In-silico design, synthesis, ADMET studies and biological evaluation of novel derivatives of Chlorogenic acid against Urease protein and H. Pylori bacterium

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Abstract
Plants have always played important role in treating human and animal diseases as a therapeutic agent for traditional medicine. Through extensive research throughout the world, potential of natural products have been identified to control the over activity of many enzymes. In-silico screening a library of chlorogenic acid derivatives highlighted some novel compounds which were found effective against urease enzyme and cancer causing H. Pylori bacterium. Selected top ligands possessing minimum binding energy and good docking score were synthesized in wet lab by suitable procedure and evaluated for urease enzyme inhibition and free radical scavenging property. Synthetic scheme includes three step reactions i. e protection of hydroxyl group of quinic acid part of chlorogenic acid with lactonisation process, anilide formation by reaction with substituted anilines followed by extraction with ethyl acetate under vacuum and deprotection of hydroxyl groups by treatment with hydrochloric acid. In-vitro results of the series concluded that compounds C4a, C4d and C4b (IC50 11.01 ± 0.013, 13.8 ± 0.041 and 15.86 ± 0.004 µM respectively in urease inhibition and 5.10 ± 0.018, 5.34 ± 0.007 and 6.01 ± 0.005 µM in antioxidant property against DPPH) were found to be significantly potent with excellent dock score − 10.091, − 10.603, − 9.833 and binding energy − 62.674, − 63.352, 56.267 kg/mol as compared to standard drugs thiourea and acetohydroxamic acid (− 3.459, − 3.049 and − 21.156 kJ/mol and − 17.454 kJ/mol) whereas compounds C4c, C4(e, h) exhibited moderate in vivo activity when compared to standard. Selected candidates from the outcome of in vitro urease inhibitory were further examined for anti-H. Pylori activity by well diffusion method against H. pylori bacterium (DSM 4867). Compound C4a showed significant anti-H. Pylori activity with zone of inhibition 10.00 ± 0.00 mm and MIC value 500 μg/mL as compared to standard drug acetohydroxamic acid having zone of inhibition 9.00 ± 0.50 mm and MIC 1000 μg/mL. Molecular docking studies also showed that compounds show strong inhibition by forming strong hydrogen bonding interactions with residues of pocket site in target protein. Hence, the present investigation studies will provide a new vision for the discovery of potent agents against H. Pylori and urease associated diseases.

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