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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry


ISSN (Print): 1871-5230
ISSN (Online): 1875-614X

Research Article

Synthesis of Novel Aryl (4-Aryl-1H-Pyrrol-3-yl) (Thiophen-2-yl) Methanone Derivatives: Molecular Modelling, In Silico ADMET, Anti-Inflammatory and Anti-Ulcer Activities

Author(s): Arif Pasha*, Sumanta Mondal and Naresh Panigrahi

Volume 20, Issue 2, 2021

Published on: 16 November, 2020

Page: [182 - 195] Pages: 14

DOI: 10.2174/1871523019999201116191622

Price: $65


Background: Due to the presence of both five-membered heterocyclics like pyrrole and thiophene in one molecule considerable attention was made for their enormous pharmacological activities out of which include anti-inflammatory and anti-ulcer activities.

Objective: Chalcones with toluenesulfonylmethyl isocyanide (TosMIC) undergo synthesis to form some new aryl (4-aryl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone derivatives. Molecular docking of synthesized compounds with protein receptors of anti-inflammatory COX-1(3N8Y), COX-2 (1PXX) along with anti-ulcer H+/K+ATPase enzyme (2XZB) followed with drug-likeness, and in silico ADMET properties.

Materials and Methods: The multicomponent reaction was carried out by the intermediate formation of α, β-unsaturated ketone from carbonyl compounds which on sequential addition undergoes [3+2] cycloaddition reaction in same medium affords aryl (4-aryl-1H-pyrrol-3-yl) (thiophen-2-yl) methanone derivatives by addition of TosMIC in basic medium had resulted in series of compounds PY1 to PY12. All the new synthesized compounds were screened for their in-vitro anti-inflammatory activity by bovine serum albumin method followe with COX assay, and in-vivo by using carrageenan-induced rat paw edema method of the selected compounds PY1, PY5 and PY12 which is also screened for anti-ulcer activity by pylorus ligation method, respectively. Molecular docking was performed using autodock tools, drug-likeness by OSIRIS property explorer and admetSAR properties.

Results and Discussion: From the synthesized compounds of aryl (4-aryl-1H-pyrrol-3-yl) (thiophen- 2-yl) methanone derivatives PY5 showed decent in-vitro and in-vivo anti-inflammatory along selectivity index of 6.2 for COX-1 with IC50(μM) value of 9.54 over diclofenac with 8.74 and PY1 showed decent in-vivo anti-ulcer activities along with drug-likeness and in silico ADMET predictions revealed that all the synthesized compounds have minimal toxic effects with good absorption as well as solubility characteristics. The selected compounds may serve as potential lead compounds for developing new anti-inflammatory and anti-ulcer drugs.

Conclusion: From the newly synthesized molecules PY5 was found to be effective for anti-inflammatory and PY1 was found to be effective for anti-ulcer activities further derivitization and designed of modification to achieve more compounds with potent anti-inflammatory and anti-ulcer activities.

Keywords: Chalcones, TosMIC, pyrrole, anti-inflammatory, anti-ulcer activities, derivatives.

Graphical Abstract
Gholap, S.S. Pyrrole: An emerging scaffold for construction of valuable therapeutic agents. Eur. J. Med. Chem., 2016, 110, 13-31.
[] [PMID: 26807541]
Fan, H.; Peng, J.; Hamann, M.T.; Hu, J.F. Lamellarins and related pyrrole-derived alkaloids from marine organisms. Chem. Rev., 2008, 108(1), 264-287.
[] [PMID: 18095718]
Ahmad, S.; Alam, O.; Naim, M.J.; Shaquiquzzaman, M.; Alam, M.M.; Iqbal, M. Pyrrole: An insight into recent pharmacological advances with structure activity relationship. Eur. J. Med. Chem., 2018, 157, 527-561.
[] [PMID: 30119011]
Tehranchian, S.; Akbarzadeh, T.; Fazeli, M.R.; Jamalifar, H.; Shafiee, A. Synthesis and antibacterial activity of 1-[1,2,4-triazol-3-yl] and 1-[1,3,4-thiadiazol-2-yl]-3-methylthio-6,7-dihydrobenzo[c]thiophen-4(5H)ones. Bioorg. Med. Chem. Lett., 2005, 15(4), 1023-1025.
[] [PMID: 15686905]
Pillai, A.D.; Rathod, P.D.; Xavier, F.P.; Padh, H.; Sudarsanam, V.; K Vasu, K. Tetra substituted thiophenes as anti-inflammatory agents: exploitation of analogue-based drug design. Bioorg. Med. Chem., 2005, 13(24), 6685-6692.
[] [PMID: 16125391]
Madhavi, K.; Soumya, K.R.; Subhashini, C. Cyanoacetylation of substituted 2-aminothiophenes and evaluation for antioxidant and antibacterial activities. Res. J. Pharm. Biol. Chem. Sci., 2017, 8, 387-394.
Noreen, M.; Rasool, N.; Gull, Y.; Zubair, M.; Mahmood, T.; Ayub, K.; Nasim, F.U.; Yaqoob, A.; Zia-Ul-Haq, M.; de Feo, V. Synthesis, density functional theory (DFT), urease inhibition and antimicrobial activities of 5-aryl thiophenes bearing sulphonylacetamide moieties. Molecules, 2015, 20(11), 19914-19928.
[] [PMID: 26556326]
Dashyan, S.S.; Paronikyan, E.G.; Noravyan, A.S.; Dzhagatspanyan, I.A.; Parinikyan, R.G.; Nazaryan, I.M.; Akopyan, A.G. Synthesis and neurotropic activity of 2,4-disubstituted pyrano[4′,3′:4,5]pyrido[2,3-b]thieno[3,2-d] pyrimidines. Russ. J. Bioorganic Chem., 2015, 41, 663-669.
Rizwan, K.; Zubair, M.; Rasool, N.; Ali, S.; Zahoor, A.F.; Rana, U.A.; Khan, S.U.; Shahid, M.; Zia-Ul-Haq, M.; Jaafar, H.Z. Regioselective synthesis of 2-(bromomethyl)-5-aryl-thiophene derivatives via palladium (0) catalyzed suzuki cross-coupling reactions: as antithrombotic and haemolytically active molecules. Chem. Cent. J., 2014, 8, 74.
[] [PMID: 25685184]
Russell, R.K.; Press, J.B.; Rampulla, R.A.; McNally, J.J.; Falotico, R.; Keiser, J.A.; Bright, D.A.; Tobia, A. Thiophene systems. 9. Thienopyrimidinedione derivatives as potential antihypertensive agents. J. Med. Chem., 1988, 31(9), 1786-1793.
[] [PMID: 2842504]
Chen, Z.; Ku, T.C.; Seley-Radtke, K.L. Thiophene-expanded guanosine analogues of Gemcitabine. Bioorg. Med. Chem. Lett., 2015, 25(19), 4274-4276.
[] [PMID: 26316465]
Benabdellah, M.; Aouniti, A.; Dafali, A.; Hammouti, B.; Benkaddour, M.; Yahyi, A.; Ettouhami, A. Investigation of the inhibitive effect of triphenyltin- 2-thiophene carboxylate on corrosion of steel in 2M H3PO4 solutions. Appl. Surf. Sci., 2006, 252, 8341-8347.
Mohamed, M.S.; Kamel, R.; Fathallah, S.S. Synthesis of new pyrroles of potential anti-inflammatory activity. Arch. Pharm. (Weinheim), 2011, 344(12), 830-839.
[] [PMID: 21956581]
Wadea, N.E.; Issac, M.M.; Osman, N.A.; Abadi, A.H. Benzofuran and pyrrole derivatives as cannabinoid receptor modulators with in vivo efficacy against ulcerative colitis. Future Med. Chem., 2019, 11(24), 3139-3159.
[] [PMID: 31838898]
Bell, M.R.; Zalay, A.W.; Oesterlin, R.; Clemans, S.D.; Dumas, D.J.; Bradford, J.C.; Rozitis, J., Jr Experimental antiulcer drugs. 1. Indole-1-alkanamides and pyrrole-1-alkanamides. J. Med. Chem., 1977, 20(4), 537-540.
[] [PMID: 850239]
Neumann, H.; Brennführer, A.; Beller, M. An Efficient and Practical Sequential One-Pot Synthesis of Suprofen, Ketoprofen and Other 2-Arylpropionic Acids. Adv. Synth. Catal., 2008, 350(14-15), 2437-2442.
Abedinifar, F.; Babazadeh Rezaei, E.; Biglar, M.; Larijani, B.; Hamedifar, H.; Ansari, S.; Mahdavi, M. Recent strategies in the synthesis of thiophene derivatives: Highlights from the 2012-2020 literature. Mol. Divers., 2020.
[] [PMID: 32734589]
Feldman, M. Peptic ulcer disease. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology, Diagnosis, Management., (11th ed). 2021,
Sharma, R.; Kumar, K.; Chouhan, M.; Grover, V.; Nair, V.A. Lithium hydroxide mediated synthesis of 3,4-disubstituted pyrroles. RscAdv, 2013, 3, 14521-14527.
Gondkar, A.S.; Deshmukh, V.K.; Chaudhari, S.R. Synthesis, characterization and in-vitro anti-inflammatory activity of some substituted 1,2,3,4 tetrahydropyrimidine derivatives. Drug invent. today, 2013, 5, 175-181.
Dragan, M.; Stan, C.D.; Panzariu, A.; Profire, L. Evaluation Of Anti-inflammatory Potential of some new ferullic acid derivatives. Farmacia, 2016, 64, 194-197.
Winter, C.A.; Risley, E.A.; Nuss, G.W. Carrageenin-induced edema in hind paw of the rat as an assay for antiiflammatory drugs. Proc. Soc. Exp. Biol. Med., 1962, 111, 544-547.
[] [PMID: 14001233]
Kulkarni, S.K. Hand book of experimental pharmacology. Vallabh Prakashan: Delhi . Delhi, 1999.
Subudhi, B.B.; Bhatta, D.; Panda, P.K.; Mishra, P.; Pradhan, D. Synthesis and antiulcer activity studies of 2-(1′-iminothioimido substituted)-1′-substituted phenyl benzoic acids. Indian J. Pharm. Sci., 2008, 70, 381-383.
[] [PMID: 20046753]
Al-Suwaidan, I.A.; Alanazi, A.M.; El-Azab, A.S.; Al-Obaid, A.M.; ElTahir, K.E.H.; Maarouf, A.R.; Abu El-Enin, M.A.; Abdel-Aziz, A.A. Molecular design, synthesis and biological evaluation of cyclic imides bearing benzenesulfonamide fragment as potential COX-2 inhibitors. Part 2. Bioorg. Med. Chem. Lett., 2013, 23(9), 2601-2605.
[] [PMID: 23528298]
Abdel-Aziz, A.A.; Abou-Zeid, L.A.; ElTahir, K.E.; Mohamed, M.A.; Abu El-Enin, M.A.; El-Azab, A.S.; El-azab, A.S. Design, synthesis of 2,3-disubstitued 4(3H)-quinazolinone derivatives as anti-inflammatory and analgesic agents: COX-1/2 inhibitory activities and molecular docking studies. Bioorg. Med. Chem., 2016, 24(16), 3818-3828.
[] [PMID: 27344214]
Sanner, M.F. Python: a programming language for software integration and development. J. Mol. Graph. Model., 1999, 17(1), 57-61.
[PMID: 10660911]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[] [PMID: 19399780]
Sidhu, R.S. Structure of Aspirin acetylated cyclooxygenase-1 in complex with Diclofenac. 2010.
Kiefer, J.R.; Rowlinson, S.W.; Prusakiewicz, J.J.; Pawlitz, J.L.; Kozak, K.R.; Kalgutkar, A.S.; Stallings, W.C.; Marnett, L.J.; Kurumbail, R.G. Crystal structure of Diclofenac bound to the cyclooxygenase active site of COX-2. 2003.
Abe, K.; Tani, K.; Fujiyoshi, Y. Conformational rearrangement of gastric H(+),K(+)-ATPase induced by an acid suppressant. Nat. Commun., 2011, 2, 155.
[] [PMID: 21224846]
Egbert, M.; Whitty, A.; Keserű, G.M.; Vajda, S. Why some targets benefit from beyond rule of five drugs. J. Med. Chem., 2019, 62(22), 10005-10025.
[] [PMID: 31188592]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2012, 64, 4-17.
[] [PMID: 11259830]
Behrouz, S.; Soltani Rad, M.N.; Taghavi Shahraki, B.; Fathalipour, M.; Behrouz, M.; Mirkhani, H. Design, synthesis, and in silico studies of novel eugenyloxy propanol azole derivatives having potent antinociceptive activity and evaluation of their β-adrenoceptor blocking property. Mol. Divers., 2019, 23(1), 147-164.
[] [PMID: 30094501]
Torres, E.; Moreno, E.; Ancizu, S.; Barea, C.; Galiano, S.; Aldana, I.; Monge, A.; Pérez-Silanes, S. New 1,4-di-N-oxide-quinoxaline-2-ylmethylene isonicotinic acid hydrazide derivatives as anti-Mycobacterium tuberculosis agents. Bioorg. Med. Chem. Lett., 2011, 21(12), 3699-3703.
[] [PMID: 21570839]

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