmol respectively. The docking results revealed that the synthesized compounds exhibited well-conserved hydrogen bonding with one or more amino acid residues in the active pocket of EGFR tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib (PDB ID:1M17). Compound IVg showed the highest MolDock score of -137.813 compared to the standard drug Imatinib having a MolDock score of -119.354.

Conclusion: Compound IVg showed the highest MolDock score and was also found to be most potent against both the cell line, A549, and MDA-MB.

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作为抗癌剂的 4-羟基-1-苯基-2(1H)-喹啉酮衍生物的对接、合成和评估。

背景：据估计，2022 年印度的癌症病例数为 14,61,427 例。化疗药物的开发降低了死亡率，但其缺点是毒性大。许多研究人员发现喹啉-2-酮具有抗癌活性，在此背景下，我们想到了合成喹啉-2-酮衍生物：本研究旨在对作为抗癌剂的 2-(2-(4-羟基-2-氧代喹啉-1(2H)-基)苯基/取代苯基)-3-(苯基氨基)噻唑烷-4-酮衍生物（IVa-g）进行对接、合成、表征和评价：二苯胺和丙二酸经磷酰氯处理后得到化合物 I，经甲酰化后得到化合物 II，与各种取代的芳香族苯肼衍生物反应后得到化合物 IIIa-g，与巯基乙酸和无水氯化锌进一步反应后得到化合物 IVa-g：结果：在所有合成的新型衍生物中，化合物 IV a-d 对 A549 细胞株的裂解率为 50%，IC50 范围为 25-50μg；化合物 IVa 和 IVb 对 MDA-MB 细胞株的裂解率为 50%，IC50 范围为 25-50μg。化合物 3-((4-氟苯基)氨基)-2-(2-(4-羟基-2-氧代喹啉-1(2H)-基)苯基)噻唑烷-4-酮（IVg）对 A549 和 MDA-MB 细胞株的活性最强，IC50 值分别为 0.0298μmol 和 0.0338μmol。对接结果显示，合成的化合物在表皮生长因子受体酪氨酸激酶结构域的活性口袋中与 4-苯胺基喹唑啉抑制剂厄洛替尼（PDB ID:1M17）的一个或多个氨基酸残基形成了保留良好的氢键。与标准药物伊马替尼的 MolDock 得分-119.354 相比，化合物 IVg 的 MolDock 得分最高，为-137.813：化合物 IVg 的 MolDock 得分最高，而且对细胞系 A549 和 MDA-MB 的药效最强。

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来源期刊

Current drug discovery technologies Pharmacology, Toxicology and Pharmaceutics-Drug Discovery

CiteScore

3.70

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0.00%

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期刊介绍： Due to the plethora of new approaches being used in modern drug discovery by the pharmaceutical industry, Current Drug Discovery Technologies has been established to provide comprehensive overviews of all the major modern techniques and technologies used in drug design and discovery. The journal is the forum for publishing both original research papers and reviews describing novel approaches and cutting edge technologies used in all stages of drug discovery. The journal addresses the multidimensional challenges of drug discovery science including integration issues of the drug discovery process.