Abstract
Dihydropyridine is an outstanding heterocyclic compound with a wide range of pharmacological potential, including antimicrobial, antioxidant, antitubercular, antiarrhythmic, insecticidal, antihypertensive, vasodilator, anti-inflammatory, antibacterial, antidiabetic and superlative moiety in drug discovery. It is also a versatile pharmacophore, a privileged scaffold, and a distinguished heterocyclic compound. Excellent outcomes have already been shown with novel targets and various modes of action for the dihydropyridines hybrids. This review focused on the mode of action, synthesis, and biological activities. As a result, numerous dihydropyridine candidates are undergoing clinical studies to treat various disorders. This article highlights how novel techniques were used to create dihydropyridines, which may be helpful to researchers in the future.
Graphical Abstract
[1]
Wang, S.X.; Li, Z.Y.; Zhang, J.C.; Li, J.T. The solvent-free synthesis of 1,4-dihydropyridines under ultrasound irradiation without catalyst. Ultrason. Sonochem., 2008, 15(5), 677-680.
[http://dx.doi.org/10.1016/j.ultsonch.2008.02.009] [PMID: 18394947]
[http://dx.doi.org/10.1016/j.ultsonch.2008.02.009] [PMID: 18394947]
[2]
Sirisha, K.; Achaiah, G.; Reddy, V.M. Facile synthesis and antibacterial, antitubercular, and anticancer activities of novel 1,4-dihydropyridines. Arch. Pharm. , 2010, 343(6), 342-352.
[http://dx.doi.org/10.1002/ardp.200900243] [PMID: 20496343]
[http://dx.doi.org/10.1002/ardp.200900243] [PMID: 20496343]
[3]
Saponara, S.; Ferrara, A.; Gorelli, B.; Shah, A.; Kawase, M.; Motohashi, N.; Molnar, J.; Sgaragli, G.; Fusi, F. 3,5-Dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7): A new multidrug resistance inhibitor devoid of effects on Langendorff-perfused rat heart. Eur. J. Pharmacol., 2007, 563(1-3), 160-163.
[http://dx.doi.org/10.1016/j.ejphar.2007.02.001] [PMID: 17349992]
[http://dx.doi.org/10.1016/j.ejphar.2007.02.001] [PMID: 17349992]
[4]
Kawase, M.; Shah, A.; Gaveriya, H.; Motohashi, N.; Sakagami, H.; Varga, A.; Molnár, J. 3,5-dibenzoyl-1,4-dihydropyridines: Synthesis and MDR reversal in tumor cells. Bioorg. Med. Chem., 2002, 10(4), 1051-1055.
[http://dx.doi.org/10.1016/S0968-0896(01)00363-7] [PMID: 11836114]
[http://dx.doi.org/10.1016/S0968-0896(01)00363-7] [PMID: 11836114]
[5]
Rucins, M.; Smits, R.; Sipola, A.; Vigante, B.; Domracheva, I.; Turovska, B.; Muhamadejev, R.; Pajuste, K.; Plotniece, M.; Sobolev, A.; Duburs, G.; Plotniece, A. Pleiotropic properties of amphiphilic dihydropyridines, dihydropyridones, and aminovinylcarbonyl compounds. Oxid. Med. Cell. Longev., 2020, 2020, 1-17.
[http://dx.doi.org/10.1155/2020/8413713] [PMID: 33488932]
[http://dx.doi.org/10.1155/2020/8413713] [PMID: 33488932]
[6]
Kumar, A.; Maurya, R.A.; Sharma, S.; Kumar, M.; Bhatia, G. Synthesis and biological evaluation of N-aryl-1,4-dihydropyridines as novel antidyslipidemic and antioxidant agents. Eur. J. Med. Chem., 2010, 45(2), 501-509.
[http://dx.doi.org/10.1016/j.ejmech.2009.10.036] [PMID: 19962217]
[http://dx.doi.org/10.1016/j.ejmech.2009.10.036] [PMID: 19962217]
[7]
Subudhi, B.B.; Panda, P.K.; Bhatta, D. Synthesis and antiulcer activity study of 1,4-dihydropyridines and their mannich bases with sulfanilamide. Indian J. Chem. - Sect. B Org. Med. Chem., 2009, 48, 725-728.
[8]
Triggle, D.J. Calcium channel antagonists: Clinical uses—Past, present and future. Biochem. Pharmacol., 2007, 74(1), 1-9.
[http://dx.doi.org/10.1016/j.bcp.2007.01.016] [PMID: 17276408]
[http://dx.doi.org/10.1016/j.bcp.2007.01.016] [PMID: 17276408]
[9]
Nangare, A.K.; Kakad, S.B.; Chavan, A.N.; Bole, S.S. ChemInform Abstract: Synthesis and signification of 1,4-dihydropyridine analogs in different pharmaceutical drug. ChemInform, 2016, 47(33), 738-749.
[http://dx.doi.org/10.1002/chin.201633237]
[http://dx.doi.org/10.1002/chin.201633237]
[10]
Ling, Y.; Hao, Z.Y.; Liang, D.; Zhang, C.L.; Liu, Y.F.; Wang, Y. The expanding role of pyridine and dihydropyridine scaffolds in drug design. Drug Des. Devel. Ther., 2021, 15, 4289-4338.
[http://dx.doi.org/10.2147/DDDT.S329547] [PMID: 34675489]
[http://dx.doi.org/10.2147/DDDT.S329547] [PMID: 34675489]
[11]
Swarnalatha, G.; Prasanthi, G.; Sirisha, N.; Madhusudhana Chetty, C. 1,4-Dihydropyridines: A multtifunctional molecule- A review. Int. J. Chemtech Res., 2011, 3, 75-89.
[12]
Aditya, H. Synthesis, characterization and docking studies of some novel dihydropyridine derivatives. World J. Pharm. Res., 2017, 6, 769-781.
[13]
Al-Said, M.S.; Bashandy, M.S.; Al-qasoumi, S.I.; Ghorab, M.M. Anti-breast cancer activity of some novel 1,2-dihydropyridine, thiophene and thiazole derivatives. Eur. J. Med. Chem., 2011, 46(1), 137-141.
[http://dx.doi.org/10.1016/j.ejmech.2010.10.024] [PMID: 21093116]
[http://dx.doi.org/10.1016/j.ejmech.2010.10.024] [PMID: 21093116]
[14]
da Costa Cabrera, D.; Santa-Helena, E.; Leal, H.P.; de Moura, R.R.; Nery, L.E.M.; Gonçalves, C.A.N.; Russowsky, D.; Montes D’Oca, M.G. Synthesis and antioxidant activity of new lipophilic dihydropyridines. Bioorg. Chem., 2019, 84, 1-16.
[http://dx.doi.org/10.1016/j.bioorg.2018.11.009] [PMID: 30471487]
[http://dx.doi.org/10.1016/j.bioorg.2018.11.009] [PMID: 30471487]
[15]
Yang, G.Z.; Shang, X.F.; Cheng, P.L.; Yin, X.D.; Zhu, J.K.; Liu, Y.Q.; Zhang, J.; Zhang, Z.J. Facile three-component synthesis, insecticidal and antifungal evaluation of novel dihydropyridine derivatives. Molecules, 2018, 23(10), 2422.
[http://dx.doi.org/10.3390/molecules23102422] [PMID: 30241413]
[http://dx.doi.org/10.3390/molecules23102422] [PMID: 30241413]
[16]
Rezvanian, A.; Heravi, M.M.; Shaabani, Z.; Tajbakhsh, M. Five-component synthesis of dihydropyridines based on diketene. Tetrahedron, 2017, 73(15), 2009-2013.
[http://dx.doi.org/10.1016/j.tet.2017.02.027]
[http://dx.doi.org/10.1016/j.tet.2017.02.027]
[17]
Gao, Y.; Wang, B.; Gao, S.; Zhang, R.; Yang, C.; Sun, Z.; Liu, Z. Design and synthesis of 1,4-dihydropyridine and cinnamic acid esters and their antioxidant properties. Chem. Res. Chin. Univ., 2016, 32(4), 594-599.
[http://dx.doi.org/10.1007/s40242-016-6047-0]
[http://dx.doi.org/10.1007/s40242-016-6047-0]
[18]
Ibraheem, H.H.; Al-Majedy, Y.K.; Salim, A.J.; Al-Bayati, R.I. Synthesis and characterization of new 1,2-dihydropyridine-3-carbonitrile compounds with study of expected biological activity. J. Al-Nahrain. Univ. Sci. , 2018, 21, 45-50.
[19]
Sun, W.; Ma, Z.; Yan, H. Biological evaluation of 4-aryl-1,4-dihydropyridines as VEGFR-2 kinase inhibitors. Russ. J. Gen. Chem., 2016, 86(12), 2891-2899.
[http://dx.doi.org/10.1134/S1070363216120574]
[http://dx.doi.org/10.1134/S1070363216120574]
[20]
Iwanami, M.; Shibanuma, T.; Fujimoto, M.; Kawai, R.; Tamazawa, K.; Takenaka, T.; Takahashi, K.; Murakami, M. Synthesis of new water-soluble dihydropyridine vasodilators. Chem. Pharm. Bull. , 1979, 27(6), 1426-1440.
[http://dx.doi.org/10.1248/cpb.27.1426] [PMID: 544055]
[http://dx.doi.org/10.1248/cpb.27.1426] [PMID: 544055]
[21]
Salama, I.; Abdel-fattah, M.A.O.; Hany, M.S.; El-sharif, S.A.; Elnaggar, M.A.M.; Rashied, R.M.H.; Piazza, G.A.; Abadi, A.H. CoMFA and CoMSIA studies of 1,2-dihydropyridine derivatives as anticancer agents. Med. Chem., 2012, 8, 372-383.
[22]
Perużyńska, M.; Borzyszkowska-Ledwig, A.; Sośnicki, J.G.; Struk, Ł.; Idzik, T.J.; Maciejewska, G.; Skalski, Ł.; Piotrowska, K.; Łukasik, P.; Droździk, M.; Kurzawski, M. Synthesis and anticancer activity of mitotic-specific 3,4-dihydropyridine-2(1H)-thiones. Int. J. Mol. Sci., 2021, 22(5), 2462.
[http://dx.doi.org/10.3390/ijms22052462] [PMID: 33671106]
[http://dx.doi.org/10.3390/ijms22052462] [PMID: 33671106]
[23]
Jaismy Jacob, P.; Thomas, A.; Venkataraman, S.; Hareeshbabu, E.; Manju, S.L. Synthesis and biological evaluation of some novel substituted 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxamides. IOP Conf. Ser. Mater. Sci. Eng., 2017, 263(2), p. 022019.
[http://dx.doi.org/10.1088/1757-899X/263/2/022019]
[http://dx.doi.org/10.1088/1757-899X/263/2/022019]
[24]
Dhinakaran, I.; Padmini, V.; Bhuvanesh, N. One-pot synthesis of N-aryl 1,4-dihydropyridine derivatives and their biological activities. J. Chem. Sci., 2015, 127(12), 2201-2209.
[http://dx.doi.org/10.1007/s12039-015-0983-y]
[http://dx.doi.org/10.1007/s12039-015-0983-y]
[25]
Sadek; Fahelelbom, K.M.S. Synthesis and calcium channel blocking activity of 1, 4-dihydropyridine derivatives containing ester substitute and phenyl carbamoyl group. Am. J. Appl. Sci., 2011, 8(4), 303-309.
[http://dx.doi.org/10.3844/ajassp.2011.303.309]
[http://dx.doi.org/10.3844/ajassp.2011.303.309]
[26]
El-Sayed, A.A.; Elsayed, E.A.; Amr, A.E.G.E. Antiproliferative activity of some newly synthesized substituted pyridine candidates using 4-(Aaryl)-6-(naphthalen-1-yl)-2-oxo-1,2-dihydropyridine-3-carbonitrile as Synthon. ACS Omega, 2021, 6(10), 7147-7156.
[http://dx.doi.org/10.1021/acsomega.1c00202] [PMID: 33748628]
[http://dx.doi.org/10.1021/acsomega.1c00202] [PMID: 33748628]
[27]
Yousuf, H.; Shamim, S.; Khan, K.M.; Chigurupati, S.; Kanwal; Hameed, S.; Khan, M.N.; Taha, M.; Arfeen, M. Dihydropyridines as potential α-amylase and α-glucosidase inhibitors: Synthesis, in vitro and in silico studies. Bioorg. Chem., 2020, 96, 103581.
[http://dx.doi.org/10.1016/j.bioorg.2020.103581] [PMID: 31978686]
[http://dx.doi.org/10.1016/j.bioorg.2020.103581] [PMID: 31978686]
[28]
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, 104379.
[http://dx.doi.org/10.1016/j.bioorg.2020.104379] [PMID: 33113411]
[http://dx.doi.org/10.1016/j.bioorg.2020.104379] [PMID: 33113411]
[29]
Peña, R.; Jiménez-Alonso, S.; Feresin, G.; Tapia, A.; Méndez-Alvarez, S.; Machín, F.; Ravelo, Á.G.; Estévez-Braun, A. Multicomponent synthesis of antibacterial dihydropyridin and dihydropyran embelin derivatives. J. Org. Chem., 2013, 78(16), 7977-7985.
[http://dx.doi.org/10.1021/jo401189x] [PMID: 23841668]
[http://dx.doi.org/10.1021/jo401189x] [PMID: 23841668]
[30]
Panda, S.; Coffin, A.; Nguyen, Q.N.; Tantillo, D.J.; Ready, J.M. Synthesis and utility of dihydropyridine boronic esters. Angew. Chem. Int. Ed., 2016, 55(6), 2205-2209.
[http://dx.doi.org/10.1002/anie.201510027] [PMID: 26694785]
[http://dx.doi.org/10.1002/anie.201510027] [PMID: 26694785]
[31]
Idhayadhulla, A.; Kumar, R.S.; Nasser, A.J.A.; Kavimani, S.; Indhumathy, S. Anti-inflammatory activity of new series of 1,4-dihydropyridine derivatives. Pharm. Chem. J., 2015, 49(7), 463-466.
[http://dx.doi.org/10.1007/s11094-015-1305-x]
[http://dx.doi.org/10.1007/s11094-015-1305-x]
[32]
Lapidot, I.; Albeck, A.; Gellerman, G.; Shatzmiller, S.; Grynszpan, F. 1,4-dihydropyridine cationic peptidomimetics with antibacterial activity. Int. J. Pept. Res. Ther., 2015, 21(3), 243-247.
[http://dx.doi.org/10.1007/s10989-015-9460-1]
[http://dx.doi.org/10.1007/s10989-015-9460-1]
[33]
Fiszer-Maliszewska, L.; Wieczorek, J.; Mordarski, M.; Balicki, R.; Kaczmarek, L.; Nantka-Namirski, P. Biological activity of 1,4-dihydropyridine derivatives. Arch. Immunol. Ther. Exp. , 1985, 33(2), 345-352.
[PMID: 4084011]
[PMID: 4084011]
[34]
Olejníková, P.; Švorc, L.; Olšovská, D.; Panáková, A.; Vihonská, Z.; Kovaryová, K.; Marchalín, S. Antimicrobial activity of novel c2-substituted 1,4-dihydropyridine analogues. Sci. Pharm., 2014, 82(2), 221-232.
[http://dx.doi.org/10.3797/scipharm.1311-04] [PMID: 24959401]
[http://dx.doi.org/10.3797/scipharm.1311-04] [PMID: 24959401]
[35]
Frank, Th.M.A.; Roveri, A.; Maiorino, M.; Ratti, E.; Ursini, F. Lacidipine: A dihydropyridine calcium antagonist with antioxidant activity. Free Radic. Biol. Med., 1992, 12, 183-187.
[http://dx.doi.org/10.1016/0891-5849(92)90025-C]
[http://dx.doi.org/10.1016/0891-5849(92)90025-C]
[36]
Semire, B. Studies of anti-hypertensive activity of 1,4-dihydropyridine derivatives: Combinations of DFT-QSAR and docking approaches. Bull. Pharm. Res. Inst., 2016, 6(3), 105-118.
[37]
Abyshev, A.Z.; Bang, N.C.; Ivkin, D.Y.; Thi, N.; Yen, H. Synthesis and antiarrhythmic activity of novel 1,4-dihydropyridine-coumarin hybrid molecules 2018, 33, 121-122.
[38]
Trivedi, A.; Dodiya, D.; Dholariya, B.; Kataria, V.; Bhuva, V.; Shah, V. Synthesis and biological evaluation of some novel 1,4-dihydropyridines as potential antitubercular agents. Chem. Biol. Drug Des., 2011, 78(5), 881-886.
[http://dx.doi.org/10.1111/j.1747-0285.2011.01233.x] [PMID: 21895982]
[http://dx.doi.org/10.1111/j.1747-0285.2011.01233.x] [PMID: 21895982]
[39]
Poondra, R.R.; Nallamelli, R.V.; Meda, C.L.T.; Srinivas, B.N.V.; Grover, A.; Muttabathula, J.; Voleti, S.R.; Sridhar, B.; Pal, M.; Parsa, K.V.L. Discovery of novel 1,4-dihydropyridine-based PDE4 inhibitors. Bioorg. Med. Chem. Lett., 2013, 23(4), 1104-1109.
[http://dx.doi.org/10.1016/j.bmcl.2012.11.121] [PMID: 23294698]
[http://dx.doi.org/10.1016/j.bmcl.2012.11.121] [PMID: 23294698]
[40]
Mollazadeh, S.; Sahebkar, A.; Kalalinia, F.; Behravan, J.; Hadizadeh, F. Synthesis, in silico and in vitro studies of new 1,4-dihydropiridine derivatives for antitumor and P-glycoprotein inhibitory activity. Bioorg. Chem., 2019, 91, 103156.
[http://dx.doi.org/10.1016/j.bioorg.2019.103156] [PMID: 31416030]
[http://dx.doi.org/10.1016/j.bioorg.2019.103156] [PMID: 31416030]
[41]
Fricke, U.; Klaus, W.; Stein, B. Novel halogenated dihydropyridine derivatives with high vascular selectivity. Naunyn Schmiedebergs Arch. Pharmacol., 1988, 338(4), 449-454.
[http://dx.doi.org/10.1007/BF00172126] [PMID: 3244387]
[http://dx.doi.org/10.1007/BF00172126] [PMID: 3244387]
[42]
Döring, H.; Kreutzer, D.; Ritter, C.; Hilgeroth, A. Discovery of novel symmetrical 1,4-dihydropyridines as inhibitors of Multidrug-Resistant Protein (MRP4) efflux pump for anticancer therapy. Molecules, 2020, 26(1), 18.
[http://dx.doi.org/10.3390/molecules26010018] [PMID: 33375210]
[http://dx.doi.org/10.3390/molecules26010018] [PMID: 33375210]
[43]
Natale, N.R.; Rogers, M.E.; Staples, R.; Triggle, D.J.; Rutledge, A. Lipophilic 4-isoxazolyl-1,4-dihydropyridines: Synthesis and structure-activity relationships. J. Med. Chem., 1999, 42(16), 3087-3093.
[http://dx.doi.org/10.1021/jm980439q] [PMID: 10447952]
[http://dx.doi.org/10.1021/jm980439q] [PMID: 10447952]
