{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T04:18:33Z","timestamp":1773116313927,"version":"3.50.1"},"reference-count":77,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Oxidative stress, the Warburg effect, and resistance to apoptosis are key hallmarks driving colorectal tumorigenesis. This study aimed to develop novel multi-target compounds capable of modulating these pathways. Methods: A library of 24 newly synthesized compounds\u2014incorporating annulated thiophene, thiazole, quinazolinone, 2-oxoindoline, and 1,2,3-oxadiazole scaffolds, as well as N-(1-(4-hydroxy-3-methoxyphenyl)-3-oxo-3-(2-(phenylcarbamothioyl)hydrazineyl) prop-1-en-2-yl)benzamide\u2014was evaluated for antioxidant activity (DPPH assay), PDK-1 and LDHA inhibition, cytotoxic effects against LoVo and HCT-116 colon carcinoma cells, with parallel assessment of safety profiles on normal HUVECs. The underlying anticancer mechanism of the most active compound was investigated through analysis of cell cycle distribution, apoptosis induction, intracellular reactive oxygen species levels, mitochondrial membrane potential disruption, and expression levels of apoptosis-related genes. Molecular docking assessed binding interactions within LDHA and PDK-1 active sites. The physicochemical, drug-likeness, and ADMET properties of the multi-bioactive candidates were predicted in silico. Results: Among the synthesized compounds, thiophenes 3b and 3d exhibited potent PDK-1\/LDHA and DPPH\/LDHA inhibitions, along with significant cytotoxic effects on LoVo\/HCT-116 cells (IC50 in \u00b5M: 190.30\/170.21 and 156.60\/160.96, respectively), while showing minimal cytotoxicity toward HUVECs. Molecular docking revealed favorable interactions with key amino acid residues within the LDHA and\/or PDK-1 active sites. Compound 3d notably induced G2\/M (LoVo) and G1 (HCT-116) arrest and promoted apoptosis via enhancing ROS generation, modulating Bax\/Bcl-2 expressions, disrupting mitochondrial membrane potential, and ultimately activating caspses-3. In silico predictions indicated their promising drug-likeness and pharmacokinetics, though high lipophilicity, poor solubility (especially for 3b), and potential toxicity risks were identified as limitations. Conclusions: Thiophenes 3b and 3d emerged as promising multi-target candidates; however, structural optimization is warranted to enhance their solubility, bioavailability, and safety to support further development as lead anti-colon cancer agents.<\/jats:p>","DOI":"10.3390\/ph18060801","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T04:46:38Z","timestamp":1748493998000},"page":"801","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["New Nitrogen-, Oxygen-, and Sulfur-Containing Heterocyclic Compounds as Anti-Colon Cancer Agents: Synthesis, Multitargeted Evaluations, Molecular Docking Simulations and ADMET Predictions"],"prefix":"10.3390","volume":"18","author":[{"given":"Nahed Nasser Eid","family":"El-Sayed","sequence":"first","affiliation":[{"name":"Egyptian Drug Authority, 51 Wezaret El-Zerra St., Giza 35521, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Najeh","family":"Krayem","sequence":"additional","affiliation":[{"name":"Laboratoire de Biochimie et de G\u00e9nie Enzymatique des Lipases, ENIS, Universit\u00e9 de Sfax, Route de Soukra 3038, Sfax BP 1173, Tunisia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hamed Ahmed","family":"Derbala","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, Cairo 11566, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shimaa","family":"Kamal","sequence":"additional","affiliation":[{"name":"Chemistry Department, Faculty of Science, Ain Shams University, Abbassia, Cairo 11566, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8125-7972","authenticated-orcid":false,"given":"Syde Nasir Abbas","family":"Bukhari","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3548-3888","authenticated-orcid":false,"given":"Mohamed K.","family":"El-Ashrey","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, Kasr Elini St., Cairo 11562, Egypt"},{"name":"Medicinal Chemistry Department, Faculty of Pharmacy, King Salman International University, South Sinai 46612, Egypt"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8196-2612","authenticated-orcid":false,"given":"Zainab M.","family":"Almarhoon","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seham","family":"Soliman Alterary","sequence":"additional","affiliation":[{"name":"Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6372-7483","authenticated-orcid":false,"given":"Abir","family":"Ben Bacha","sequence":"additional","affiliation":[{"name":"Biochemistry Department, College of Sciences, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101174","DOI":"10.1016\/j.tranon.2021.101174","article-title":"Global colorectal cancer burden in 2020 and projections to 2040","volume":"14","author":"Xi","year":"2021","journal-title":"Trans. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Nelson, V.K., Nuli, M.V., Mastanaiah, J., Saleem, T.S.M., Birudala, G., Jamous, Y.F., Alshargi, O., Kotha, K.K., Sudhan, H.H., and Mani, R.R. (2023). 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