Synthesis, crystallographic characterization, molecular docking and biological activity of isoquinoline derivatives
Abuelizz et al. Chemistry Central Journal
Synthesis, crystallographic characterization, molecular docking and biological activity of isoquinoline derivatives
Hatem A. Abuelizz 0
Rashad Al‑Salahi 0
Jamil Al‑Asri 2
Jérémie Mortier 2
Mohamed Marzouk 1 6
Essam Ezzeldin 0 5
Azza A. Ali 4
Mona G. Khalil 3
Gerhard Wolber 2
Hazem A. Ghabbour 0
Abdulrahman A. Almehizia 0
Gehad A. Abdel Jaleel 7
0 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University , P.O. Box 2457, Riyadh 11451 , Saudi Arabia
1 Department of Chemistry, College of Science and Humanities, Prince Sattam bin Abdulaziz University , 83, Alkharj , Saudi Arabia
2 Department of Pharmaceutical & Medicinal Chemistry, Institute of Pharmacy, Freie Universität Berlin , Königin‐Luise Str. 2‐4, 14195 Berlin , Germany
3 Department of Pharmacology & Toxicology, Faculty of Phar‐ macy, Modern University for Technology and Information , Cairo , Egypt
4 Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al‐Azhar University , Cairo , Egypt
5 Drug Bioavailability Lab., College of Pharmacy, King Saud University , P.O. Box 2457, Riyadh 11451 , Saudi Arabia
6 Chemistry of Natural Products Group, Center of Excellence for Advanced Sciences, National Research Centre , Dokki, Cairo 12622 , Egypt
7 Department of Pharmacology, National Research Centre , El‐Bohoth St., Dokki, Cairo 12622 , Egypt
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.
Introduction
Inflammation is an important defense mechanism against
infective, chemical, and physical aggressions.
Deregulation of this mechanism can lead to pathological
perturbations in the body, as observed for example with allergies,
autoimmune diseases and organ transplantation
rejection [
1
]. A key modulator of the inflammatory response is
prostaglandin E2 (PGE2), generated at the inflammation
site from arachidonic acid via the cyclooxygenase (COX)
enzyme [
2
].
Non-steroidal anti-inflammatory drugs (NSAIDs) are
widely used against inflammation, as for example in the
treatment of chronic and acute inflammation [
3
], pain
management [
4
], and fever [
5
]. However,
cardiovascular problems, gastrointestinal lesions and nephrotoxicity
have been observed in case of long NSAIDs treatment
[
6
]. Therefore, the discovery of novel anti-inflammatory
drugs with less side effects remains an intensive area of
research in medicinal chemistry. Two isoforms of the
cyclooxygenase have been characterized: COX-1 and
COX-2. COX-2 levels increase after inflammatory stimuli
induced by mitogens or cytokines, and can be lowered
by glucocorticoids [
7
]. Recent discovery indicates that
renal toxicity and gastrointestinal side effects observed
with NSAIDs can be due to COX-1 inhibition, while
selective inhibition of COX-2 shows a comparable
antiinflammatory response with less side effects [
8
]. As an
example, naproxen is a non-selective COX inhibitor, like
oxicam, it belongs to a group of NSAID displaying mixed
COX inhibition, characterized by slow, reversible, and
weak inhibitor binding. Contrary to other NSAIDs that
inhibit COX reversibly and rapidly (mefenamic acid and
ibuprofen), or irreversibly and slowly (indomethacin and
diclofenac), naproxen contributes to the cardioprotective
effect because of their weak inhibition of COX [
9
].
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 also found in various
natural products, such as quinine (anti-malarial) and
quinidine (anti-arrhythmic) [
14
]. Furthermore, many
isoquinoline alkaloids, including cepharanthine, berbe (...truncated)