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Bioinspired Quinoline-2 Derivatives Based on the Natural Alkaloid 2-Phenylquinoline from Conchocarpus longifolius (A.St.-Hil.) Kallunki & Pirani: Pharmacological Evaluation of Their Gastroprotective Potential
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DOI：10.3390/molecules31162815.png)
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Abstract
En 中文
The treatment of gastric ulcers based on antisecretory drugs is often associated with side effects and high recurrence rates, reinforcing the need for new therapeutic alternatives. Medicinal chemistry guided by natural prototypes represents a productive strategy in this context. The antiulcer potential of 2-phenylquinoline (2-PQ), an alkaloid from Conchocarpus longifolius (A.St.-Hil.) Kallunki & Pirani (syn. Galipea longiflora Krause), has been previously reported by our research group. In the present work, four 2-PQ derivatives were synthesized—2,4-diphenylquinoline (1), 2-(4-methoxyphenyl) quinoline (2), 2-phenylquinolin-4-ol (3), and 4-methoxy-2-phenylquinoline (4)—and evaluated for gastroprotective activity in the HCl/ethanol-induced gastric ulcer model in mice. The quinoline derivatives were prepared mainly by trifluoroacetic acid-catalyzed condensations of aminated benzaldehyde or benzophenone precursors with the corresponding ketones under reflux at 100 °C, affording yields of 68–94%. Compound 3 was synthesized via a two-step sequence involving the acylation of 2-aminobenzophenone followed by base-induced cyclization, providing an 85% yield. Compound 4 was obtained by O-methylation of compound 3 using iodomethane (MeI) and potassium carbonate (K2CO3) in dimethylformamide (DMF), affording a 95% yield. So, this study provides the first comparative analysis linking structural modifications to gastroprotective activity in synthetic quinoline derivatives inspired by 2-phenylquinoline, a natural alkaloid previously shown to exert gastroprotective effects. Carbenoxolone (200 mg/kg, p.o., positive control) inhibited gastric lesion formation by 94.1%. The synthetic quinoline derivatives also showed significant gastroprotective activity after oral administration (30 mg/kg), reducing ulcer area by 72.4% (compound 1), 76.1% (compound 2), 49.1% (compound 3), and 66.1% (compound 4). Compounds 2, 3, and 4 further retained efficacy following intraperitoneal administration (3 mg/kg), whereas compound 1 was inactivated by this route. Overall, compound 4 exhibited the greatest efficacy, significantly reducing the gastric lesion area, decreasing lipid hydroperoxide (LOOH) and tumor necrosis factor-alpha (TNF-α) levels, and increasing glutathione (GSH) content in ulcerated gastric tissue. These findings suggest that its gastroprotective effects are mediated by antioxidant and anti-inflammatory mechanisms, identifying compound 4 as the most promising candidate for the prevention and treatment of peptic ulcers. Its promising pharmacological profile warrants further investigation to elucidate its molecular mechanisms of action, assess its safety and efficacy in additional preclinical studies, and explore its potential for future therapeutic development.
Keywords:
<i>Conchocarpus longifolius</i>
alkaloid
quinolines
gastroprotection
organic synthesis
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4.6
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6.4W
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23.7W
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