Generic placeholder image

Medicinal Chemistry


ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

Review Article

Mannich Bases: Centrality in Cytotoxic Drug Design

Author(s): Neha V. Bhilare*, Vinayak S. Marulkar, Pramodkumar J. Shirote, Shailaja A. Dombe, Vilas J. Pise, Pallavi L. Salve, Shantakumar M. Biradar, Vishal D. Yadav, Prakash D. Jadhav, Anjali A. Bodhe, Smita P. Borkar, Prachi M. Ghadge, Pournima A. Shelar, Apurva V. Jadhav and Kirti C. Godse

Volume 18, Issue 7, 2022

Published on: 07 February, 2022

Page: [735 - 756] Pages: 22

DOI: 10.2174/1573406418666211220124119

Price: $65


Mannich bases identified by Professor Carl Mannich have been the most extensively explored scaffolds for more than 100 years now. The versatile biological roles that they play have promoted their applications in many clinical conditions. The present review highlights the application of Mannich bases as cytotoxic agents, categorizing them into synthetic, semisynthetic, and prodrugs classes, and gives an exhaustive account of the work reported in the last two decades. The methods of synthesis of these cytotoxic agents, their anti-cancer potential in various cell lines, and promising leads for future drug development have also been discussed. Structure-activity relationships, along with the targets on which these cytotoxic Mannich bases act, have been included as well.

Keywords: Mannich bases, cytotoxicity, structure activity relationship, aminomethylation, n-mannich bases, o-mannich bases, prodrugs.

Next »
Graphical Abstract
Mannich, C.; Krösche, W. About a condensation product of formaldehyde, ammonia and antipyrine. Arch. Pharm. (Weinheim), 1912, 250(1), 647-667.
Roman, G. Mannich bases in medicinal chemistry and drug design. Eur. J. Med. Chem., 2015, 89, 743-816.
[] [PMID: 25462280]
Bala, S.; Sharma, N.; Kajal, A.; Kamboj, S.; Saini, V. Mannich bases: An important pharmacophore in present scenario. Int. J. Med. Chem., 2014, 2014, 191072.
[] [PMID: 25478226]
Dembic, Z. Antitumor drugs and their targets. Molecules, 2020, 25(23), E5776.
[] [PMID: 33297561]
Bhilare, N.V.; Auti, P.B.; Marulkar, V.S.; Pise, V.J. Diverse thiophenes as scaffolds in anti-cancer drug development: A concise review. Mini Rev. Med. Chem., 2021, 21(2), 217-232.
[] [PMID: 33267760]
Aeluri, R.; Alla, M.; Polepalli, S.; Jain, N. Synthesis and antiproliferative activity of imidazo[1,2-a]pyrimidine Mannich bases. Eur. J. Med. Chem., 2015, 100, 18-23.
[] [PMID: 26067381]
Bajaj, S.; Roy, P.P.; Singh, J. Synthesis, thymidine phosphorylase inhibitory and computational study of novel 1,3,4-oxadiazole-2-thione derivatives as potential anticancer agents. Comput. Biol. Chem., 2018, 76, 151-160.
[] [PMID: 30015176]
Chen, J.; Lou, J.; Liu, T.; Wu, R.; Dong, X.; He, Q.; Yang, B.; Hu, Y. Synthesis and in-vitro antitumor activities of some mannich bases of 9-alkyl-1,2,3,4-tetrahydrocarbazole-1-ones. Arch. Pharm. (Weinheim), 2009, 342(3), 165-172.
[] [PMID: 19212985]
da Silva, G.B.; Neves, A.P.; Vargas, M.D.; Marinho-Filho, J.D.B.; Costa-Lotufo, L.V. New insights into 3-(aminomethyl)naphthoquinones: Evaluation of cytotoxicity, electrochemical behavior and search for structure-activity correlation. Bioorg. Med. Chem. Lett., 2016, 26(15), 3537-3542.
[] [PMID: 27363939]
Dimmock, J.R.; Kumar, P.; Nazarali, A.J.; Motaganahalli, N.L.; Kowalchuk, T.P.; Beazely, M.A.; Wilson Quail, J.; Oloo, E.O.; Allen, T.M.; Szydlowski, J.; DeClercq, E.; Balzarini, J. Cytotoxic 2,6-bis(arylidene)cyclohexanones and related compounds. Eur. J. Med. Chem., 2000, 35(11), 967-977.
[] [PMID: 11137225]
Dimmock, J.R.; Jha, A.; Kumar, P.; Zello, G.A.; Quail, J.W.; Oloo, E.O.; Oucharek, J.J.; Pasha, M.K.; Seitz, D.; Sharma, R.K.; Allen, T.M.; Santos, C.L.; Manavathu, E.K.; De Clercq, E.; Balzarini, J.; Stables, J.P. Cytotoxic 1,4-bis(2-oxo-1-cycloalkylmethylene)benzenes and re-lated compounds. Eur. J. Med. Chem., 2002, 37(1), 35-44.
[] [PMID: 11841873]
Dimmock, J.R.; Padmanilayam, M.P.; Das, U.; Zello, G.A.; Sharma, R.K.; Shrivastav, A.; Selvakumar, P.; Pasha, M.K.; Nienaber, K.H.; Lee, J.S.; Allen, T.M.; Santos, C.L.; Balzarini, J.; De Clercq, E. Cytotoxic mannich bases of 1-arylidene-2-tetralones. J. Enzyme Inhib. Med. Chem., 2003, 18(4), 313-324.
[] [PMID: 14567546]
Fu, Y.; Yang, Y.; Zhou, S.; Liu, Y.; Yuan, Y.; Li, S.; Li, C. Ciprofloxacin containing Mannich base and its copper complex induce anti-tumor activity via different mechanism of action. Int. J. Oncol., 2014, 45(5), 2092-2100.
[] [PMID: 25174498]
Karakaya, G.; Ercan, A.; Oncul, S.; Aytemir, M.D. Synthesis and cytotoxic evaluation of Kojic acid derivatives with inhibitory activity on melanogenesis in human melanoma cells. Anticancer. Agents Med. Chem., 2018, 18(15), 2137-2148.
[] [PMID: 29607787]
Thipparapu, G.; Ajumeera, R.; Venkatesan, V. Novel dihydropyrimidine derivatives as potential HDAC inhibitors: In silico study. Silico Pharmacol., 2017, 5(1), 1-9.
[] [PMID: 29085767]
Kucukoglu, K.; Gul, M.; Atalay, M.; Mete, E.; Kazaz, C.; Hanninen, O.; Gul, H.I. Synthesis of some Mannich bases with dimethylamine and their hydrazones and evaluation of their cytotoxicity against Jurkat cells. Arzneimittelforschung, 2011, 61(6), 366-371.
[] [PMID: 21827048]
Gul, M.; Mete, E.; Atalay, M.; Arik, M.; Gul, H.I. Cytotoxicity of 1-aryl-3-buthylamino-1-propanone hydrochlorides against Jurkat and L6 cells. Arzneimittelforschung, 2009, 59(7), 364-369.
[] [PMID: 19728564]
Gul, H.I.; Vepsalainen, J.; Gul, M.; Erciyas, E.; Hanninen, O. Cytotoxic activities of mono and bis Mannich bases derived from acetophe-none against Renca and Jurkat cells. Pharm. Acta Helv., 2000, 74(4), 393-398.
[] [PMID: 10812939]
Gul, H.I.; Gul, M.; Hänninen, O. Cytotoxic activities of some mono and bis Mannich bases derived from acetophenone in brine shrimp bioassay. Arzneimittelforschung, 2002, 52(11), 840-843.
[] [PMID: 12489256]
Gul, H.I.; Gul, M.; Erciyas, E. Syntheses and stability studies of some Mannich bases of acetophenones and evaluation of their cytotoxici-ty against Jurkat cells. Arzneimittelforschung, 2002, 52(8), 628-635.
[] [PMID: 12236052]
Gul, M.; Gul, H.I.; Das, U.; Hanninen, O. Biological evaluation and structure-activity relationships of bis-(3-aryl-3-oxo-propyl)-methylamine hydrochlorides and 4-aryl-3-arylcarbonyl-1-methyl-4-piperidinol hydrochlorides as potential cytotoxic agents and their al-kylating ability towards cellular glutathione in human leukemic T cells. Arzneimittelforschung, 2005, 55(6), 332-337.
[] [PMID: 16032973]
Gul, H.I.; Yerdelen, K.O.; Gul, M.; Das, U.; Pandit, B.; Li, P.K.; Secen, H.; Sahin, F. Synthesis of 4′-hydroxy-3′-piperidinomethylchalcone derivatives and their cytotoxicity against PC-3 cell lines. Arch. Pharm., 2007, 340(4), 195-201.
[] [PMID: 17351963]
Kandeel, M.M.; Abdou, N.A.; Kadry, H.H.; El-masry, R.M. Synthesis and in vitro antitumor activity of some new Mannich bases. Int. J. Chemtech Res., 2014, 5(1), 401-408.
Ivanova, Y.; Momekov, G.; Petrov, O.; Karaivanova, M.; Kalcheva, V. Cytotoxic Mannich bases of 6-(3-aryl-2-propenoyl)-2(3H)-benzoxazolones. Eur. J. Med. Chem., 2007, 42(11-12), 1382-1387.
[] [PMID: 17459529]
Reddy, M.V.B.; Su, C.R.; Chiou, W.F.; Liu, Y.N.; Chen, R.Y.H.; Bastow, K.F.; Lee, K.H.; Wu, T.S. Design, synthesis, and biological eval-uation of Mannich bases of heterocyclic chalcone analogs as cytotoxic agents. Bioorg. Med. Chem., 2008, 16(15), 7358-7370.
[] [PMID: 18602831]
Yamali, C.; Gul, H.I.; Sakagami, H.; Supuran, C.T. Synthesis and bioactivities of halogen bearing phenolic chalcones and their corresponding bis Mannich bases. J. Enzyme Inhib. Med. Chem., 2016, 31(sup4), 125-131.
[] [PMID: 27594305]
Gul, H.I.; Tugrak, M.; Gul, M.; Mazlumoglu, S.; Sakagami, H.; Gulcin, I.; Supuran, C.T. New phenolic Mannich bases with piperazines and their bioactivities. Bioorg. Chem., 2019, 90, 103057.
[] [PMID: 31226471]
Tugrak, M.; Yamali, C.; Sakagami, H.; Gul, H.I. Synthesis of mono Mannich bases of 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one and evaluation of their cytotoxicities. J. Enzyme Inhib. Med. Chem., 2016, 31(5), 818-823.
[] [PMID: 26247355]
Tugrak, M.; Gul, H.I.; Bandow, K.; Sakagami, H.; Gulcin, I.; Ozkay, Y.; Supuran, C.T. Synthesis and biological evaluation of some new mono Mannich bases with piperazines as possible anticancer agents and carbonic anhydrase inhibitors. Bioorg. Chem., 2019, 90, 103095.
[] [PMID: 31288135]
Dutta Gupta, S.; Bommaka, M.K.; Mazaira, G.I.; Galigniana, M.D.; Subrahmanyam, C.V.S.; Gowrishankar, N.L.; Raghavendra, N.M. Mo-lecular docking study, synthesis and biological evaluation of Mannich bases as Hsp90 inhibitors. Int. J. Biol. Macromol., 2015, 80, 253-259.
[] [PMID: 26116388]
Hollósy, F.; Lóránd, T.; Örfi, L.; Erös, D.; Kéri, G.; Idei, M. Relationship between lipophilicity and antitumor activity of molecule library of Mannich ketones determined by high-performance liquid chromatography, clogP calculation and cytotoxicity test. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2002, 768(2), 361-368.
[] [PMID: 11888064]
Issa, S.; Walchshofer, N.; Kassab, I.; Termoss, H.; Chamat, S.; Geahchan, A.; Bouaziz, Z. Synthesis and antiproliferative activity of oxa-zinocarbazole and N,N-bis(carbazolylmethyl)amine derivatives. Eur. J. Med. Chem., 2010, 45(6), 2567-2577.
[] [PMID: 20236739]
Kumbhare Basehare, R.M.; Vijay Kumar, K.; Janaki Ramaiah, M.; Dadmal, T.; Pushpavalli, S.N.; Mukhopadhyay, D.; Divya, B.; Anjana Devi, T.; Kosurkar, U.; Pal-Bhadra, M. Synthesis and biological evaluation of novel Mannich bases of 2-arylimidazo[2,1-b]benzothiazoles as potential anti-cancer agents. Eur. J. Med. Chem., 2011, 46(9), 4258-4266.
[] [PMID: 21775028]
Shivarama Holla, B.; Veerendra, B.; Shivananda, M.K.; Poojary, B. Synthesis characterization and anticancer activity studies on some Mannich bases derived from 1,2,4-triazoles. Eur. J. Med. Chem., 2003, 38(7-8), 759-767.
[] [PMID: 12932907]
Megally Abdo, N.Y.; Kamel, M.M. Synthesis and anticancer evaluation of 1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-triazoles and Man-nich bases. Chem. Pharm. Bull. (Tokyo), 2015, 63(5), 369-376.
[] [PMID: 25948330]
Hu, G.; Wang, G.; Duan, N.; Wen, X.; Cao, T.; Xie, S.; Huang, W. Design, synthesis and antitumor activities of fluoroquinolone C-3 heter-ocycles (IV): S-triazole Schiff–Mannich bases derived from ofloxacin. Acta Pharm. Sin. B, 2012, 2(3), 312-317.
Milošev, M.Z. Jakovljevic K.; Joksovic M.D.; Stanojkovic T.; Matic I.Z.; Perovic M.; Tešic V.; Kanazir, S.; Mladenovic M.; Rodic M.V.; Leovac, V.M.; Trifunovic S.; Markovic V. Mannich bases of 1,2,4-triazole-3-thione containing adamantane moiety: Synthesis, preliminary anticancer evaluation, and molecular modeling studies. Chem. Biol. Drug Des., 2017, 89(6), 943-952.
[] [PMID: 27933733]
Popiolek, L Rzymowska, J.; Kosikowska, U.; Hordyjewska, A.; Wujec, M.; Malm, A. Synthesis, antiproliferative and antimicrobial ac-tivity of new Mannich bases bearing 1,2,4-triazole moiety. J. Enzyme Inhib. Med. Chem., 2014, 29(6), 786-795.
[] [PMID: 24506202]
Pape, V.F.S.; May, N.V.; Gál, G.T.; Szatmári, I.; Szeri, F.; Fülöp, F.; Szakács, G.; Enyedy, É.A. Impact of copper and iron binding proper-ties on the anticancer activity of 8-hydroxyquinoline derived Mannich bases. Dalton Trans., 2018, 47(47), 17032-17045.
[] [PMID: 30460942]
Shaw, A.Y.; Chang, C.Y.; Hsu, M.Y.; Lu, P.J.; Yang, C.N.; Chen, H.L.; Lo, C.W.; Shiau, C.W.; Chern, M.K. Synthesis and structure-activity relationship study of 8-hydroxyquinoline-derived Mannich bases as anticancer agents. Eur. J. Med. Chem., 2010, 45(7), 2860-2867.
[] [PMID: 20359788]
Narayana, P.; Pannala, R.; Bobbala, P.; Reddy, R. Synthesis, in vitro antiproliferative activity, antioxidant activity and molecular modeling studies of new carbazole Mannich bases. Med. Chem. Res., 2017, 26, 2243-2259.
Vedarethinam, V.; Dhanaraj, K.; Ilavenil, S.; Arasu, M.V.; Choi, K.C.; Al-Dhabi, N.A.; Srisesharam, S.; Lee, K.D.; Kim, H.; Dhanapal, T.; Sivanesan, R.; Choi, H.S.; Kim, Y.O. Antitumor effect of the Mannich base(1,3-bis-((3-Hydroxynaphthalen-2-yl)phenylmethyl)urea) on hepatocellular carcinoma. Molecules, 2016, 21(5), 1-15.
[] [PMID: 27187346]
Detsi, A.; Bouloumbasi, D.; Prousis, K.C.; Koufaki, M.; Athanasellis, G.; Melagraki, G.; Afantitis, A.; Igglessi-Markopoulou, O.; Konto-giorgis, C.; Hadjipavlou-Litina, D.J. Design and synthesis of novel quinolinone-3-aminoamides and their alpha-lipoic acid adducts as anti-oxidant and anti-inflammatory agents. J. Med. Chem., 2007, 50(10), 2450-2458.
[] [PMID: 17444626]
Kontogiorgis, C.; Hadjipavlou-Litina, D. Biological evaluation of several coumarin derivatives designed as possible anti-inflammatory/antioxidant agents. J. Enzyme Inhib. Med. Chem., 2003, 18(1), 63-69.
[] [PMID: 12751823]
Kassab, R.M.; Gomha, S.M.; Muhammad, Z.A.; El-Khouly, A.S. Synthesis, biological profile, and molecular docking of some new bis- imidazole fused templates and investigation of their cytotoxic potential as anti-tubercular and/or anticancer prototypes. Med. Chem., 2021, 17(8), 875-886.
[] [PMID: 33292124]
Bibi, S.; Wang, Y-B.; Tang, D-X.; Kamal, M.A.; Yu, H. Prospects for discovering the secondary metabolites of Cordyceps Sensu Lato by the integrated strategy. Med. Chem., 2021, 17(2), 97-120.
[] [PMID: 31880251]
Faisca Phillips, A.M.; Guedes da Silva, M.F.C.; Pombeiro, A.J.L. The stereoselective nitro-Mannich reaction in the synthesis of active pharmaceutical ingredients and other biologically active compounds. Front Chem., 2020, 8, 30.
[] [PMID: 32047742]
Ismail, M.I.; Mohamady, S.; Samir, N.; Abouzid, K.A.M. Design, synthesis, and biological evaluation of novel 7H-[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazine inhibitors as antitumor agents. ACS Omega, 2020, 5(32), 20170-20186.
[] [PMID: 32832771]
Morak-Miodawska, B.; Pluta, K.; Latocha, M.; Jelen M.; Kusmierz, D. Synthesis, anticancer activity, and apoptosis induction of novel 3,6-diazaphenothiazines. Molecules, 2019, 24(2), 1-10.
[] [PMID: 30642021]
Habtemariam, S. Recent advances in berberine inspired anticancer approaches: From drug combination to novel formulation technology and derivatization. Molecules, 2020, 25(6), E1426.
[] [PMID: 32245062]
Tahlan, S.; Kumar, S.; Ramasamy, K.; Lim, S.M.; Shah, S.A.A.; Mani, V.; Pathania, R.; Narasimhan, B. Design, synthesis and biological profile of heterocyclic benzimidazole analogues as prospective antimicrobial and antiproliferative agents. BMC Chem., 2019, 13(1), 50.
[] [PMID: 31384798]
Bhat, S.; Shim, J.S.; Zhang, F.; Chong, C.R.; Liu, J.O. Substituted oxines inhibit endothelial cell proliferation and angiogenesis. Org. Biomol. Chem., 2012, 10(15), 2979-2992.
[] [PMID: 22391578]
Abdelhafez, O.M.; Abedelatif, N.A.; Badria, F.A. DNA binding, antiviral activities and cytotoxicity of new furochromone and benzofuran derivatives. Arch. Pharm. Res., 2011, 34(10), 1623-1632.
[] [PMID: 22076762]
Chen, Y.; Cass, S.L.; Kutty, S.K.; Yee, E.M.H.; Chan, D.S.H.; Gardner, C.R.; Vittorio, O.; Pasquier, E.; Black, D.S.C.; Kumar, N. Synthe-sis, biological evaluation and structure-activity relationship studies of isoflavene based Mannich bases with potent anti-cancer activity. Bioorg. Med. Chem. Lett., 2015, 25(22), 5377-5383.
[] [PMID: 26432036]
Csuk, R.; Sczepek, R.; Siewert, B.; Nitsche, C. Cytotoxic betulin-derived hydroxypropargylamines trigger apoptosis. Bioorg. Med. Chem., 2013, 21(2), 425-435.
[] [PMID: 23245801]
Euzébio, F.P.G.; Santos, F.J.L.D.; Piló-Veloso, D.; Alcântara, A.F.C.; Ruiz, A.L.T.G.; Carvalho, J.E.; Foglio, M.A.; Ferreira-Alves, D.L.; Fátima, Ad. Synthesis, antiproliferative activity in cancer cells and theoretical studies of novel 6α,7β-dihydroxyvouacapan-17β-oic acid Mannich base derivatives. Bioorg. Med. Chem., 2010, 18(23), 8172-8177.
[] [PMID: 21041092]
Inci Gul, H.; Yamali, C.; Tugce Yasa, A.; Unluer, E.; Sakagami, H.; Tanc, M.; Supuran, C.T. Carbonic anhydrase inhibition and cytotoxici-ty studies of Mannich base derivatives of thymol. J. Enzyme Inhib. Med. Chem., 2016, 31(6), 1375-1380.
[] [PMID: 26850788]
Gyuris, M.; Hackler, L., Jr; Nagy, L.I.; Alföldi, R.; Rédei, E.; Marton, A.; Vellai, T.; Faragó, N.; Ózsvári, B.; Hetényi, A.; Tóth, G.K.; Sipos, P.; Kanizsai, I.; Puskás, L.G. Mannich curcuminoids as potent anticancer agents. Arch. Pharm. (Weinheim), 2017, 350(7), 1-22.
[] [PMID: 28547897]
Yerdelen, K.; Inci, H.; Sakagami, H.; Umemura, N. Synthesis and cytotoxic activities of a curcumin analogue and its bis- Mannich deriva-tives. Lett. Drug Des. Discov., 2015, 12(8), 643-649.
Ha, L.; Qian, Y.; Zhang, S.; Ju, X.; Sun, S.; Guo, H.; Wang, Q.; Li, K.; Fan, Q.; Zheng, Y.; Li, H. Synthesis and biological evaluation of Scutellaria flavone cyclaneaminol Mannich base derivatives as novel CDK1 inhibitors. Anticancer. Agents Med. Chem., 2016, 16(7), 914-924.
[] [PMID: 26411959]
Huczynski, A.; Rutkowski, J.; Borowicz, I.; Wietrzyk, J.; Maj, E.; Brzezinski, B. One-pot synthesis and cytotoxicity studies of new Man-nich base derivatives of polyether antibiotic-lasalocid acid. Bioorg. Med. Chem. Lett., 2013, 23(18), 5053-5056.
[] [PMID: 23932361]
Bhilare, N.V.; Dhaneshwar, S.S.; Mahadik, K.R. Amelioration of hepatotoxicity by biocleavable aminothiol chimeras of isoniazid: Design, synthesis, kinetics and pharmacological evaluation. World J. Hepatol., 2018, 10(7), 496-508.
[] [PMID: 30079136]
Bhilare, N.V.; Dhaneshwar, S.S.; Mahadik, K.R.; Dasgupta, A. Co-drug of isoniazid and sulfur containing antioxidant for attenuation of hepatotoxicity and treatment of tuberculosis. Drug Chem. Toxicol., 2020, 1-11.
[] [PMID: 32543916]
Bhilare, N.V.; Dhaneshwar, S.S.; Mahadik, K.R.; Dasgupta, A.; Zende, T.; Kapoor, S. Hepatoprotective bile acid co-drug of isoniazid: Synthesis, kinetics and investigation of antimycobacterial potential. Pharm. Chem. J., 2020, 54(7), 678-688.
Li, W.; Li, X.; Liu, M.; Wang, Q. Synthesis and antiproliferative activity of thioxoflavones Mannich base derivatives. Arch. Pharm. (Weinheim), 2017, 350(7), 1-7.
[] [PMID: 28605048]
Nguyen, V.S.; Shi, L.; Luan, F.Q.; Wang, Q.A. Synthesis of kaempferide Mannich base derivatives and their antiproliferative activity on three human cancer cell lines. Acta Biochim. Pol., 2015, 62(3), 547-552.
[] [PMID: 26345098]
Mahal, K.; Ahmad, A.; Schmitt, F.; Lockhauserbäumer, J.; Starz, K.; Pradhan, R.; Padhye, S.; Sarkar, F.H.; Koko, W.S.; Schobert, R.; Ers-feld, K.; Biersack, B. Improved anticancer and antiparasitic activity of new lawsone Mannich bases. Eur. J. Med. Chem., 2017, 126, 421-431.
[] [PMID: 27912173]
Nariya, P.; Falguni, S.; Hitarthi, V.; Ranjitsinh, D.; Sonal, T. Synthesis and characterization of Mannich bases of Lawsone and their anti-cancer activity. Synth. Commun., 2020, 50(11), 1724-1735.
Neves, A.P.; da Silva, G.B.; Vargas, M.D.; Pinheiro, C.B. Visentin, Ldo.C.; Filho, J.D.B.M.; Araújo, A.J.; Costa-Lotufo, L.V.; Pessoa, C.; de Moraes, M.O. Novel platinum(II) complexes of 3-(aminomethyl)naphthoquinone Mannich bases: Synthesis, crystal structure and cyto-toxic activities. Dalton Trans., 2010, 39(42), 10203-10216.
[] [PMID: 20871881]
Neves, A.P.; Pereira, M.X.G.; Peterson, E.J.; Kipping, R.; Vargas, M.D.; Silva, F.P., Jr; Carneiro, J.W.M.; Farrell, N.P. Exploring the DNA binding/cleavage, cellular accumulation and topoisomerase inhibition of 2-hydroxy-3-(aminomethyl)-1,4-naphthoquinone Mannich bases and their platinum(II) complexes. J. Inorg. Biochem., 2013, 119, 54-64.
[] [PMID: 23186648]
Mistry, B.; Patel, R.V.; Keum, Y.S.; Kim, D.H. Synthesis of N-Mannich bases of berberine linking piperazine moieties revealing anticancer and antioxidant effects. Saudi J. Biol. Sci., 2017, 24(1), 36-44.
[] [PMID: 28053569]
Mistry, B.M.; Shin, H-S.; Keum, Y-S.; Pandurangan, M.; Kim, D.H.; Moon, S.H.; Kadam, A.A.; Shinde, S.K.; Patel, R.V. Synthesis and evaluation of antioxidant and cytotoxicity of the N-Mannich base of berberine bearing benzothiazole moieties. Anticancer. Agents Med. Chem., 2017, 17(12), 1652-1660.
[] [PMID: 28699489]
Xu, T.; Zheng, Z.; Guo, Y.; Bai, L.P. Semisynthesis of novel magnolol-based Mannich base derivatives that suppress cancer cells via inducing autophagy. Eur. J. Med. Chem., 2020, 205, 112663.
[] [PMID: 32791403]
Liu, C.; Dong, L.; Wang, S.; Wang, Q. Synthesis and antiproliferative activity of pterostilbene and 3′-methoxy pterostilbene Mannich base derivatives against Hela cells. Mol. Divers., 2015, 19(4), 737-743.
[] [PMID: 26162533]
Poorvashree, J.; Suneela, D. Novel drug delivery of dual acting prodrugs of hydroxychloroquine with aryl acetic acid NSAIDs: Design, kinetics and pharmacological study. Drug Deliv. Transl. Res., 2017, 7(5), 709-730.
[] [PMID: 28828678]
Gaudana, R.; Parenky, A.; Vaishya, R.; Samanta, S.K.; Mitra, A.K. Development and characterization of nanoparticulate formulation of a water soluble prodrug of dexamethasone by HIP complexation. J. Microencapsul., 2011, 28(1), 10-20.
[] [PMID: 20939702]
Mao, Y.; Zhang, Y.; Luo, Z.; Zhan, R.; Xu, H.; Chen, W.; Huang, H. Synthesis, biological evaluation and low-toxic formulation develop-ment of glycosylated paclitaxel prodrugs. Molecules, 2018, 23(12), E3211.
[] [PMID: 30563132]
Su, H.; Zhang, P.; Cheetham, A.G.; Koo, J.M.; Lin, R.; Masood, A.; Schiapparelli, P.; Quiñones-Hinojosa, A.; Cui, H. Supramolecular crafting of self-assembling camptothecin prodrugs with enhanced efficacy against primary cancer cells. Theranostics, 2016, 6(7), 1065-1074.
[] [PMID: 27217839]
Müller, C.E. Prodrug approaches for enhancing the bioavailability of drugs with low solubility. Chem. Biodivers., 2009, 6(11), 2071-2083.
[] [PMID: 19937841]
Stella, V.J.; Nti-Addae, K.W. Prodrug strategies to overcome poor water solubility. Adv. Drug Deliv. Rev., 2007, 59(7), 677-694.
[] [PMID: 17628203]
Kumar, D.; Kumar, M.; Saravanan, C.; Singh, S.K. Curcumin: A potential candidate for matrix metalloproteinase inhibitors. Expert Opin. Ther. Targets, 2012, 16(10), 959-972.
[] [PMID: 22913284]
Marinelli, L.; Fornasari, E.; Eusepi, P.; Ciulla, M.; Genovese, S.; Epifano, F.; Fiorito, S.; Turkez, H.; Örtücü, S.; Mingoia, M.; Simoni, S.; Pugnaloni, A.; Di Stefano, A.; Cacciatore, I. Carvacrol prodrugs as novel antimicrobial agents. Eur. J. Med. Chem., 2019, 178, 515-529.
[] [PMID: 31207463]
Sanches, B.M.A.; Ferreira, E.I. Is prodrug design an approach to increase water solubility? Int. J. Pharm., 2019, 568, 118498.
[] [PMID: 31301465]
Anuruddha, C.; Jagdale, S.C.; Preeti, G. Amino acid conjugation: An approach to enhance aqueous solubility and permeability of poorly water soluble drug ritonavir. J. Drug Deliv. Ther., 2019, 9(3), 252-256.
Zimmermann, S.C.; Tichý, T.; Vávra, J.; Dash, R.P.; Slusher, C.E.; Gadiano, A.J.; Wu, Y. Jancarík, A.; Tenora, L.; Monincová, L.; Prchalová, E.; Riggins, G.J.; Majer, P.; Slusher, B.S.; Rais, R. N-substituted prodrugs of mebendazole provide improved aqueous solubility and oral bioavailability in mice and dogs. J. Med. Chem., 2018, 61(9), 3918-3929.
[] [PMID: 29648826]
Piplani, M.; Rajak, H.; Sharma, P.C. Synthesis and characterization of N-Mannich based prodrugs of ciprofloxacin and norfloxacin: In vitro anthelmintic and cytotoxic evaluation. J. Adv. Res., 2017, 8(4), 463-470.
[] [PMID: 28721301]
D’Souza, A.J.M.; Topp, E.M. Release from polymeric prodrugs: linkages and their degradation. J. Pharm. Sci., 2004, 93(8), 1962-1979.
[] [PMID: 15236447]
Greenwald, R.B.; Choe, Y.H.; Conover, C.D.; Shum, K.; Wu, D.; Royzen, M. Drug delivery systems based on trimethyl lock lactonization: Poly(ethylene glycol) prodrugs of amino-containing compounds. J. Med. Chem., 2000, 43(3), 475-487.
[] [PMID: 10669575]
Haag, R.; Kratz, F. Polymer therapeutics: Concepts and applications. Angew. Chem. Int. Ed., 2006, 45(8), 1198-1215.
[] [PMID: 16444775]
Hoste, K.; De Winne, K.; Schacht, E. Polymeric prodrugs. Int. J. Pharm., 2004, 277(1-2), 119-131.
[] [PMID: 15158975]
Li, C.; Wallace, S. Polymer-drug conjugates: Recent development in clinical oncology. Adv. Drug Deliv. Rev., 2008, 60(8), 886-898.
[] [PMID: 18374448]
Shen, W. Chen, Haijiao; Wu, M.; Zhang, T.; Zhu, L.; Zhao, Y. Synthesis, cytotoxicity, anti-migration and anti-invasion activity of diphyl-lin heterocyclic derivatives. Med. Chem., 2020, 18(1), 122-129.
[] [PMID: 33349219]
Zhao, Y.J.; Wei, W.; Su, Z.G.; Ma, G.H. Poly (ethylene glycol) prodrug for anthracyclines via N-Mannich base linker: Design, synthesis and biological evaluation. Int. J. Pharm., 2009, 379(1), 90-99.
[] [PMID: 19540322]
Aytemir, M.; Ozcelik, B.; Orhan, I.E.; Karakaya, G.; Senol, F.S. Kojic acid-derived Mannich bases with biological effect. U.S. Patent US20170197946A1, 2018.
Keana, J.F.; Westberg, P.; Curd, J.; Lalani, A.S. Mannich base Noxide drugs. U.S. Patent US US8410075B2, 2013.
Van Der Westhuizen, J.H.; Nor Eljaleel, A.E.M.; Bonnet, S.L.; Wilhelm-Mouton, A. Aminoalkyl substituted chalcones and analogues and derivatives thereof. World patent WO2011151789A2, 2011.
Aytemir, M.; Ercan, A.; Karakaya, G.; Öncül, S. Anti-cancer and anti tyrosinase activities of kojic acid derived compounds. World Patent WO2019194769, 2019.
Murugan, M.; Rajamohan, R.; Anitha, A.; Praveena, A.; Sabari, C.L.; Anbarasi, K.; Senthil, S.; Rajesh, P. Improvement of in-vitro cytotoxicity on breast cancer cell lines by the molecular encapsulation of amodiaquine with 2-hydroxypropyl-beta-cyclodextrin. Indian Patent IN202041034716, 2020.
Dimmock, J.R.; Manavathu, E.K. Mannich bases of conjugated styryl ketones. U.S. patent US 6,017,933, 2000.
Moon, M.W.; Morozowich, W.; Gao, P.; Tang, P.C. Mannich base prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives. U.S. Patent US 6,710,067, 2004.
Koch, T.; Coleman, M.; Cogan, P.; Burke, P.; Post, G.; Burkhart, D.; McKenzie, A.; Jackson, K.; Kalet, B. inventors; University of Colorado Boulder. Targeted drug-formaldehyde conjugates and methods of making and using the same. U.S. Patent application US 10/570,471, 2007.
Dimmock, J.R.; Das, U. Antineoplastic compounds. U.S. Patent US 7,582,655, 2009.

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy