Synthesis, crystallographic characterization, molecular docking and biological activity of isoquinoline derivatives

Hatem A Abuelizz,Gerhard Wolber,Jamil Al-Asri,Azza A Ali,Jérémie Mortier,Rashad Al-Salahi,Mohamed Marzouk,Mona G Khalil,Abdulrahman A Almehizia,Gehad A Abdel Jaleel,Essam Ezzeldin,Hazem A Ghabbour

doi:10.1186/s13065-017-0321-1

Abstract

The main objective of this work was to synthesize novel compounds with a benzo[de][1,2,4]triazolo[5,1-a]isoquinoline scaffold by employing (dioxo-benzo[de]isoquinolin-2-yl) thiourea as a building block. Molecular docking was conducted in the COX-2 active site to predict the plausible binding mode and rationalize the structure–activity relationship of the synthesized compounds. The structures of the synthesized compounds were confirmed by HREI-MS, and NMR spectra along with X-ray diffraction were collected for products 1 and 5. Thereafter, anti-inflammatory effect of molecules 1–20 was evaluated in vivo using carrageenan-induced paw edema method, revealing significant inhibition potency in albino rats with an activity comparable to that of the standard drugs indomethacin. Compounds 8, 9, 15 and 16 showed the highest anti-inflammatory activity. However, thermal sensitivity-hot plat test, a radiological examination and motor coordination assessment were performed to test the activity against rheumatoid arthritis. The obtained results indicate promising anti-arthritic activity for compounds 9 and 15 as significant reduction of the serum level of interleukin-1β [IL-1β], cyclooxygenase-2 [COX-2] and prostaglandin E2 [PGE2] was observed in CFA rats.

Highlights

Inflammation is an important defense mechanism against infective, chemical, and physical aggressions
Thereafter, anti-inflammatory effect of molecules 1–20 was evaluated in vivo using carrageenan-induced paw edema method, revealing significant inhibi‐ tion potency in albino rats with an activity comparable to that of the standard drugs indomethacin
The present investigation explored the significance of the molecular-hybridization development of novel compounds with strong activity against the inflammationinduced-by-carrageenan model

Summary

Introduction

Inflammation is an important defense mechanism against infective, chemical, and physical aggressions. The quinolone ring system is often found in synthetic compounds with various biological activities, including anti-convulsant [10], anti-malarial [11], anti-microbial [12], and anti-inflammatory [13] effects. Quinolines and their isomers isoquinolines are found in various natural products, such as quinine (anti-malarial) and quinidine (anti-arrhythmic) [14]. A wide range of triazole containing compounds are clinically used drugs and developed via molecular hybridization approach including anticancer, antifungal, antibacterial, antiviral, antitubercular, anti-inflammatory, antiparasitic, anticonvulsant, antihistaminic and other biological activities [21]. Triazole and isoquinoline can be promising chemical fragments for the design of novel anti-inflammatory drugs

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Discussion

Conclusion