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.

Autor: Parmar DR; Department of Chemistry, Faculty of Basic and Applied Sciences, Madhav University, Abu Road, Sirohi, Rajasthan, India; Piramal Pharma Limited - Discovery Solutions, Plot no. 18, Pharmaceutical Special Economic Zone, Village Matoda, Ahmedabad, Gujarat, India., Soni JY; Department of Chemistry, Faculty of Basic and Applied Sciences, Madhav University, Abu Road, Sirohi, Rajasthan, India. Electronic address: medchemgroup.pds@gmail.com., Guduru R; Piramal Pharma Limited - Discovery Solutions, Plot no. 18, Pharmaceutical Special Economic Zone, Village Matoda, Ahmedabad, Gujarat, India., Rayani RH; Department of Chemistry, Faculty of Basic and Applied Sciences, Madhav University, Abu Road, Sirohi, Rajasthan, India; Piramal Pharma Limited - Discovery Solutions, Plot no. 18, Pharmaceutical Special Economic Zone, Village Matoda, Ahmedabad, Gujarat, India., Kusurkar RV; Department of Chemistry, Faculty of Basic and Applied Sciences, Madhav University, Abu Road, Sirohi, Rajasthan, India; Piramal Pharma Limited - Discovery Solutions, Plot no. 18, Pharmaceutical Special Economic Zone, Village Matoda, Ahmedabad, Gujarat, India., Vala AG; Department of Chemistry, Faculty of Basic and Applied Sciences, Madhav University, Abu Road, Sirohi, Rajasthan, India; Piramal Pharma Limited - Discovery Solutions, Plot no. 18, Pharmaceutical Special Economic Zone, Village Matoda, Ahmedabad, Gujarat, India., Talukdar SN; In vitro Department, Piramal Pharma Limited - Discovery Solutions, Plot no. 18, Pharmaceutical Special Economic Zone, Village Matoda, Ahmedabad, Gujarat, India; Pharmacokinetics Drug Metabolism Department, Syngene Amgen Research Centre, Plot no. 1,2,3,4, and 5, Bommasandra Jigani Link Road, Bommasandra Industrial Area, Bengaluru, Karnataka, India., Eissa IH; Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo11884, Egypt., Metwaly AM; Pharmacognosy and Medicinal Plants Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt., Khalil A; Department of Chemistry, College of Science, King Faisal University, Al-Hofuf, Al-Ahsa 31982, Saudi Arabia; Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt., Zunjar V; School of Engineering and Technology, Navrachana University, Vadodara, Gujarat, India., Battula S; Department of Chemistry, Uka Tarsadia University, Maliba campus, Bardoli, Gujarat, India.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2021 Oct; Vol. 115, pp. 105206. Date of Electronic Publication: 2021 Jul 27.
DOI: 10.1016/j.bioorg.2021.105206
Abstrakt: 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 EC 50 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 EC 50 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 EC 50 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.
(Copyright © 2021. Published by Elsevier Inc.)
Databáze: MEDLINE
Externí odkaz: