Discovery of new anticancer thiourea-azetidine hybrids: design, synthesis, in vitro antiproliferative, SAR, in silico molecular docking against VEGFR-2, ADMET, toxicity, and DFT studies

• Published in: Bioorganic chemistry 2021-10, Vol.115, p.105206, Article 105206
• Main Authors: Parmar, Deepa R., Soni, Jigar Y., Guduru, Ramakrishna, Rayani, Rahul H., Kusurkar, Rakesh V., Vala, Anand G., Talukdar, Sahista N., Eissa, Ibrahim H., Metwaly, Ahmed M., Khalil, Ahmed, Zunjar, Vishwanath, Battula, Satyanarayana
• Format: Article
• Language: English
• Subjects: ADMET; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Azetidines - chemistry; Azetidines - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Density Functional Theory; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Structure-Activity Relationship; Thiourea - chemistry; Thiourea - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2021.105206

[Display omitted] •New azetidine-thiourea hybrids were designed and synthesized as VEGFR-2 inhibitors.•3B was found to be more potent than Doxorubicin in PC3, A431 and 786-O cell lines.•ADMET, VEGFR-2 moleuclar docking and DFT studies were carried out.•Compounds possess druglikeness characteristics as it showed low toxicity and good absorption. With the aim to discover potent and novel antitumor agents, a series of thiourea compounds bearing 3-(4-methoxyphenyl)azetidine moiety were designed according to the essential pharmacophoric features of the reported VEGFR-2 inhibitors and synthesized. All the synthesized compounds were evaluated for their in vitro anticancer activity against various human cancer cell lines (lung (A549), prostate (PC3), breast (MCF-7), liver (HepG2), colon (HCT-116), ovarian (SKOV-3), skin (A431), brain (U251) and kidney (786-O)). 3-(4-Methoxy-3-(2-methoxypyridin-4-yl)phenyl)-N-(4-methoxyphenyl)azetidine-1-carbothioamide (3B) was found to be most potent member against PC3, U251, A431, and 786-O cancer cell lines with EC50 values 0.25, 0.6, 0.03, and 0.03 µM, respectively and showed more potency than Doxorubicin in PC3, A431, and 786-O cell lines. Compounds 1B to 7B showed EC50 values ranging from 0.03 to 12.55 µM in A431 cell line. Compound 3-(4-methoxy-3-(pyridin-4-yl)phenyl)-N-(4-methoxyphenyl)azetidine-1-carbothioamide (1B) was found to be highly efficient in A431 and 786-O cell line with EC50 values of 0.77 and 0.73 µM respectively. All the compounds exhibited good to moderate cytotoxic activity. The pharmacophoric features and molecular docking studies confirmed the potentialities of compounds 1B, 2B, 3B and 5B to be VEGFR-2 inhibitors. Moreover, in silico ADMET prediction indicated that most of the synthesized compounds have drug-like properties, possess low adverse effects and toxicity. In addition, the DFT studies for the most active compounds (1B and 3B) were carried out. In the end, our studies revealed that the compounds 1B and 3B represent promising anticancer potentialities through their VEGFR-2 inhibition.