Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Crystallography
2.3. Hirshfeld Surface Analysis
2.4. Energy Framework Calculation
2.5. Pharmacology
2.6. Computational Studies
3. Materials and Methods
3.1. Chemistry
3.2. General Synthetic Procedure for 4-methoxy-1-(2-(substituted phenyl)-2-oxoethyl)pyridinium Bromides (3a–e)
3.3. Synthetic Procedure for the Synthesis of Ethyl 3-(4-bromobenzoyl)-2-ethyl-7-methoxyindolizine-1-carboxylate (5e)
3.4. Crystallography
3.5. In Vitro COX-2 Inhibition Assay
3.6. Computational Studies
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Sample Availability
References
- Lipscomb, J. Management of Nonsteroidal Anti-inflammatory Drug-Induced Hypersensitivity Reactions. US Pharm. 2019, 44, 22–26. [Google Scholar]
- Ricciotti, E.; Tang, S.-Y.; Barekat, K.; Veglia, F.; Maseda, D.; Bittinger, K.; Bushman, F.; FitzGerald, G.A. The impact of cyclooxygenase-2 selective and non-isoform selective NSAIDs on the gut microbiota. FASEB J. 2019, 33, 516. [Google Scholar]
- Moro, M.G.; Oliveira, M.D.d.S.; Oliveira, L.R.d.; Teixeira, S.A.; Muscará, M.N.; Spolidorio, L.C.; Holzhausen, M. Effects of Selective Versus Non-Selective COX-2 Inhibition on Experimental Periodontitis. Braz. Dent. J. 2019, 30, 133–138. [Google Scholar] [CrossRef]
- Takeuchi, K.; Amagase, K. Roles of cyclooxygenase, prostaglandin E2 and EP receptors in mucosal protection and ulcer healing in the gastrointestinal tract. Curr. Pharm. Des. 2018, 24, 2002–2011. [Google Scholar] [CrossRef]
- Pannunzio, A.; Coluccia, M. Cyclooxygenase-1 (COX-1) and COX-1 inhibitors in cancer: A review of oncology and medicinal chemistry literature. Pharmaceuticals 2018, 11, 101. [Google Scholar] [CrossRef] [Green Version]
- Omar, Y.M.; Abdu-Allah, H.H.; Abdel-Moty, S.G. Synthesis, biological evaluation and docking study of 1, 3, 4-thiadiazole-thiazolidinone hybrids as anti-inflammatory agents with dual inhibition of COX-2 and 15-LOX. Bioorg. Chem. 2018, 80, 461–471. [Google Scholar] [CrossRef]
- Deb, P.K.; Mailabaram, R.P.; Al-Jaidi, B.; Saadh, M. Molecular basis of binding interactions of NSAIDs and computer-aided drug design approaches in the pursuit of the development of cyclooxygenase-2 (COX-2) selective inhibitors. Nonsteroidal Anti Inflamm. Drugs 2017, 6, 101–121. [Google Scholar]
- Zarghi, A.; Zebardast, T.; Daraie, B.; Hedayati, M. Design and synthesis of new 1, 3-benzthiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors. Bioorg. Med. Chem. 2009, 17, 5369–5373. [Google Scholar] [CrossRef] [PubMed]
- Wallace, J.L. How do NSAIDs cause ulcer disease? Baillieres Best Pract. Res. Clin. Gastroenterol. 2000, 14, 147–159. [Google Scholar] [CrossRef] [Green Version]
- Gubin, J.; de Vogelaer, H.; Inion, H.; Houben, C.; Lucchetti, J.; Mahaux, J.; Rosseels, G.; Peiren, M.; Clinet, M. Novel heterocyclic analogs of the new potent class of calcium entry blockers: 1-[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines. J. Med. Chem. 1993, 36, 1425–1433. [Google Scholar] [CrossRef] [PubMed]
- Cingolani, G.M.; Claudi, F.; Massi, M.; Venturi, F. Indolizine derivatives with biological activity VI 1-(2-aminoethyl)-3-benzyl-7-methoxy-2-methylindolizine, benanserin structural analogue. Cingolani 1990, 25, 709–712. [Google Scholar] [CrossRef]
- Hagishita, S.; Yamada, M.; Shirahase, K.; Okada, T.; Murakami, Y.; Ito, Y.; Matsuura, T.; Wada, M.; Kato, T.; Ueno, M.; et al. Potent Inhibitors of Secretory Phospholipase A2: Synthesis and Inhibitory Activities of Indolizine and Indene Derivatives. J. Med. Chem. 1996, 39, 3636–3658. [Google Scholar] [CrossRef]
- Sandeep, C.; Venugopala, K.N.; Mohammed, A.K.; Mahesh, A.; Basavaraj, P.; Rashmi, S.K.; Rashmi, V.; Odhav, B. Review on chemistry of natural and synthetic indolizines with their chemical and pharmacological properties. J. Basic Clin. Pharm. 2016, 8, 49–61. [Google Scholar]
- Vaught, J.L.; Carson, J.R.; Carmosin, R.J.; Blum, P.S.; Persico, F.J.; Hageman, W.E.; Shank, R.P.; Raffa, R.B. Antinociceptive action of McN-5195 in rodents: A structurally novel (indolizine) analgesic with a nonopioid mechanism of action. J. Pharmacol. Exp. Ther. 1990, 255, 1–10. [Google Scholar]
- Bhat, M.A.; Al-Omar, M.A.; Alsaif, N.A.; Almehizia, A.A.; Naglah, A.M.; Razak, S.; Khan, A.A.; Ashraf, N.M. Novel sulindac derivatives: Synthesis, characterisation, evaluation of antioxidant, analgesic, anti-inflammatory, ulcerogenic and COX-2 inhibition activity. J. Enzyme Inhib. Med. Chem. 2020, 35, 921–934. [Google Scholar] [CrossRef]
- Venugopala, K.N.; Al-Attraqchi, O.H.A.; Tratrat, C.; Nayak, S.K.; Morsy, M.A.; Aldhubiab, B.E.; Attimarad, M.; Nair, A.B.; Sreeharsha, N.; Venugopala, R.; et al. Novel Series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates as promising anti-inflammatory agents: Molecular modeling studies. Biomolecules 2019, 9, 661. [Google Scholar] [CrossRef] [Green Version]
- Sandeep, C.; Venugopala, K.N.; Khedr, M.A.; Padmashali, B.; Kulkarni, R.S.; Rashmi, V.; Odhav, B. Design and synthesis of novel indolizine analogues as COX-2 inhibitors: Computational perspective and in vitro screening. Indian J. Pharm. Educ. Res. 2017, 51, 452–460. [Google Scholar] [CrossRef] [Green Version]
- Shrivastava, S.K.; Srivastava, P.; Bandresh, R.; Tripathi, P.N.; Tripathi, A. Design, synthesis, and biological evaluation of some novel indolizine derivatives as dual cyclooxygenase and lipoxygenase inhibitor for anti-inflammatory activity. Bioorg. Med. Chem. 2017, 25, 4424–4432. [Google Scholar] [CrossRef] [PubMed]
- Sandeep, C.; Padmashali, B.; Venugopala, K.N.; Kulkarni, R.S.; Venugopala, R.; Odhav, B. Synthesis and characterization of ethyl 7-acetyl-2-substituted 3-(substituted benzoyl)indolizine-1-carboxylates for in vitro anticancer activity. Asian J. Chem. 2016, 28, 1043–1048. [Google Scholar] [CrossRef]
- Ghinet, A.; Abuhaie, C.-M.; Gautret, P.; Rigo, B.; Dubois, J.; Farce, A.; Belei, D.; Bîcu, E. Studies on indolizines. Evaluation of their biological properties as microtubule-interacting agents and as melanoma targeting compounds. Eur. J. Med. Chem. 2015, 89, 115–127. [Google Scholar] [CrossRef] [PubMed]
- Mederski, W.; Beier, N.; Burgdorf, L.T.; Gericke, R.; Klein, M.; Tsaklakidis, C. Indolizine Derivatives and the Use Thereof as Antidiabetics. U.S. Patent US-8106067-B2, 31 January 2012. [Google Scholar]
- Jaisankar, P.; Pal, B.; Manna, K.N.; Pradhan, P.K.; Medda, S.; Basu, M.K.; Giri, V.S. Synthesis of antileishmanial (5R)-(-)-5-carbomethoxy-3-formyl-5,6-dihydroindolo-[2,3-a]-indolizine. Arkivoc 2003, 9, 150–157. [Google Scholar] [CrossRef] [Green Version]
- Hazra, A.; Mondal, S.; Maity, A.; Naskar, S.; Saha, P.; Paira, R.; Sahu, K.B.; Paira, P.; Ghosh, S.; Sinha, C.; et al. Amberlite-IRA-402 (OH) ion exchange resin mediated synthesis of indolizines, pyrrolo [1,2-a] quinolines and isoquinolines: Antibacterial and antifungal evaluation of the products. Eur. J. Med. Chem. 2011, 46, 2132–2140. [Google Scholar] [CrossRef] [PubMed]
- Olejnikova, P.; Birosova, L.; Svorc, L. Antimicrobial and antimutagenic properties of newly synthesized derivatives of indolizine. Sci. Pharm. 2009, 77, 216. [Google Scholar] [CrossRef]
- Nasir, A.I.; Gundersen, L.L.; Rise, F.; Antonsen, O.; Kristensen, T.; Langhelle, B.; Bast, A.; Custers, I.; Haenen, G.R.; Wikstrom, H. Inhibition of lipid peroxidation mediated by indolizines. Bioorg. Med. Chem. Lett. 1998, 8, 1829–1832. [Google Scholar] [CrossRef]
- Mishra, B.B.; Tiwari, V.K. Natural products in drug discovery: Clinical evaluations and investigations. Oppor. Chall. Scope Nat. Prod. Med. Chem. 2011, 661, 1–61. [Google Scholar]
- Chandrashekharappa, S.; Venugopala, K.N.; Nayak, S.K.; Gleiser, R.M.; García, D.A.; Kumalo, H.M.; Kulkarni, R.S.; Mahomoodally, F.M.; Venugopala, R.; Mohan, M.K.; et al. One-pot microwave assisted synthesis and structural elucidation of novel ethyl 3-substituted-7-methylindolizine-1-carboxylates with larvicidal activity against Anopheles arabiensis. J. Mol. Struct. 2018, 1156, 377–384. [Google Scholar] [CrossRef]
- Sandeep, C.; Venugopala, K.N.; Gleiser, R.M.; Chetram, A.; Padmashali, B.; Kulkarni, R.S.; Venugopala, R.; Odhav, B. Greener synthesis of indolizine analogues using water as a base and solvent: Study for larvicidal activity against Anopheles arabiensis. Chem. Biol. Drug Des. 2016, 88, 899–904. [Google Scholar] [CrossRef]
- Smith, S.C.; Clarke, E.D.; Ridley, S.M.; Bartlett, D.; Greenhow, D.T.; Glithro, H.; Klong, A.Y.; Mitchell, G.; Mullier, G.W. Herbicidal indolizine-5,8-diones: Photosystem I redox mediators. Pest Manag. Sci. 2005, 61, 16–24. [Google Scholar] [CrossRef] [PubMed]
- Venugopala, K.N.; Uppar, V.; Sandeep, C.; Abdallah, H.H.; Pillay, M.; Deb, P.K.; Morsy, M.A.; Aldhubiab, B.E.; Attimarad, M.; Nair, A.B.; et al. Cytotoxicity and antimycobacterial properties of pyrrolo[1,2-a]quinoline derivatives: Molecular target identification and molecular docking studies. Antibiotics 2020, 9, 233. [Google Scholar] [CrossRef]
- Sandeep, C.; Venugopala, K.N. Novel Substituted Indolizine Scaffolds for MDR Strains of Mycobacterium tuberculosis, Synthetic Methodology and Chemical Structures Thereof. Indian Patent Application Number IN 201941002546 A, 3 April 2020. [Google Scholar]
- Hasija, A.; Bhandary, S.; Venugopala, K.N.; Chandrashekharappa, S.; Chopra, D. Structural investigation of methyl 3-(4-fluoro-benzo-yl)-7-methyl-2-phenyl-indolizine-1-carboxyl-ate, an inhibitory drug towards Mycobacterium tuberculosis. Acta Cryst. E Cryst. Commun. 2020, 76, 567–571. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Venugopala, K.N.; Tratrat, C.; Chandrashekharappa, S.; Attimarad, M.; Sreeharsha, N.; Nair, A.B.; Pottathil, S.; Venugopala, R.; Al-Attraqchi, O.H.A.; Morsy, M.A.; et al. Anti-tubercular potency and computationally-assessed drug-likeness and toxicology of diversely substituted indolizines. Indian J. Pharm. Educ. Res. 2019, 53, 545–552. [Google Scholar] [CrossRef] [Green Version]
- Venugopala, K.N.; Tratrat, C.; Pillay, M.; Mahomoodally, F.M.; Bhandary, S.; Chopra, D.; Morsy, M.A.; Haroun, M.; Aldhubiab, B.E.; Attimarad, M.; et al. Anti-tubercular activity of substituted 7-methyl and 7-formylindolizines and in silico study for prospective molecular target identification. Antibiotics 2019, 8, 247. [Google Scholar] [CrossRef] [Green Version]
- Venugopala, K.N.; Chandrashekharappa, S.; Pillay, M.; Abdallah, H.H.; Mahomoodally, F.M.; Bhandary, S.; Chopra, D.; Attimarad, M.; Aldhubiab, B.E.; Nair, A.B.; et al. Computational, crystallographic studies, cytotoxicity and anti-tubercular activity of substituted 7-methoxy-indolizine analogues. PLoS ONE 2019, 14, e0217270. [Google Scholar] [CrossRef] [Green Version]
- Venugopala, K.N.; Khedr, M.A.; Pillay, M.; Nayak, S.K.; Chandrashekharappa, S.; Aldhubiab, B.E.; Harsha, S.; Attimard, M.; Odhav, B. Benzothiazole analogs as potential anti-TB agents: Computational input and molecular dynamics. J. Biomol. Struct. Dyn. 2019, 37, 1830–1842. [Google Scholar] [CrossRef]
- Khedr, M.A.; Pillay, M.; Chandrashekharappa, S.; Chopra, D.; Aldhubiab, B.E.; Attimarad, M.; Alwassil, O.I.; Mlisana, K.; Odhav, B.; Venugopala, K.N. Molecular modeling studies and anti-TB activity of trisubstituted indolizine analogues; molecular docking and dynamic inputs. J. Biomol. Struct. Dyn. 2018, 36, 2163–2178. [Google Scholar] [CrossRef] [PubMed]
- Xue, Y.; Tang, J.; Ma, X.; Li, Q.; Xie, B.; Hao, Y.; Jin, H.; Wang, K.; Zhang, G.; Zhang, L.; et al. Synthesis and biological activities of indolizine derivatives as alpha-7 nAChR agonists. Eur. J. Med. Chem. 2016, 115, 94–108. [Google Scholar] [CrossRef]
- Alwassil, O.I.; Chandrashekharappa, S.; Nayak, S.K.; Venugopala, K.N. Design, synthesis, and structural elucidation of novel NmeNANAS inhibitors for the treatment of meningococcal infection. PLoS ONE 2019, 14, e0223413. [Google Scholar] [CrossRef] [PubMed]
- Ingle, K.S.; Mohurle, S.A.; Bairagi, K.M.; Shaikh, T.R.; Venugopala, K.N.; Chandrashekharappa, S.; Gonnade, R.G.; Nayak, S.K. Synthesis, crystal structure and Hirshfeld surface analysis of the hydrated form of N′, N-(1,4-phenylenebis(methanylylidene) di(iso-nicotinic hydrazide). Chem. Data Collect. 2020, 28, 100401. [Google Scholar] [CrossRef]
- Chopra, D.; Venugopala, K.N.; Jayashree, B.S.; Guru Row, T.N. 3-(2-Anilino-1,3-thiazol-4-yl)-2H-chromen-2-one. Acta Crystallogr. Sect. E 2006, 62, o2663–o2665. [Google Scholar] [CrossRef]
- Maste, M.M.; Mahapatra, S.; Ramachandran, K.K.; Venugopala, K.N.; Bhat, A.R. N-(2-Amino-3,5-dibromobenzyl)-N-methylcyclohexan-1-aminium p-toluenesulfonate. Acta Crystallogr. Sect. E Struct. Rep. Online 2011, 67, o2032. [Google Scholar] [CrossRef] [PubMed]
- Chopra, D.; Venugopala, K.N.; Rao, G.K. (5S)-1,4-Bis{[(1E)-4-methylbenzylidene]amino}-5-(thien-2-yl)pyrrolidin-2-one. Acta Crystallogr. Sect. E 2007, 63, o2840. [Google Scholar] [CrossRef]
- Bhandary, S.; Girish, Y.R.; Venugopala, K.N.; Chopra, D. Crystal structure analysis of [5-(4-methoxyphenyl)-2-methyl-2H-1, 2, 3-triazol-4-yl](thiophen-2-yl) methanone. Acta Crystallogr. Sect. E Crystallogr. Commun. 2018, 74, 1178–1181. [Google Scholar] [CrossRef] [Green Version]
- Bairagi, K.M.; Kumar, V.B.S.; Bhandary, S.; Venugopala, K.N.; Nayak, S.K. Structural analysis of 2-iodobenzamide and 2-iodo-N-phenylbenzamide. Acta Crystallogr. Sect. E 2018, 74, 1130–1133. [Google Scholar] [CrossRef]
- Venugopala, K.N. Design, microwave assisted synthesis and characterization of substituted 1, 2, 4-oxadiazole analogues as promising pharmacological agents. Asian J. Chem. 2017, 29, 1767–1770. [Google Scholar] [CrossRef]
- Venugopala, K.N. Synthesis and structural elucidation of novel 2,4-disubstituted 1,3-oxazole analogues for pharmacological properties. Asian J. Chem. 2018, 30, 684–688. [Google Scholar] [CrossRef]
- Venugopala, K.N.; Ramachandra, P.; Tratrat, C.; Gleiser, R.M.; Bhandary, S.; Chopra, D.; Morsy, M.A.; Aldhubiab, B.E.; Attimarad, M.; Nair, A.B. Larvicidal activities of 2-aryl-2, 3-dihydroquinazolin-4-ones against malaria vector Anopheles arabiensis, In Silico ADMET prediction and molecular target investigation. Molecules 2020, 25, 1316. [Google Scholar] [CrossRef] [Green Version]
- Panini, P.; Venugopala, K.N.; Odhav, B.; Chopra, D. Polymorphism in two biologically active dihydropyrimidinium hydrochloride derivatives: Quantitative inputs towards the energetics associated with crystal packing. Acta Crystallogr. Sect. B Struct. Sci. Cryst. Eng. Mater. 2014, 70, 681–696. [Google Scholar] [CrossRef]
- Venugopala, K.N.; Rao, G.D.; Bhandary, S.; Pillay, M.; Chopra, D.; Aldhubiab, B.E.; Attimarad, M.; Alwassil, O.I.; Harsha, S.; Mlisana, K. Design, synthesis, and characterization of (1-(4-aryl)-1H-1, 2, 3-triazol-4-yl) methyl, substituted phenyl-6-methyl-2-oxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylates against Mycobacterium tuberculosis. Drug Des. Devel. Ther. 2016, 10, 2681. [Google Scholar] [CrossRef] [Green Version]
- Munshi, P.; Venugopala, K.N.; Jayashree, B.S.; Guru Row, T.N. Concomitant Polymorphism in 3-Acetylcoumarin: Role of Weak C–H···O and C–H···π Interactions. Cryst. Growth Des. 2004, 4, 1105–1107. [Google Scholar] [CrossRef]
- Nayak, S.K.; Venugopala, K.N.; Chopra, D.; Row, T.N.G. Insights into conformational and packing features in a series of aryl substituted ethyl-6-methyl-4-phenyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates. CrystEngComm 2011, 13, 591–605. [Google Scholar] [CrossRef]
- Deb, P.K.; Kaur, R.; Chandrasekaran, B.; Bala, M.; Gill, D.; Kaki, V.R.; Akkinepalli, R.R.; Mailavaram, R. Synthesis, anti-inflammatory evaluation, and docking studies of some new thiazole derivatives. Med. Chem. Res. 2014, 23, 2780–2792. [Google Scholar] [CrossRef]
- Dhingra, M.S.; Deb, P.K.; Chadha, R.; Singh, T.; Karan, M. Synthesis, evaluation, and molecular docking studies of cycloalkyl/aryl-3, 4, 5-trimethylgallates as potent non-ulcerogenic and gastroprotective anti-inflammatory agents. Med. Chem. Res. 2014, 23, 87–106. [Google Scholar] [CrossRef]
- Kishore, D.P.; Maillabaram, R.; Rao, A.R.; Rao, P.M. Antiinflammatory evaluation and docking studies of some new thienopyrimidines. Asian J. Chem. 2013, 25, 10583. [Google Scholar] [CrossRef]
- Bali, A.; Ohri, R.; Deb, P.K. Synthesis, evaluation and docking studies on 3-alkoxy-4-methanesulfonamido acetophenone derivatives as non ulcerogenic anti-inflammatory agents. Eur. J. Med. Chem. 2012, 49, 397–405. [Google Scholar] [CrossRef] [PubMed]
- Balakumar, C.; Lamba, P.; Kishore, D.P.; Narayana, B.L.; Rao, K.V.; Rajwinder, K.; Rao, A.R.; Shireesha, B.; Narsaiah, B. Synthesis, anti-inflammatory evaluation and docking studies of some new fluorinated fused quinazolines. Eur. J. Med. Chem. 2010, 45, 4904–4913. [Google Scholar] [CrossRef]
- Venugopala, K.N.; Jayashree, B.S. Synthesis and characterization of Schiff bases of aminothiazolylbromocoumarin for their analgesic and anti-inflammatory activity. Asian J. Chem. 2004, 16, 407–411. [Google Scholar]
- Venugopala, K.N.; Jayashree, B.S.; Attimarad, M. Synthesis and evaluation of some substituted 2-arylamino coumarinyl thiazoles as potential NSAIDs. Asian J. Chem. 2004, 16, 872–876. [Google Scholar]
- Venugopala, K.N.; Chandrashekharappa, S.; Bhandary, S.; Chopra, D.; Khedr, M.A.; Aldhubiab, B.E.; Attimarad, M.; Odhav, B. Efficient synthesis and characterization of novel substituted 3-benzoylindolizine analogues via the cyclization of aromatic cycloimmoniumylides with electron-deficient alkenes. Curr. Org. Synth. 2018, 15, 388–395. [Google Scholar] [CrossRef]
- Spackman, M.A.; McKinnon, J.J.; Jayatilaka, D. Electrostatic potentials mapped on Hirshfeld surfaces provide direct insight into intermolecular interactions in crystals. CrystEngComm 2008, 10, 377–388. [Google Scholar] [CrossRef]
- Turner, M.J.; Grabowsky, S.; Jayatilaka, D.; Spackman, M.A. Accurate and Efficient Model Energies for Exploring Intermolecular Interactions in Molecular Crystals. J. Phys. Chem. Lett. 2014, 5, 4249–4255. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Deb, P.K.; Al-Attraqchi, O.; Al-Qattan, M.N.; Raghu Prasad, M.; Tekade, R.K. Chapter 19—Applications of Computers in Pharmaceutical Product Formulation. In Dosage Form Design Parameters; Tekade, R.K., Ed.; Academic Press: Massachusetts, MA, USA, 2018; pp. 665–703. [Google Scholar] [CrossRef]
- Kalgutkar, A.S.; Crews, B.C.; Rowlinson, S.W.; Marnett, A.B.; Kozak, K.R.; Remmel, R.P.; Marnett, L.J. Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. Proc. Natl. Acad. Sci. USA 2000, 97, 925–930. [Google Scholar] [CrossRef] [Green Version]
- APEX 2, SAINT; SADABS Bruker AXS Inc.: Madison, WI, USA, 2012. Available online: https://journals.iucr.org/e/services/stdswrefs.html (accessed on 9 June 2021).
- Sheldrick, G. Crystal structure refinement with SHELXL. Acta Crystallogr. Sect. C 2015, 71, 3–8. [Google Scholar] [CrossRef] [PubMed]
- Farrugia, L.J. WinGX and ORTEP for Windows: An update. J. Appl. Crystallogr. 2012, 45, 849–854. [Google Scholar] [CrossRef]
- Chandrashekharappa, S.; Venugopala, K.N.; Tratrat, C.; Mahomoodally, F.M.; Aldhubiab, B.E.; Haroun, M.; Venugopala, R.; Mohan, M.K.; Kulkarni, R.S.; Attimarad, M.V.; et al. Efficient synthesis and characterization of novel indolizines: Exploration of in vitro COX-2 inhibitory activity and molecular modelling studies. New J. Chem. 2018, 42, 4893–4901. [Google Scholar] [CrossRef]
Compound | Mol Formulae (Mol Mass) | R | R1 | Yield (%) a,b | m.p. (°C) | cLogP c |
---|---|---|---|---|---|---|
5a | C23H20N2O6 (420) | 4-CN | COOC2H5 | 72 | 171 | 3.4454 |
5b | C22H20FNO6 (413) | 4-F | COOC2H5 | 77 | 147 | 4.0199 |
5c | C22H20BrNO6 (473) | 4-Br | COOC2H5 | 73 | 134 | 4.7399 |
5d | C23H23NO7 (425) | 3-OCH3 | COOC2H5 | 75 | 142 | 4.0294 |
5e | C21H20BrNO4 (430) | 4-Br | C2H5 | 69 | 108 | 6.2773 |
DATA | 5c |
---|---|
Formula | C22H20BrNO6 |
Formula weight | 474.30 |
CCDC | 2,045,116 |
Temperature (K) | 173(2) |
Wavelength (Å) | 0.71073 |
Crystal system | Monoclinic |
Space group | P 21/n |
a (Å) | 12.0479(6) |
b (Å) | 17.8324(10) |
c (Å) | 19.6052(11) |
α (˚) | 90.000 |
β (˚) | 100.372(1) |
γ (˚) | 90.000 |
V (Å3) | 4143.8(4) |
Z’, Z | 2, 8 |
Density (g·cm−3) | 1.52 |
μ (mm−1) | 2.023 |
F (000) | 1936.0 |
θ (min, max) | 1.6, 28.3 |
hmin, max, kmin, max, lmin, max. | −16, 15; −23, 23; −26, 26 |
No. of refl. | 10,282 |
No of unique ref./Obs. ref. | 10,282/6833 |
No. parameters | 576 |
Rall, Robs | 0.079, 0.041 |
wRall, wRobs | 0.100, 0.088 |
Δρmin, max(eÅ−3) | −0.473, 0.393 |
G.O.O.F. | 1.024 |
D–X···A | D–X (Å) | X···A (Å) | D···A (Å) | <D–X···A (o) |
---|---|---|---|---|
C21B–H21B···O1B i | 0.95 | 2.55 | 3.109(3) | 118 |
C1A–H1A···O6A i | 0.95 | 2.27 | 2.851(3) | 119 |
C1A–H1A···O6A i | 0.95 | 2.26 | 2.855(3) | 120 |
C2A–H2A···O6B ii | 0.95 | 2.52 | 3.466(3) | 174 |
C4B–H4B1···O4A iii | 0.98 | 2.50 | 3.442(3) | 162 |
C13B–H13C···π iv | 0.98(24) | 2.92 | 3.735(3) | 140 |
C13B–H13C···π* v | 0.98(24) | 2.86 | 3.785(3) | 156 |
Color | N | Symop | R | E_ele | E_pol | E_dis | E_rep | E_tot |
---|---|---|---|---|---|---|---|---|
1 | - | 4.55 | −22.8 | −5.1 | −98.5 | 37.6 | −84.7 | |
1 | - | 14.58 | −0.5 | 0 | −0.4 | 0 | −0.8 | |
1 | - | 11.1 | 4.2 | −5.5 | −31.3 | 16.2 | −14.4 | |
1 | - | 14.41 | 0.2 | 0 | −0.3 | 0 | −0.1 | |
1 | - | 13.98 | 0 | 0 | −1.3 | 0 | −1.3 | |
1 | - | 17.79 | 0.2 | 0 | −0.2 | 0 | 0 | |
1 | - | 11.16 | 1 | −4.4 | −22.6 | 8.9 | −15 | |
1 | - | 16.73 | 0.1 | 0 | −0.1 | 0 | 0 | |
1 | - | 18.83 | 0.3 | 0 | −0.2 | 0 | 0.2 | |
1 | - | 12.4 | 0.8 | 0 | −0.8 | 0 | 0.1 | |
1 | −x + 1/2, y + 1/2, −z + 1/2 | 11.15 | −16.2 | −1.2 | −22.8 | 49.6 | 2.5 | |
1 | x + 1/2, −y + 1/2, z + 1/2 | 12.57 | −0.6 | 0 | −0.6 | 0 | −1.2 | |
1 | −x, −y, −z | 18.25 | 0.3 | 0 | −0.1 | 0 | 0.2 | |
2 | −x + 1/2, y + 1/2, −z + 1/2 | 12.35 | −0.3 | −0.1 | −2.1 | 0 | −2.3 | |
1 | x + 1/2, −y + 1/2, z + 1/2 | 10.75 | −2.2 | −0.3 | −3.1 | 0 | −5.2 | |
1 | x, y, z | 12.05 | −11.3 | −2.6 | −26.1 | 14.3 | −25.2 | |
1 | −x, −y, −z | 23.43 | 0.1 | 0 | 0 | 0 | 0.1 | |
1 | x, y, z | 17.83 | −0.1 | 0 | −0.2 | 0 | −0.3 | |
1 | −x, −y, −z | 16.07 | −0.3 | 0 | −0.1 | 0 | −0.4 | |
1 | x + 1/2, −y + 1/2, z + 1/2 | 22.54 | 0 | 0 | 0 | 0 | 0 |
Compound | Compound Structure | IC50 * (µM) |
---|---|---|
5a | | 5.84 ± 0.03 a |
5b | | 6.73 ± 0.03 a,b |
5c | | 6.99 ± 0.03 b |
5d | | 8.49 ± 0.03, b,c |
5e | | 7.38 ± 0.03 c,d |
Indomethacin | | 6.84 ± 0.03 b,d |
Celecoxib | | 0.05 ± 0.03 a |
Entry | R1 | R2 | CDocker Interaction Energy | Residues Interaction | |||
---|---|---|---|---|---|---|---|
H-Bonding | pi–pi | pi-alkyl pi-halogen | Alkyl-alkyl Alkyl-halogen | ||||
5a | CO2Et | 4-CN | 39.51 | Arg120 | Trp387 Gly526 | Val349, Leu352, Ala527, Val523, Tyr355 | Val116, Val349, Leu531, Leu534 |
5b | CO2Et | 4-F | 38.22 | Arg120 | Val349, Leu352, Ala527, Val523, Tyr355 | Val116, Leu359, Leu531 | |
5c | CO2Et | 4-Br | 46.69 | - | Tyr385 | Val349, Leu352, Ala527, Val523, Tyr385, Trp387, Phe381 | Val116, Val349, Leu359, Leu 531, Leu534, Leu384, Met522 |
5d | CO2Et | 3-OCH3 | 53.29 | Arg120 | Tyr385 Trp387 Gly526 | Val349, Leu352, Ala527, Val523, Tyr355 | Val116, Leu359, Leu531 |
5e | Et | 4-Br | 48.54 | - | Trp387 | Val349, Leu352, Ala527, Val523, Tyr385, Trp387, Phe381 | Val116, Val349, Leu359, Leu 531, Leu534, Leu384, Met522 |
Indomethacin | 55.36 | Arg120 (ionic) | Val349, Leu352, Ala527, Val523, Trp387 | Val349, Ala527, Leu531, Leu384, Met522 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Venugopala, K.N.; Chandrashekharappa, S.; Tratrat, C.; Deb, P.K.; Nagdeve, R.D.; Nayak, S.K.; Morsy, M.A.; Borah, P.; Mahomoodally, F.M.; Mailavaram, R.P.; et al. Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives. Molecules 2021, 26, 3550. https://doi.org/10.3390/molecules26123550
Venugopala KN, Chandrashekharappa S, Tratrat C, Deb PK, Nagdeve RD, Nayak SK, Morsy MA, Borah P, Mahomoodally FM, Mailavaram RP, et al. Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives. Molecules. 2021; 26(12):3550. https://doi.org/10.3390/molecules26123550
Chicago/Turabian StyleVenugopala, Katharigatta N., Sandeep Chandrashekharappa, Christophe Tratrat, Pran Kishore Deb, Rahul D. Nagdeve, Susanta K. Nayak, Mohamed A. Morsy, Pobitra Borah, Fawzi M. Mahomoodally, Raghu Prasad Mailavaram, and et al. 2021. "Crystallography, Molecular Modeling, and COX-2 Inhibition Studies on Indolizine Derivatives" Molecules 26, no. 12: 3550. https://doi.org/10.3390/molecules26123550