Synthesis of novel γ-carboline derivatives and their in silico studies on 5HT1, H1 and CCR2 antagonist receptors

Siddalingamurthy, E. and Mahadevan, K. M. and Jagadeesh, N. M. and Kumara, M. N. (2014) Synthesis of novel γ-carboline derivatives and their in silico studies on 5HT1, H1 and CCR2 antagonist receptors. International Journal of Pharmacy and Pharmaceutical Sciences, 6 (10). pp. 548-554. ISSN 0975-1491

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Abstract

Objective: Synthesis of novel γ-carboline precursor 4 by using mild, inexpensive and eco friendly T3P as catalyst and synthesis of γ-carbolinesulfonamides, amides and tertiary amines 5a-l from compound 4 as a key intermediate. In silico docking studies against 5HT1, H1 and CCR2 antagonist receptors of all 5a-l compounds. Methods: The reaction was carried out by taking mixture of 1 equiv. of phenyl hydrazine hydrochloride, 1 equiv. of N-Boc piperidone and 0.25 equiv. of T3P(50% in EtOAc) in toulene at 90 °C. After 6hr the product γ-carboline 4 was obtained by water workup followed boc deprotection by HCl in dioxane treatment. Further, the sulfonation, amidation and reductive amination were carried out to γ-carboline 4 to get derivatives of γ-carboline 5a-l. The synthesized compounds were docked against 5HT1, H1 and CCR2 antagonist receptors using AutoDock v 4.2. Results: An excellent yield of γ-carboline precursor 4 was obtained by using mild, inexpensive and eco friendly T3P catalyst. Among the synthesized compounds, the 5b and 5c were shown three hydrogen bonding interaction having-10.1082 and-13.9105 kcal/mol of interaction energy with H1 protein at the active site amino acids ARG175, TYR185 and SER128 respectively. The inhibitory constants were found to be 88.7015 and 56.2123 μM respectively. Conclusion: An eco friendly procedure to prepare γ-carboline 4 using mild and inexpensive T3P catalyst through Fischer indole synthesis was developed. The advantage of this method was easy isolation and high yield. In silico docking study reveals that the γ-carboline containing sulphanamides and amides groups exhibits more affinity towards 5HT and H1 protein receptors than on CCR2. Hence the further study in this direction might lead to identify novel compounds to inhibit 5HT1, H1 antagonist receptors.

Item Type:	Article
Uncontrolled Keywords:	Article, carbon nuclear magnetic resonance, column chromatography, proton nuclear magnetic resonance, synthesis, molecular docking, chemical reaction, binding site, static electricity, amidation, antibody combining site, chemokine receptor CCR2 antagonist, gamma carboline derivative, histamine H1 receptor antagonist, inhibition constant, serotonin 1 antagonist, sulfonation
Subjects:	C Chemical Science > Chemistry
Divisions:	Yuvaraj college > Chemistry
Depositing User:	Arshiya Kousar Library Assistant
Date Deposited:	27 Aug 2019 05:31
Last Modified:	27 Aug 2019 05:31
URI:	http://eprints.uni-mysore.ac.in/id/eprint/4449

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