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

Chemistry Central Journal, Oct 2017

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.

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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)


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Hatem A. Abuelizz, Rashad Al-Salahi, Jamil Al-Asri, Jérémie Mortier, Mohamed Marzouk, Essam Ezzeldin, Azza A. Ali, Mona G. Khalil, Gerhard Wolber, Hazem A. Ghabbour, Abdulrahman A. Almehizia, Gehad A. Abdel Jaleel. Synthesis, crystallographic characterization, molecular docking and biological activity of isoquinoline derivatives, Chemistry Central Journal, 2017, pp. 103, Volume 11, Issue 1, DOI: 10.1186/s13065-017-0321-1