View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Institutional Repository of the Freie Universität Berlin Abuelizz et al. Chemistry Central Journal (2017) 11:103 DOI 10.1186/s13065-017-0321-1 RESEARCH ARTICLE Open Access Synthesis, crystallographic characterization, molecular docking and biological activity of isoquinoline derivatives Hatem A. Abuelizz1* , Rashad Al‑Salahi1, Jamil Al‑Asri2, Jérémie Mortier2, Mohamed Marzouk3,4, Essam Ezzeldin1,5, Azza A. Ali6, Mona G. Khalil7, Gerhard Wolber2, Hazem A. Ghabbour1, Abdulrahman A. Almehizia1 and Gehad A. Abdel Jaleel8 Abstract The main objective of this work was to synthesize novel compounds with a benzo[de][1,2,4]triazolo[5,1-a]isoquinoline scafold by employing (dioxo-benzo[de]isoquinolin-2-yl) thiourea as a building block. Molecular docking was con‑ ducted in the COX-2 active site to predict the plausible binding mode and rationalize the structure–activity relation‑ ship of the synthesized compounds. The structures of the synthesized compounds were confrmed by HREI-MS, and NMR spectra along with X-ray difraction were collected for products 1 and 5. Thereafter, anti-infammatory efect of molecules 1–20 was evaluated in vivo using carrageenan-induced paw edema method, revealing signifcant inhibi‑ tion 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-infammatory 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 signifcant reduction of the serum level of interleukin-1β [IL-1β], cyclooxygenase-2 [COX-2] and prostaglandin E2 [PGE2] was observed in CFA rats. Introduction have been observed in case of long NSAIDs treatment Infammation is an important defense mechanism against [6]. Terefore, the discovery of novel anti-infammatory infective, chemical, and physical aggressions. Deregula- drugs with less side efects remains an intensive area of tion of this mechanism can lead to pathological perturba- research in medicinal chemistry. Two isoforms of the tions in the body, as observed for example with allergies, cyclooxygenase have been characterized: COX-1 and autoimmune diseases and organ transplantation rejec- COX-2. COX-2 levels increase after infammatory stimuli tion [1]. A key modulator of the infammatory response is induced by mitogens or cytokines, and can be lowered prostaglandin ­E2 ­(PGE2), generated at the infammation by glucocorticoids [7]. Recent discovery indicates that site from arachidonic acid via the cyclooxygenase (COX) renal toxicity and gastrointestinal side efects observed enzyme [2]. with NSAIDs can be due to COX-1 inhibition, while Non-steroidal anti-infammatory drugs (NSAIDs) are selective inhibition of COX-2 shows a comparable anti- widely used against infammation, as for example in the infammatory response with less side efects [8]. As an treatment of chronic and acute infammation [3], pain example, naproxen is a non-selective COX inhibitor, like management [4], and fever [5]. However, cardiovascu- oxicam, it belongs to a group of NSAID displaying mixed lar problems, gastrointestinal lesions and nephrotoxicity COX inhibition, characterized by slow, reversible, and weak inhibitor binding. Contrary to other NSAIDs that inhibit COX reversibly and rapidly (mefenamic acid and *Correspondence: [email protected] ibuprofen), or irreversibly and slowly (indomethacin and 1 Department of Pharmaceutical Chemistry, College of Pharmacy, King diclofenac), naproxen contributes to the cardioprotective Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia Full list of author information is available at the end of the article efect because of their weak inhibition of COX [9]. © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Abuelizz et al. Chemistry Central Journal (2017) 11:103 Page 2 of 14 Te quinolone ring system is often found in synthetic Procedure for preparation of 1‑(1,3‑dioxo‑1H‑benzo[de] compounds with various biological activities, including isoquinolin‑2(3H)‑yl)thiourea (1) anti-convulsant [10], anti-malarial [11], anti-microbial To a solution of 1,8-naphthalic anhydride (2.2 mmol) in [12], and anti-infammatory [13] efects. Quinolines and boiling glacial acetic acid (15 mL), thiosemicarbazide their isomers isoquinolines are also found in various (2.8 mmol) was added and left the mixture stirring natural products, such as quinine (anti-malarial) and qui- under refux for 1 h. Te obtained solid was separated nidine (anti-arrhythmic) [14]. Furthermore, many isoqui- and washed with water. Recrystallization by a mixture noline alkaloids, including cepharanthine, berberine and of toluene and DMF yielded the fnal product as color- tetrandine, have shown anti-infammatory efect [15]. less crystals (90%); mp 243–244 °C; 1H NMR (500 MHz, Te binding afnity and the solubility in physiological DMSO-d6): δ 9.82 (s, 1H, –NH–), 8.55 (br d, J = 8 Hz, conditions can be considerably afected by the position 2H, H-3/8), 8.51 (br d, J 8 Hz, 2H, H-5/6), 7.99 (br = 13 of the nitrogen bearing a side chain on the isoquinoline s, 2H, –NH2), 7.92 (t, J = 8 Hz, 2H, H-4/7); C NMR skeleton [16]. Terefore, a huge efort has been spent in (125 MHz, DMSO-d6): δ 181.8 (C=S), 162.0 (C-2/9), developing novel and efective isoquinoline derivatives. 134.7 (C-5/6), 131.3 (C-5a), 130.9 (C-3/8), 127.3 (C-4/7), On the other hand, the triazole moiety is found in many 122.7 (C-2a/8a), 119.0 (C-2b); HRMS (EI), m/z Calcd for •+ important biologically active compounds. Synthesized C13H9N3O2S (M) 271.0983, found 271.1013. molecules with a triazole moiety possess anti-tubercular [17], antimicrobial [18], anti-cancer [19] and anti-infam- Procedure for preparation of 10‑(methylthio)‑7H‑benzo[de] matory [20] activity. Triazole-based heterocyclic deriva- [1,2,4]triazolo[5,1‑a]isoquinolin‑7‑one (3) tives have enhanced biological activity or possess new A mixture of I or 2 (1 mmol) with dimethyl-N-cyanoimi- biological activities [21]. A wide range of triazole con- dodithiocarbonate (1 mmol) in N,N-dimethyl formamide taining compounds are clinically used drugs and devel- (10 mL) was refuxed in the presence of triethylamine oped via molecular hybridization approach including for 4 h. Afterwards, the mixture was poured into ice/ anticancer, antifungal, antibacterial, antiviral, antituber- water, the resulting solid was fltered, washed with water cular, anti-infammatory, antiparasitic, anticonvulsant, and dried. Analytically pure product obtained as yellow antihistaminic and other biological activities [21]. Tere- amorphous powder (67%); mp 268–269 °C; 1H NMR fore, triazole and isoquinoline can be promising chemi- (700 MHz, DMSO-d6): δ 8.75 (br d, J = 7.7 Hz, 1H, H-6), cal fragments for the design of novel anti-infammatory 8.61 (br d, J = 8.4 Hz, 1H, H-3), 8.59 (br d, J = 8.4 Hz, 1H, drugs. H-8), 8.47 (br d, J = 7.7 Hz, 1H, H-5), 7.99 (t, J = 7.7 Hz, Considering the importance of the isoquinoline and 1H, H-4), 7.93 (t, J 7.7 Hz, 1H, H-7), 2.73 (s, 3H, –S– 13 = triazole moieties in the wide range of anti-infammatory CH3); C NMR (176 MHz, DMSO-d6): δ 166.0 (C-9), treatments and its interesting activity profle, we con- 156.6 (>C–S–CH3), 155.9 (C-2), 137.0 (C-6), 134.3 (C-3), ducted a molecular-hybridization design of novel anti- 133.5 (C-5), 132.3 (C-8a), 128.4 (C-8), 128.1 (C-4), 128.0 infammatory compounds. Toward the development of (C-7), 126.1 (C-5a), 122.9 (C-2b), 118.2 (C-2a), 14.2 (S- ·+ new efective and selective anti-infammatory agents, the CH3); EI-MS, m/z (%): 267 [(M , 100)]; HRMS (EI), m/z ·+ [1,2,4]triazole and [5,1-a]isoquinoline were integrated to Calcd for C14H9N3OS (M) 267.0466, found 267.0490. develop a novel class of inhibitor. Procedure for preparation of 10‑(methylsulfonyl)‑7H‑benz Materials and methods o[de][1,2,4]triazolo[5,1‑a]isoquinolin‑7‑one (5) Melting points were determined on open glass capillar- An amount of 3 (1 mmol) was dissolved in boiling gla- ies using a STUART Melting point SMP 10 apparatus and cial acetic acid (12 mL), afterward H 2O2 (12 mL), was are uncorrected. NMR spectra were recorded on a Bruker added dropwise over a period of 10 min., while heat- AMX 500 spectrometer in DMSO-d6 and reported as δ ing. After the addition was complete, the mixture was ppm values relative to TMS at 500/700 and 125/176 MHz poured into hot water and left at room temperature, the for 1H and 13C NMR, respectively. J values were recorded obtained solid was collected, washed with water and in Hz. HREI-MS spectra were measured on a JEOL dried. Recrystallization from DMF gave analytically pure MStation JMS-700 system. X-ray data were collected colored as pale brown amorphous powder (60%); mp 1 on a Bruker APEX-II D8 Venture area difractometer, 218–219 °C; H NMR (500 MHz, DMSO-d6): δ 8.93 (br d, equipped with graphite monochromatic Mo Kα radia- J = 7.5 Hz, 1H, H-6), 8.29 (br d, J = 8 Hz, 1H, H-3), 8.26 tion, λ = 0.71073 Å at 100 (2) K.