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Current Organic Chemistry


ISSN (Print): 1385-2728
ISSN (Online): 1875-5348

Mini-Review Article

An Overview of Recent Advances in Hantzsch’s Multicomponent Synthesis of 1,4- Dihydropyridines: A Class of Prominent Calcium Channel Blockers

Author(s): Keshav Kumar Saini, Rupal Rani, Muskan, Neena Khanna, Bhupinder Mehta and Rakesh Kumar*

Volume 27, Issue 2, 2023

Published on: 17 April, 2023

Page: [119 - 129] Pages: 11

DOI: 10.2174/1385272827666230403112419

Price: $65


Among all the heterocyclic scaffolds, 1,4-dihydropyridine (1,4-DHPs) is an important class of nitrogen-containing heterocyclic compounds possessing prominent therapeutic effects, which play an essential role in pharmaceutical chemistry. Multicomponent reactions (MCRs) have proven to be an invaluable tool for swiftly synthesizing large and structurally diverse molecules from simple starting materials. The chemists have discovered a large number of new MCRs for the synthesis of 1,4-dihydropyridine. The synthesis of 1,4-Dihydropyridine via multicomponent reaction is an efficient procedure in terms of delivering adequate structural diversity, which is essential for the process of discovering new 1,4-DHPs compounds and their therapeutics.1,4-dihydropyridines are well-known L-type calcium channel blockers. This review aims to study and summarize the recent developments in the multicomponent synthesis of 1,4-dihydropyridines and their fused analogs that act as potent antihypertensive drugs. The findings of this study will prove to be an invaluable resource for researchers in the areas of heterocyclic chemistry, medicinal chemistry, and drug design.

Keywords: Calcium channel blockers, multicomponent reactions, dihydropyridine, hypertension, one-pot synthesis, hantzsch synthesis.

Graphical Abstract
Frąk, W.; Wojtasińska, A.; Lisińska, W.; Młynarska, E.; Franczyk, B.; Rysz, J. Pathophysiology of cardiovascular diseases: New insights into molecular mechanisms of atherosclerosis, arterial hypertension, and coronary artery disease. Biomedicines, 2022, 10(8), 1938.
[] [PMID: 36009488]
Vrsalovic, M.; Vrsalovic Presecki, A.; Aboyans, V. Cardiac troponins predict mortality and cardiovascular outcomes in patients with peripheral artery disease: A systematic review and meta‐analysis of adjusted observational studies. Clin. Cardiol., 2022, 45(2), 198-204.
[] [PMID: 35132665]
Edgar, L.; James, L.; Swapnil, H. Hypertension Secrets; Elsevier: Amsterdam, 2022.
Fuchs, F.D.; Whelton, P.K. High blood pressure and cardiovascular disease. Hypertension, 2020, 75(2), 285-292.
Ntchapda, F.; Talla, E.R.; Adjia, H.; Bonabe, C.; Kopodjing, A.B.; Miaffo, D.; Etet, P.F.S. Diuretic and antihypertensive activity of the aqueous extract of Haematostaphis barteri stem bark in adrenaline-induced hypertensive Wistar Rats. J Phytopharmacol, 2022, 11(1), 24-31.
Chitra, S.M.; Anbu, N.; Uma, K.S. Antihypertensive activity of polyherbal siddha formulation Veppampoo Mathirai – A Review. Res. J. Pharm. Technol., 2022, 15(3), 1365-1370.
WHO. Cardiovascular Diseases. Available from:
Oliveira, C.B.; Kaplan, M.J. Cardiovascular disease risk and pathogenesis in systemic lupus erythematosus. Semin. Immunopathol., 2022, 44(3), 309-324.
[] [PMID: 35355124]
Bryniarski, P.; Nazimek, K.; Marcinkiewicz, J. Immunomodulatory activity of the most commonly used antihypertensive drugs-angiotensin converting enzyme inhibitors and angiotensin II receptor blockers. Int. J. Mol. Sci., 2022, 23(3), 1772.
Chen, P.; Ren, Y.; Zhang, Y.; Liu, Y.; Shi, H.; Chen, Z.; Wang, L. Characterization of ACE inhibitory peptide from Cassia tora L. Globulin fraction and its antihypertensive activity in SHR. Eur. Food Res. Technol., 2022, 248(7), 1917-1928.
Blazquez-Barbadillo, C.; González, J.F.; Porcheddu, A.; Virieux, D.; Menéndez, J.C.; Colacino, E. Benign synthesis of therapeutic agents: Domino synthesis of unsymmetrical 1,4-diaryl-1,4-dihydropyridines in the ball-mill. Green Chem. Lett. Rev., 2022, 15(4), 881-892.
Upadhyay, R.K.; Saini, K.K.; Deswal, N.; Singh, T.; Tripathi, K.P.; Kaushik, P.; Shakil, N.A.; Bharti, A.C.; Kumar, R. Synthesis of benzothiazoleappended bis-triazole-based structural isomers with promising antifungal activity against Rhizoctonia solani. RSC Advances, 2022, 12(37), 24412-24426.
[] [PMID: 36128524]
Rucins, M.; Plotniece, A.; Bernotiene, E.; Tsai, W.B.; Sobolev, A. Recent approaches to chiral 1,4-dihydropyridines and their fused analogues. Catalysts, 2020, 10(9), 1019.
Rezaei, A.; Ghorbani-Choghamarani, A.; Tahmasbi, B. Synthesis and characterization of nickel metal organic framework including 4,6-diamino-2-mercaptopyrimidine and its catalytic application in organic reactions. Catal. Lett., 2022, 1-7.
Nikoorazm, M.; Tahmasbi, B.; Gholami, S.; Moradi, P. Copper and nickel immobilized on cytosine@MCM‐41: As highly efficient, reusable and organic–inorganic hybrid nanocatalysts for the homoselective synthesis of tetrazoles and pyranopyrazoles. Appl. Organomet. Chem., 2020, 34(11), 1-20.
Moradi, P.; Hajjami, M. Magnetization of biochar nanoparticles as a novel support for fabrication of organo nickel as a selective, reusable and magnetic nanocatalyst in organic reactions. New J. Chem., 2021, 45(6), 2981-2994.
Kikhavani, T.; Moradi, P.; Mashari-Karir, M.; Naji, J. A new copper Schiff‐base complex of 3,4‐diaminobenzophenone stabilized on magnetic MCM‐41 as a homoselective and reusable catalyst in the synthesis of tetrazoles and pyranopyrazoles. Appl. Organomet. Chem., 2022, 36(12), 1-17.
Bandyopadhyay, D.; Salazar, T.; Gonzalez, A. Dihydropyridines as calcium channel blockers: An overview. J. Anal. Pharm. Res., 2017, 5(4), 00148.
Pepine, C.J. The role of calcium antagonists in ischaemic heart disease. Eur. Heart J., 1995, 16(Suppl. H), 19-24.
[] [PMID: 8846801]
Sueta, D.; Tabata, N.; Hokimoto, S. Clinical roles of calcium channel blockers in ischemic heart diseases. Hypertens. Res., 2017, 40(5), 423-428.
[] [PMID: 28123178]
Kumar, R.S.; Idhayadhulla, A.; Abdul Nasser, A.J.; Selvin, J. Synthesis and anticoagulant activity of a new series of 1,4-dihydropyridine derivatives. Eur. J. Med. Chem., 2011, 46(2), 804-810.
[] [PMID: 21220179]
Velena, A.; Zarkovic, N.; Gall Troselj, K.; Bisenieks, E.; Krauze, A.; Poikans, J.; Duburs, G. 1,4-dihydropyridine derivatives: Dihydronicotinamide analogues—model compounds targeting oxidative stress. Oxid. Med. Cell. Longev., 2016, 2016, 1892412.
[] [PMID: 26881016]
Bahekar, S.; Shinde, D. Synthesis and anti-inflammatory activity of 1, 4-dihydropyridines. Acta pharmaceutica., 2002, 52(4), 281-7.
Clark, K.B. Biotic activity of Ca2+-modulating non-traditional antimicrobial and -viral agents. Front. Microbiol., 2013, 4(DEC), 381.
[] [PMID: 24376441]
Viradiya, D.; Mirza, S.; Shaikh, F.; Kakadiya, R.; Rathod, A.; Jain, N.; Rawal, R.; Shah, A. Design and synthesis of 1,4-dihydropyridine derivatives as anti-cancer agent. Anticancer. Agents Med. Chem., 2017, 17(7), 1003-1013.
[] [PMID: 27924733]
Mohamed, M.F.; Darweesh, A.F.; Elwahy, A.H.M.; Abdelhamid, I.A. Synthesis, characterization and antitumor activity of novel tetrapodal 1,4-dihydropyridines: P53 induction, cell cycle arrest and low damage effect on normal cells induced by genotoxic factor H2O2. RSC Advances, 2016, 6(47), 40900-40910.
Triggle, D.J. 1,4-Dihydropyridines as calcium channel ligands and privileged structures. Cell. Mol. Neurobiol., 2003, 23(3), 293-303.
[] [PMID: 12825828]
Ramírez-San Juan, E.; Soriano-Ursúa, M.A.; Espinosa-Raya, J.; Correa-Basurto, J.; Trujillo-Ferrara, J.G.; Miranda-Ruvalcaba, R.; Delgado-Reyes, F.; Gómez-Pliego, R. Anticonvulsant effects of bis-1,4-dihydropyridines and the probable role of L-type calcium channels suggested by docking simulations. Med. Chem. Res., 2014, 23(12), 5149-5159.
Santa-Helena, E.; Cabrera, D.C.; D’Oca, M.G.M.; Scaini, J.L.R.; de Oliveira, M.W.B.; Werhli, A.V.; Machado, K.S.; Gonçalves, C.A.N.; Nery, L.E.M. Long-chain fatty dihydropyridines: Docking calcium channel studies and antihypertensive activity. Life Sci., 2020, 259(July), 118210.
[] [PMID: 32763289]
Reinert, J.P.; Tiemann, A.R.; Barlow, M.L.; Veronin, M.A. Evaluating the efficacy and safety of calcium channel blockers as adjunctive analgesics to opioid therapy: A literature review. J. Pharm. Pract. Res., 2022, 52(1), 7-18.
Friedel, H.A.; Sorkin, E.M. Nisoldipine. Drugs, 1988, 36(6), 682-731.
[] [PMID: 3065058]
Flynn, J.T. Nifedipine in the treatment of hypertension in children. J. Pediatr., 2002, 140(6), 0787-0788.
[] [PMID: 12072894]
Elmfeldt, D.; Hedner, T. Felodipine? A new vasodilator, in addition to? -receptor blockade in hypertension. Eur. J. Clin. Pharmacol., 1983, 25(5), 571-575.
[] [PMID: 6141051]
Fares, H.; DiNicolantonio, J.J.; O’Keefe, J.H.; Lavie, C.J. Amlodipine in hypertension: A first-line agent with efficacy for improving blood pressure and patient outcomes. Open Heart, 2016, 3(2), e000473.
[] [PMID: 27752334]
Chandra, K.S.; Ramesh, G. The fourth-generation Calcium channel blocker: Cilnidipine. Indian Heart J., 2013, 65(6), 691-695.
[] [PMID: 24407539]
Clouqueur, E.; Gautier, S.; Vaast, P.; Coulon, C.; Deruelle, P.; Subtil, D.; Debarge, V. Effets indésirables des inhibiteurs calciques utilisés dans le cadre de la tocolyse. J. Gynecol. Obstet. Biol. Reprod., 2015, 44(4), 341-356.
[] [PMID: 25726253]
Stason, W.B.; Schmid, C.H.; Niedzwiecki, D.; Whiting, G.W.; Luo, D.; Ross, S.D.; Chalmers, T.C.; Chalmers, T.C. Safety of nifedipine in patients with hypertension: A meta-analysis. Hypertension, 1997, 30(1), 7-14.
[] [PMID: 9231814]
Andersson, O.; Bengtsson, C.; Elmfeldt, D.; Haglund, K.; Hedner, T.; Seideman, P.; Sjöberg, K.H.; Strömgren, E.; Aberg, H.; Ostman, J. Short-term effects of felodipine, a new dihydropyridine, in hypertension. Br. J. Clin. Pharmacol., 1984, 17(3), 257-263.
[] [PMID: 6712859]
Leonetti, G.; Magnani, B.; Pessina, A.C.; Rappelli, A.; Trimarco, B.; Zanchetti, A. Tolerability of long-term treatment with lercanidipine versus amlodipine and lacidipine in elderly hypertensives. Am. J. Hypertens., 2002, 15(11), 932-940.
[] [PMID: 12441211]
Tippens, A.S. Isradipine. xPharm: The Comprehensive Pharmacology Reference; Elsevier: Amsterdam, 2007, pp. 1-6.
Goa, K. L.; Sorkin, E. M. Nitrendipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the treatment of hypertension. Drugs, 1987, 33(2), 123-155.
Sheraz, M.A.; Ahsan, S.F.; Khan, M.F.; Ahmed, S.; Ahmad, I. Formulations of Amlodipine: A Review. J. Pharm., 2016, 2016, 8961621.
[] [PMID: 27822402]
Ferri, N.; Corsini, A.; Pontremoli, R. Antihypertensive treatment with calcium channel blockers and renal protection: Focus on lercanidipine and lercanidipine/enalapril. Eur. Rev. Med. Pharmacol. Sci., 2022, 26(20), 7482-7492.
[] [PMID: 36314318]
Liau, C. S. Barnidipine: A new calcium channel blocker for hypertension treatment. Expert Rev. Cardiovasc. Ther., 2014, 3(2), 207-213.
Buchiya, F. A review: Analytical methods for determination of cilnidipine in biological fluid and pharmaceutical dosage forms. PharmaTutor., 2014, 2(11), 22-9.
McCormack, P.L.; Wagstaff, A.J. Lacidipine. Drugs, 2003, 63(21), 2327-2356.
[] [PMID: 14524737]
Minami, J.; Kawano, Y.; Makino, Y.; Matsuoka, H.; Takishita, S. Effects of cilnidipine, a novel dihydropyridine calcium antagonist, on autonomic function, ambulatory blood pressure and heart rate in patients with essential hypertension. Br. J. Clin. Pharmacol., 2000, 50(6), 615-620.
[] [PMID: 11136301]
Saini, A.; Kumar, S.; Sandhu, J.S. Hantzsch Reaction: Recent advances in Hantzsch 1,4-Dihydropyridines. J. Sci. Ind. Res., 2008, 67(2), 95-111.
Shen, L.; Cao, S.; Wu, J.; Zhang, J.; Li, H.; Liu, N.; Qian, X. A revisit to the Hantzsch reaction: Unexpected products beyond 1,4-dihydropyridines. Green Chem., 2009, 11(9), 1414-1420.
Karthick, R.; Velraj, G.; Pachamuthu, M.P.; Karthikeyan, S. Synthesis, spectroscopic, DFT, and molecular docking studies on 1,4-dihydropyridine derivative compounds: A combined experimental and theoretical study. J. Mol. Model., 2022, 28(1), 5.
[] [PMID: 34889990]
Tambe, A.; Sadaphal, G.; Dhawale, R.; Shirole, G. Pumice-based sulfonic acid: A sustainable and recyclable acidic catalyst for one-pot synthesis of pyrazole anchored 1,4-dihydropyridine derivatives at room temperature. Res. Chem. Intermed., 2022, 48(3), 1273-1286.
Khaled, A.; Stiti, M.Z.; Habila, T.; Ferkhi, M.; Pirotte, B.; Pireaux, J.J.; Khelili, S. Synthesis and characterization of La1–xSrxMn1-yZnyO3 perovskites as an efficient and recoverable catalyst for the Hantzsch reaction. J. Chem. Sci., 2022, 134(3), 86.
More, K.A.; Gandhare, N.V.; Ali, P.S.; Pathan, N.B.; Al-Mousa, K.M. An expeditious one pot green synthesis of novel bioactive 1, 4-dihydropyridine derivatives at ambient temperature and molecular modelling. Curr. Res. Green Sustain. Chem., 2021, 4(May), 100108.
Erşatır, M.; Türk, M.; Giray, E.S. An efficient and green synthesis of 1,4-dihydropyridine derivatives through multi-component reaction in subcritical EtOH. J. Supercrit. Fluids, 2021, 176, 105303.
M, S.; Sreekumar, K. Dual solvent-catalyst role of deep eutectic solvents in Hantzsch dihydropyridine synthesis. Synth. Commun., 2021, 51(11), 1-12.
Nosrati, A.; Amirnejat, S.; Javanshir, S. Preparation, antibacterial activity, and catalytic application of magnetic graphene oxide‐fucoidan in the synthesis of 1,4‐dihydropyridines and polyhydroquinolines. Chem. Open, 2021, 10(12), 1186-1196.
[] [PMID: 34851041]
Kerru, N.; Maddila, S.; Jonnalagadda, S.B. A Facile and catalyst-free microwave-promoted multicomponent reaction for the synthesis of functionalised 1,4-Dihydropyridines with superb selectivity and yields. Front Chem., 2021, 9(March), 638832.
[] [PMID: 33869142]
McLaughlin, C.; Bitai, J.; Barber, L.J.; Slawin, A.M.Z.; Smith, A.D. Catalytic enantioselective synthesis of 1,4-dihydropyridines via the addition of C(1)-ammonium enolates to pyridinium salts. Chem. Sci., 2021, 12(36), 12001-12011.
[] [PMID: 34667566]
Jafari-Chermahini, M.T.; Tavakol, H. One‐Pot synthesis of Hantzsch 1,4‐dihydropyridines by a series of iron oxide nanoparticles: Putative synthetic TRPV6 calcium channel blockers. Chem. Select, 2021, 6(9), 2360-2365.
Wu, K.; Bai, Y.; Chen, D.; Chen, L.; Huang, Y.; Bai, S.; Li, Y. Green synthesis of 1,4-dihydropyridines using cobalt carbon nanotubes as recyclable catalysts. Environ. Chem. Lett., 2021, 19(2), 1903-1910.
Sharma, M.G.; Pandya, J.; Patel, D.M.; Vala, R.M.; Ramkumar, V.; Subramanian, R.; Gupta, V.K.; Gardas, R.L.; Dhanasekaran, A.; Patel, H.M. One-Pot assembly for synthesis of 1,4-Dihydropyridine scaffold and their biological applications. Polycycl. Aromat. Compd., 2021, 41(7), 1495-1505.
Anaikutti, P.; Makam, P. Dual active 1, 4-dihydropyridine derivatives: Design, green synthesis and in vitro anti-cancer and anti-oxidant studies. Bioorg. Chem., 2020, 105(October), 104379.
[] [PMID: 33113411]
Alponti, L.H.R.; Picinini, M.; Urquieta-Gonzalez, E.A.; Corrêa, A.G. USYzeolite catalyzed synthesis of 1,4-dihydropyridines under microwave irradiation: Structure and recycling of the catalyst. J. Mol. Struct., 2021, 1227, 129430.
Cahyana, A.H.; Ardiansah, B.; Aisy, N.R. An efficient one-pot multicomponent synthesis of 1,4-Dihydropyridines catalyzed by guanidine hydrochloride. IOP Conf. Ser. Mater. Sci. Eng., 2020, 763(1), 012048.
Jiang, L.; Ye, W.; Su, W. One-pot multicomponent synthesis of highly functionalized 1,4-dihydropyridines using porcine pancreatic lipase. Chem. Res. Chin. Univ., 2019, 35(2), 235-238.
Xiong, X.; Yi, C.; Liao, X.; Lai, S. An effective one-pot access to 2-Amino-4H-benzo[b]pyrans and 1,4-Dihydropyridines via γ-Cyclodextrin-catalyzed multi-component tandem reactions in deep eutectic solvent. Catal. Lett., 2019, 149(6), 1690-1700.
Jiang, L.; Ye, L.; Gu, J.; Su, W.; Ye, W. Mechanochemical enzymatic synthesis of 1,4‐dihydropyridine calcium antagonists and derivatives. J. Chem. Technol. Biotechnol., 2019, 94(8), 2555-2560.
Khumalo, M.R.; Maddila, S.N.; Maddila, S.; Jonnalagadda, S.B. Microwave‐assisted one‐step four‐component reaction for synthesis of 1,4‐dihydropyridines catalyzed by triethylamine. Chem. Select, 2019, 4(43), 12503-12506.
Rezaei, N.; Ranjbar, P.R. The efficient synthesis of Hantzsch 1,4-dihydropyridines via metal-free oxidative C C coupling by HBr and DMSO. Tetrahedron Lett., 2018, 59(46), 4102-4106.
Moradi, L.; Zare, M. Ultrasound-promoted green synthesis of 1,4-dihydropyridines using fuctionalized MWCNTs as a highly efficient heterogeneous catalyst. Green Chem. Lett. Rev., 2018, 11(3), 197-208.
Maleki, A.; Firouzi-Haji, R.; Hajizadeh, Z. Magnetic guanidinylated chitosan nanobiocomposite: A green catalyst for the synthesis of 1,4-dihydropyridines. Int. J. Biol. Macromol., 2018, 116, 320-326.
[] [PMID: 29751038]
Mayurachayakul, P.; Pluempanupat, W.; Srisuwannaket, C.; Chantarasriwong, O. Four-component synthesis of polyhydroquinolines under catalyst- and solvent-free conventional heating conditions: mechanistic studies. RSC Advances, 2017, 7(89), 56764-56770.
Shabalala, S.; Maddila, S.; van Zyl, W.E.; Jonnalagadda, S.B. Innovative efficient method for the synthesis of 1,4-dihydropyridines using Y2O3 loaded on ZrO2 as catalyst. Ind. Eng. Chem. Res., 2017, 56(40), 11372-11379.
Shaldam, M.A.; El-Hamamsy, M.H.; Saleh, D.O.; El-Moselhy, T.F. Synthesis, evaluation of pharmacological activity, and molecular docking of 1,4-dihydropyridines as calcium antagonists. Chem. Pharm. Bull., 2016, 64(4), 297-304.
[] [PMID: 26822207]
Ravikumar Naik, T.R.; Shivashankar, S.A. Heterogeneous bimetallic ZnFe2O4 nanopowder catalyzed synthesis of Hantzsch 1,4-dihydropyridines in water. Tetrahedron Lett., 2016, 57(36), 4046-4049.
Shabalala, S.; Maddila, S.; van Zyl, W.E.; Jonnalagadda, S.B. A facile, efficacious and reusable Sm2O3/ZrO2 catalyst for the novel synthesis of functionalized 1,4-dihydropyridine derivatives. Catal. Commun., 2016, 79, 21-25.
Cao, S.; Zhong, S.; Hu, C.; Wan, J.P.; Wen, C. An environmentally benign catalytic method for versatile synthesis of 1,4-dihydropyridines via multicomponent reactions. Chin. J. Chem., 2015, 33(5), 568-572.
Ghorbani-Choghamarani, A.; Seydyosefi, Z.; Tahmasbi, B. Tribromide ion supported on boehmite nanoparticles as a reusable catalyst for organic reactions. C. R. Chim., 2018, 21(11), 1011-1022.
Ghorbani-Choghamarani, A.; Heidarnezhad, Z.; Tahmasbi, B.; Azadi, G. TEDETA@BNPs as a basic and metal free nanocatalyst for Knoevenagel condensation and Hantzsch reaction. J. Indian Chem. Soc., 2018, 15(10), 2281-2293.
Ghorbani-Choghamarani, A.; Zolfigol, M.A.; Hajjami, M.; Goudarziafshar, H.; Nikoorazm, M.; Yousefi, S.; Tahmasbi, B. Nano aluminium nitride as a solid source of ammonia for the preparation of hantzsch 1,4-dihydropyridines and bis-(1,4-dihydropyridines) in water via one pot multicomponent reaction. J. Braz. Chem. Soc., 2011, 22(3), 525-531.
Ghorbani-Choghamarani, A.; Tahmasbi, B.; Moradi, Z. S- Benzylisothiourea complex of palladium on magnetic nanoparticles: A highly efficient and reusable nanocatalyst for synthesis of polyhydroquinolines and Suzuki reaction. Appl. Organomet. Chem., 2017, 31(8), e3665.
Koolivand, M.; Nikoorazm, M.; Ghorbani-Choghamarani, A.; Azadbakht, R.; Tahmasbi, B. Ni–citric acid coordination polymer as a practical catalyst for multicomponent reactions. Sci. Rep., 2021, 11(1), 24475.
[] [PMID: 34963682]

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