Abstract
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.
Highlights
In the Kingdom of Saudi Arabia, colon and rectal cancer (CRC) is the second most common cancer type, constituting 14.4% of all the newly diagnosed cancer cases in 2018 [1]
Concerning initiation of the CRC, dysbiosis associated with the abundance of: Bacteroides fragilis (B. fragilis), Escherichia coli (E. coli), and Enterococcus feacalis (E. feacalis) strains has been shown to contribute to neotumorigenesis [4]
This reprogrammed metabolism is associated with the upregulation of lactate dehydrogenase A (LDHA) that acts to diminish pyruvate entry into the tricarboxylic acid cycle (TCA) in the mitochondria, and facilitates its rapid conversion to lactate in the cytoplasm
Summary
In the Kingdom of Saudi Arabia, colon and rectal cancer (CRC) is the second most common cancer type, constituting 14.4% of all the newly diagnosed cancer cases in 2018 [1]. In addition to this, during the development of the tumors, the transformed cells switch from mitochondrial respiration to aerobic glycolysis, the “Warburg effect” [15], to obtain their increased need from energy and nutrients This reprogrammed metabolism is associated with the upregulation of LDHA that acts to diminish pyruvate entry into the tricarboxylic acid cycle (TCA) in the mitochondria, and facilitates its rapid conversion to lactate in the cytoplasm. Considering the multifactorial nature of CRC and in continuation to our ongoing research targeting this malignancy [29], we report the synthesis and characterization of some new Schiff’s bases incorporating quinoxalin-2(1H)one and 2-methyl-3H-quinazolin-4-one scaffolds They were evaluated for antibacterial and enzymatic inhibitory activities against COX-2 and LDHA. The absorption, distribution, metabolism, excretion (ADME), and the toxicity properties of all the synthesized compounds were predicted to explore their pharmacokinetic properties
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