Synthesis and Characterization of Some New Quinoxalin-2(1H)one and 2-Methyl-3H-quinazolin-4-one Derivatives Targeting the Onset and Progression of CRC with SAR, Molecular Docking, and ADMET Analyses

被引:7
作者
El-Sayed, Nahed N. E. [1 ]
Al-Otaibi, Taghreed M. [2 ]
Alonazi, Mona [3 ]
Masand, Vijay H. [4 ]
Barakat, Assem [2 ,5 ]
Almarhoon, Zainab M. [2 ]
Ben Bacha, Abir [3 ,6 ]
机构
[1] Egyptian Drug Author, 51 Wezaret El Zerra St, Giza 35521, Egypt
[2] King Saud Univ, Dept Chem, Coll Sci, POB 2455, Riyadh 11451, Saudi Arabia
[3] King Saud Univ, Dept Biochem, Coll Sci, POB 22452, Riyadh 11495, Saudi Arabia
[4] Vidya Bharati Coll, Dept Chem, Amravati 444602, Maharashtra, India
[5] Alexandria Univ, Dept Chem, Fac Sci, POB 426, Alexandria 21321, Egypt
[6] Univ Sfax, Fac Sci Sfax, Lab Plant Biotechnol Appl Crop Improvement, Sfax 3038, Tunisia
来源
MOLECULES | 2021年 / 26卷 / 11期
关键词
colorectal cancer; dysbiosis; cyclooxygenase-2; lactate dehydrogenase A; quinazoline; quinoxaline; ADMET; COLORECTAL-CANCER; ANTICANCER; INHIBITION; TOXICITY; CYCLOOXYGENASE-2; PERMEABILITY; ANTIBIOTICS; METABOLISM; EXPRESSION; RESISTANCE;
D O I
10.3390/molecules26113121
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The pathogenesis of colorectal cancer is a multifactorial process. Dysbiosis and the overexpression of COX-2 and LDHA are important effectors in the initiation and development of the disease through chromosomal instability, PGE2 biosynthesis, and induction of the Warburg effect, respectively. Herein, we report the in vitro testing of some new quinoxalinone and quinazolinone Schiff's bases as: antibacterial, COX-2 and LDHA inhibitors, and anticolorectal agents on HCT-116 and LoVo cells. Moreover, molecular docking and SAR analyses were performed to identify the structural features contributing to the biological activities. Among the synthesized molecules, the most active cytotoxic agent, (6d) was also a COX-2 inhibitor. In silico ADMET studies predicted that (6d) would have high Caco-2 permeability, and %HIA (99.58%), with low BBB permeability, zero hepatotoxicity, and zero risk of sudden cardiac arrest, or mutagenicity. Further, (6d) is not a potential P-gp substrate, instead, it is a possible P-gpI and II inhibitor, therefore, it can prevent or reverse the multidrug resistance of the anticancer drugs. Collectively, (6d) can be considered as a promising lead suitable for further optimization to develop anti-CRC agents or glycoproteins inhibitors.
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页数:26
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