Abstract
Background: For the development of suitable lead molecules to different diseases is a highly challenging task for medicinal chemists. Nowadays, hybrid pharmacophore concept has developed as a useful structural modification tool in the drug design of new drug candidates for different diseases. Hybrid pharmacophore approach consists of combination of two or more pharmacophoric moieties from different biologically active compounds with complementary functions or different mechanisms of action into a single molecule. This often results in synergistic activity or enhanced drug efficacy.
Objective: To develop the suitable leads for different diseases there will be a lot of scope to study the substitution of heterocyclic moieties on the different positions of isatin ring. The broad and potent activities of the isatin and their derivatives have been established them as pharmacologically significant scaffolds. In this review, an attempt has been made with specifically emphasizing the hybridization of Isatin with different derivatives of heterocyclic compounds on the different positions of the isatin ring (aryl ring, isatin nitrogen and C2/C3 carbonyl moieties).
Conclusion: This review highlighted the recent advances of dual acting isatin-heterocyclic hybrids presenting various pharmacological activities viz., anticancer, antitubercular, anti-inflammatory and antimicrobial.
Keywords: Isatin, heterocyclic, hybrid pharmacophore approach, pharmacological agents, anticancer, antitubercular, anti-inflammatory, antimicrobial.
Graphical Abstract
[1]
Dickson, M.; Gagnon, J.P. Key factors in the rising cost of new drug discovery and development. Nat. Rev. Drug Discov., 2004, 3, 417-429.
[2]
DiMasi, J.; Hansen, R.; Grabowski, H. The price of innovation: New estimates of drug development costs. J. Health Econ., 2003, 22, 151-185.
[3]
Adams, C.P.; Brantner, V.V. Estimating the cost of new drug development: Is it really 802 million dollars? Drug Dev., 2006, 25, 23-24.
[4]
Viegas-Junior, C.; Danuello, A.; Bolzani, V.D.S.; Barreiro, E.J.; , C.A.M. Fraga Molecular hybridization: A useful tool in the design of new drug prototypes. Curr. Med. Chem., 2007, 14, 1829-1852.
[5]
Fortin, S.; Berube, G. Advances in the development of hybrid anticancer drugs. Expert Opin. Drug Discov., 2013, 8, 1029-1047.
[6]
Meunier, B. Hybrid molecules with a dual mode of action: Dream or reality? Acc. Chem. Res., 2008, 41, 69-77.
[7]
Hulsman, N.; Medema, J.P.; Bos, C.; Jongejan, A.; Leurs, R.; Smit, M.J.; de Esch, I.J.; Richel, D.; Wijtmans, M. Chemical insights in the concept of hybrid drugs: the antitumor effect of nitric oxide-donating aspirin involves a quinone methide but not nitric oxide nor aspirin. J. Med. Chem., 2007, 50, 2424-2431.
[8]
Bode, A.M.; Dong, Z.G. Cancer prevention research - then and now. Nat. Rev. Cancer, 2009, 9, 508-516.
[11]
Guo, Y.; Chen, F. TLC-UV-spectrophotometric and TLC-scanning determination of isatin in leaf of Isatis. Zhongcaoyao, 1986, 17, 8-11.
[12]
Bergman, J.; Lindstorm, J.O.; Tilstam, U. The structure and properties of some indolic constituents in the Couroupita guianensis aubl. Tetrahedron, 1985, 4, 12879-12881.
[13]
Wei, L.; Wang, Q.; Liu, X. Application of thin-layer chromatographyin quality control of Chinese medicinal preparations.II. Quliative analysis of Chinese Chinese medicinal preparations of Chansu. Yaowu Fenxi Zazhi, 1982, 2, 288-291.
[14]
Da Silva, J.F.M.; Garden, S.J.; Pinto, A.C. The Chemistry of Isatins: a Review from 1975 to 1999. J. Braz. Chem. Soc., 2001, 12(3), 273-324.
[15]
Medvedev, A.E.; Clow, A.; Sandler, M.; Glover, V. Isatin: A link between natriuretic peptides and monoamines? Biochem. Pharmacol., 1996, 52(3), 385-391.
[16]
Da Silva, J.F.M.; Garden, S.J.; Pinto, A.C. The chemistry of isatins: a review from 1975 to 1999. J. Braz. Chem. Soc., 2001, 12, 273-324.
[17]
Batanero, B.; Barba, F. Electrosynthesis of tryptanthrin. Tetrahedron Lett., 2006, 47, 8201-8203.
[18]
Aboul-Fadl, T.; Bin-Jubair, F.A.S.; Aboul-Wafa, O. Schiff bases of indoline-2,3-dione (isatin) derivatives and nalidixic acid carbohydrazide, synthesis, antitubercular activity and pharmacophoric model building. Eur. J. Med. Chem., 2010, 45, 4578-4586.
[19]
Domenech, A.; Domenech-Carbo, M.T.; Sanchez del Rio, M. Vazquez de Agredos, Pascual, M.L.; Lima, E. Maya Blue as a nanostructured polyfunctional hybrid organic-inorganic material: The need to change paradigms. New J. Chem., 2009, 33, 2371-2379.
[21]
Popp, F.D.; Katritzky, A.R.; Boulton, A.J. The Chemistry of Isatin.inAdvances in Heterocyclic Chemistry; Academic Press, 1975, pp. 1-58.
[22]
Mesropyan, E.G.; Avetisyan, A.A. New isatin derivatives. Russ. J. Org. Chem., 2009, 45, 1583-1593.
[23]
Ivashchenko, A.V.; Dziomko, V.M. Reactions of isatin and its derivatives with aromatic and heterocyclic ortho-diamines. Usp. Khim., 1977, 46, 228-238.
[24]
Shvekhgeimer, M.G.A. Synthesis of heterocyclic compounds by
the cyclization of isatin and its derivatives (review). Chem. Heterocycl.
Compd. (Engl. Transl.) 1996, 32, 249.
[25]
Joshi, K.C.; Joshi, R. Isatin: A versatile molecule for the synthesis of novel spiro heterocycles. J. Indian Chem. Soc., 1999, 76, 643-649.
[26]
Medvedev, A.; Igosheva, N.; Crumeyrolle-Arias, M.; Glover, V. Isatin: role in stress and anxiety.Stress, 2005. 8, 175 -183.59
[27]
Medvedev, A.; Buneeva, O.; Glover, V. Biological targets for isatin and its analogues: implications for therapy. Biologics Targets Therapy, 2007, 1, 151-162.
[28]
Chen, G.; Hao, X. Recent studies on the bioactivities of isatin. Tianran Chanwu Yanjiu Yu Kaifa., 2010, 22, 356-360.
[29]
Pandeya, S.N.; Smitha, S.; Jyoti, M.; Sridhar, S.K. Biological activities of isatin and its derivatives. Acta Pharm., 2005, 55, 27-46.
[30]
Abele, E.; Abele, R.; Dzenitis, O.; Lukevics, E. Indole and Isatin Oximes: Synthesis, reactions, and biological activity. Chem. Heterocycl. Compd., 2003, 39, 3-35.
[31]
Karpenko, A.; Shibinskaya, M.; Zholobak, N.; Olevinskaya, Z.; Lyakhov, S.; Litvinova, L.; Spivak, M.; Andronati, S. Synthesis, DNA-binding, and interferon-inducing properties of isatin and benzoisatin hydrazones. Pharm. Chem. J., 2006, 40, 595-602.
[32]
Vine, K.L.; Matesic, L.; Locke, J.M.; Ranson, M.; Skropeta, D. Cytotoxic and anticancer activities of isatin and its derivatives: A comprehensive review from 2000-2008. Anti-Cancer Agent. Med. Chem., 2009, 9, 397-414.
[33]
Pal, M.; Sharma, N.K. Priyanka; Jha, K.K. Synthetic and biological multiplicity of isatin. J. Adv. Sci. Res., 2011, 2, 35-44.
[34]
Bhrigu, B.; Pathak, D.; Siddiqui, N.; Alam, M.S.; Ahsan, W. Search for biological active Isatins: A short review. Int. J. Pharm. Sci. Drug Res., 2010, 2, 229-235.
[35]
Tarek, A.F.; Bin-Jubair, F.A.S. Anti-tubercular activity of isatin derivatives. Int. J. Res. Pharm. Sci., 2010, 1, 113-126.
[36]
Harris, P.A. Oxindole inhibitors of cyclin-dependent kinases as anti-tumor agents, taylor and francis group; Boca Raton, FL, USA, 2007.
[37]
Cerchiaro, G.; Ferreira, A.; Md, C. Oxindoles and copper complexes with oxindolederivatives as potential pharmacological agents. J. Braz. Chem. Soc., 2006, 17, 1473-1485.
[38]
Sing, G.S.; Desta, Z.Y. Isatins as privileged molecules in design and synthesis of spiro- fused cyclic frameworks. Chem. Rev., 2012, 112, 6104-6155.
[39]
Pakravan, P.; Kashnian, S.; Khodae, M.M.; Harding, F.J. Biochemical and pharmacological characterization of isatin and its derivatives: From structure to activity. Pharmacol. Rep., 2013, 65, 313-335.
[40]
Karalı, N.; Gürsoy, A.; Kandemirli, F. Synthesis and structure- antituberculosis activity relationship of 1H-indole-2,3-dione derivatives. Bioorg. Med. Chem., 2007, 15, 5888-5904.
[42]
Kumar, A.; Kumar, R. A Review on Synthesis of Schiff’s bases of 2-amino-4-phenylthiazole. Int. Res. J. Pharm., 2011, 2(6), 11-12.
[43]
Patel, N.B.; Shaikh, F.M. New 4-Thiazolidinones of Nicotinic Acid with 2-Amino-6-methylbenzothiazole and their Biological Activity. Sci. Pharm., 2010, 78(4), 753-765.
[44]
Bala, S.; Kamboj, S.; Kumar, A. Heterocyclic 1, 3, 4-oxadiazole compounds with diverse biological activities: A comprehensive review. J. Pharm. Res., 2010, 3(12), 2993-2997.
[45]
Motzer, R.J.; Michaelson, M.D.; Redman, B.G.; Hudes, G.R.; Wilding, G.; Figlin, R.A.; Ginsberg, M.S.; Kim, S.T.; Baum, C.M.; De Primo, S.E.; Li, J.Z.; Bello, C.L.; Theuer, C.P.; George, D.J.; Rini, B.I. Activity of SU11248, a multi-targeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J. Clin. Oncol., 2006, 24, 16-24.
[46]
Prenen, H.; Cools, J.; Mentens, N.; Folens, C.; Sciot, R.; Schoffski, P.; Van Oosterom, A.; Marynen, P.; Debiec-Rychter, M. Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin. Cancer Res., 2006, 12, 2622-2627.
[47]
Reddy, L.; Odhav, B.; Bhoola, K.D. Natural products for cancer prevention: A global perspective. Pharmacol. Ther., 2003, 99, 1-13.
[48]
Ramshid, P.K.; Jagadeeshan, S.; Krishnan, A.; Mathew, M.; Nair, S.A.; Pillai, M.R. Synthesis and in vitro evaluation of some isatin thiazolidinone hybrid analogues as anti-proliferative agents. Med. Chem., 2010, 6, 306-312.
[49]
Kaminskyy, D.; Khyluk, D.; Vasylenko, O.; Zaprutko, L.; Lesky, R. A Facile Synthesis and anticancer activity evaluation of Spiro [Thiazolidinone-Isatin] conjugates. Sci. Pharm., 2011, 79, 763-777.
[50]
Havrylyuk, D.; Zimenkovsky, B.; Vasylenko, O.; Gzella, A.; Lesyk, R. Synthesis of new 4-Thiazolidinone-, pyrazoline-, and isatin based conjugates with promising antitumor activity. J. Med. Chem., 2012, 55, 8630-8641.
[51]
Sharma, M.; Sharma, S.; Buddhiraja, A.; Saxena, A.K.; Nepali, K.; Bedi, P.M.S. Synthesis and cytotoxicity studies of 3, 5-diaryl N-acetyl pyrazoline-isatin hybrids. Med. Chem. Res., 2014, 23, 4337-4344.
[52]
Solomon, V.R.; Hu, C.; Lee, H. Hybrid pharmacophore design and synthesis of isatin-benzothiazole analogs for their anti-breast cancer activity. Bioorg. Med. Chem., 2009, 17(21), 7585-7592.
[53]
Hays, S.J.; Rice, M.J.; Ortwine, D.F.; Johnson, G.; Schwarz, R.D.; Boyd, D.K.; Copeland, L.F.; Vartanian, M.G.; Boxer, P.A. Substituted 2-benzothiazolamines as sodium flux inhibitors: quantitative structure-activity relationships and anticonvulsant activity. J. Pharm. Sci., 1994, 83, 1425-1432.
[54]
Kumar, K.; Sagar, S.; Esau, L.; Kaur, M.; Kumar, V. Synthesis of novel 1H-1, 2, 3-triazole tethered C-5 substituted uracil-isatin conjugates and their cytotoxic evaluation. Eur. J. Med. Chem., 2012, 58, 153-159.
[55]
aGarden, S.J.; Torres, J.C.; da Silva, J.F.M.; Pinto, A.C. A convenient methodology for the N-alkylation of isatin compounds. Synth. Commun., 1998, 28, 1679-1689.
bBouhfid, R.; Joly, N.; Massoui, M.; Cecchelli, R.; Lequart, V.; Martin, P.; Essassi, E.M. An efficient synthesis of new spiro [indolo-3(1H), 2’ (3’H)- oxadiazolyl] and 1-(Triazol-4-ylmethyl) isatin Derivatives Heterocycles, 2005, 65, 2949-2955..
bBouhfid, R.; Joly, N.; Massoui, M.; Cecchelli, R.; Lequart, V.; Martin, P.; Essassi, E.M. An efficient synthesis of new spiro [indolo-3(1H), 2’ (3’H)- oxadiazolyl] and 1-(Triazol-4-ylmethyl) isatin Derivatives Heterocycles, 2005, 65, 2949-2955..
[56]
Raghu Raj. Pardeep, S. Synthesis of 1H-1, 2, 3-triazole linked b-lactameisatin bi-functional hybrids and preliminary analysis of in vitro activity against the protozoal parasite Trichomonas vaginalis. Eur. J. Med. Chem., 2013, 63, 897-906.
[57]
Singh, P.; Sachdeva, S.; Raj, R.; Kumar, V.; Mahajan, M.P.; Nasser, S.; Vivas, L.; Gut, J.; Rosenthal, P.J.; Feng, T.S.; Chibale, K. Antiplasmodial and cytotoxicity evaluation of 3-functionalized 2-azetidinone derivatives. Bioorg. Med. Chem. Lett., 2011, 21, 4561-4563.
[58]
Singh, P.; Sharma, P.; Anand, A.; Bedi, P.M.; Kaur, T.; Saxena, A.K.; Kumar, V. Azide-alkyne cycloaddition en route to novel 1H-1, 2, 3-triazole tethered isatin conjugates with in vitro cytotoxic evaluation. Eur. J. Med. Chem., 2012, 55, 455-461.
[59]
Solomon, V.R.; Hu, C.; Lee, H. Design and synthesis of anti-breast cancer agents from 4-piperazinylquinoline: a hybrid pharmacophore approach. Bioorg. Med. Chem., 2010, 18, 1563-1572.
[60]
Taher, A.T.; Khalil, N.A.; Ahmed, E.M. Synthesis of novel isatin-thiazoline and isatinbenzimidazole conjugates as anti-breast cancer agents. Arch. Pharm. Res., 2011, 34, 1615-1621.
[61]
Ramla, M.M.; Omar, M.A.; El-Khamry, A.M.; El-Diwani, H.I. Synthesis and antitumor activity of 1-substituted-2-methyl-5-nitrobenzimidazoles. Bioorg. Med. Chem., 2006, 14, 7324-7332.
[62]
Rostom, S.A. Synthesis and in vitro antitumor evaluation of some indeno [1,2-c]pyrazol(in)es substituted with sulfonamide, sulfonylurea(-thiourea) pharmacophores, and some derived thiazole ring systems. Bioorg. Med. Chem., 2006, 14, 6475-6485.
[63]
Havrylyuk, D.; Kovach, N.; Zimenkovsky, B.; Vasylenko, O.; Lesyk, R. Synthesis and anticancer activity of isatin-based pyrazolines and thiazolidines conjugates. Arch. Pharm. , 2011, 344, 514-522.
[64]
Palaska, E.; Aytemir, V.; Uzbay, I.T.; Erol, D. Synthesis and antidepressant activities of some 3,5-diphenyl-2-pyrazolines. Eur. J. Med. Chem., 2001, 36, 539-543.
[65]
Kaplanciklia, Z.A.; Turan-Zitounia, G.; Ozdemira, A.; Can, O.V.; Chevallet, P. Synthesis and antinociceptive activities of some pyrazoline derivatives. Eur. J. Med. Chem., 2009, 44, 2606-2610.
[66]
Karpenko, A.S.; Dorovskykh, I.V.; Shibinskaya, M.O.; Maltsev, G.V.; Lyakhova, H.A.; Gusyeva, J.O. Synthesis, antiviral and interferon inducing activities of the carboxy-derivatives of the planar polycyclic compounds. Ukr. Bioorg. Acta, 2008, 6(2), 65-72.
[67]
Abdel-Aziz, H.A.; Eldehna, W.M.; Keeton, A.B.; Piazza, G.A.; Kadi, A.N.; Attawa, M.W. Isatin-benzoazine molecular hybrids as potential antiproliferative agents: Synthesis and in vitro pharmacological profiling. Drug Des. Devel. Ther., 2017, 11, 2333-2346.
[68]
Eldehna, W.M.; Almahli, H.; Al-Ansary, G.H.; Ghabbour, H.A.; Aly, M.H.; Ismael, O.E. Synthesis and in vitro anti-proliferative activity of some novel isatins conjugated with quinazoline/ phthalazine hydrazines against triple-negative breast cancer MDA-MB-231 cells as apoptosis inducing agents. J. Enzyme Inhib. Med. Chem., 2017, 32, 600-613.
[69]
aMiura, K.; Nakagawa, T.; Hosomi, A. Lewis base-promoted aldol reaction of dimethylsilyl enolates in aqueous dimethylformamide: use of calcium chloride as a lewis base catalyst. J. Am. Chem. Soc., 2002, 124(4), 536-537.
bMiura, K.; Tamaki, K.; Nakagawa, T.; Hosomi, A. A novel catalytic system for the mannich-type reaction of silyl enolates: stereoselective synthesis of β-aminoketones. Angew. Chem. Int. Ed., 2000, 39, 1958-1960.
cPasunooti, K.K.; Chai, H.; Jensen, C.N.; Gorityala, B.K.; Wang, S.; Liu, X.W. Microwave-assisted, copper-catalyzed three-component synthesis of dihydropyrimidinones under mild conditions. Tetrahedron Lett., 2011, 52, 80-84.
bMiura, K.; Tamaki, K.; Nakagawa, T.; Hosomi, A. A novel catalytic system for the mannich-type reaction of silyl enolates: stereoselective synthesis of β-aminoketones. Angew. Chem. Int. Ed., 2000, 39, 1958-1960.
cPasunooti, K.K.; Chai, H.; Jensen, C.N.; Gorityala, B.K.; Wang, S.; Liu, X.W. Microwave-assisted, copper-catalyzed three-component synthesis of dihydropyrimidinones under mild conditions. Tetrahedron Lett., 2011, 52, 80-84.
[70]
Akhaja, T.N.; Raval, J.P. Design, synthesis, in vitro evaluation of tetrahydropyrimidine-isatin hybrids as potential antibacterial, antifungal and anti-tubercular agents. Chin. Chem. Lett., 2012, 23, 446-449.
[71]
Akhaja, T.N.; Raval, J.P. Design, synthesis and in vitro evaluation of tetr ahydropyrimidine-isatin hybrids as potential antitubercular and antimalarial agents. Chin. Chem. Lett., 2012, 23, 785-788.
[72]
Akhaja, T.N.; Raval, J.P. 1, 3-Dihydro-2H-indol-2-ones derivatives: design, synthesis, in vitro antibacterial, antifungal and antitubercular study. Eur. J. Med. Chem., 2011, 46, 5573-5579.
[73]
Aboul-Fadl, T.; Mohammed, F.A.; Hassan, E.A. Synthesis, antitubercular activity and pharmacokinetic studies of some Schiff bases derived from 1-alkylisatin and isonicotinic acid hydrazide (INH). Arch. Pharm. Res., 2003, 26, 778-785.
[74]
Aboul-Fadl, T.; Bin-Jubair, F.A.; Aboul-Wafa, O. Schiff Bases of indoline-2,3-dione (isatin) derivatives and nalidixic acid carbohydrazide, synthesis, antitubercular activity and pharmacophoric model building. Eur. J. Med. Chem., 2010, 45, 457-4586.
[75]
Hans, R.H.; Su, H.; Chibale, K. Novel tetracyclic structures from the synthesis of thiolactone-isatin hybrids. Beilstein J. Org. Chem., 2010, 6, 78.
[76]
Wang, C.L.J.; Salvino, J.M. Total synthesis of (±) thiolactomycin. Tetrahedron Lett., 1984, 25, 5243-5246.
[77]
Chu, W.; Rothfuss, J.; Chu, Y.; Zhou, D.; Mach, R.H. Synthesis and in vitro evaluation of sulfonamide isatin michael acceptors as small molecule inhibitors of caspase-6. J. Med. Chem., 2009, 52, 2188-2191.
[78]
Hans, R.H.; Wiid, I.J.; van Helden, P.D.; Wan, B.; Franzblau, S.G.; Gut, J.; Rosenthal, P.J.; Chibale, K. Novel thiolactone-isatin hybrids as potential antimalarial and antitubercular agents. Bioorg. Med. Chem. Lett., 2011, 21, 2055-2058.
[79]
Sharma, P.K.; Balwani, S.; Mathur, D.; Malhotra, S.; Singh, B.K.; Prasad, A.K.; Len, C.; Van der Eycken, E.V.; Ghosh, B.; Richards, N.G.; Parmar, V.S. Synthesis and anti-inflammatory activity evaluation of novel triazolyl-isatin hybrids. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1520-1526.
Article Metrics
19
2