Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

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

Research Article

Synthetic Dihydropyridines as Novel Antiacanthamoebic Agents

Author(s): Ayaz Anwar*, Ruqaiyyah Siddiqui, Abdul Hameed, Muhammad R. Shah and Naveed A. Khan

Volume 16, Issue 7, 2020

Page: [841 - 847] Pages: 7

DOI: 10.2174/1573406415666190722113412

Price: $65

Abstract

Background: Acanthamoeba is an opportunistic pathogen widely spread in the environment. Acanthamoeba causes excruciating keratitis which can lead to blindness. The lack of effective drugs and its ability to form highly resistant cyst are one of the foremost limitations against successful prognosis. Current treatment involves mixture of drugs at high doses but still recurrence of infection can occur due to ineffectiveness of drugs against the cyst form. Pyridine and its natural and synthetic derivatives are potential chemotherapeutic agents due to their diverse biological activities.

Objective: To study the antiamoebic effects of four novel synthetic dihydropyridine (DHP) compounds against Acanthamoeba castellanii belonging to the T4 genotype. Furthermore, to evaluate their activity against amoeba-mediated host cells cytopathogenicity as well as their cytotoxicity against human cells.

Methods: Dihydropyridines were synthesized by cyclic dimerization of alkylidene malononitrile derivatives. Four analogues of functionally diverse DHPs were tested against Acanthamoeba castellanii by using amoebicidal, encystation and excystation assays. Moreover, Lactate dehydrogenase assays were carried out to study cytopathogenicity and cytotoxicity against human cells.

Results: These compounds showed significant amoebicidal and cysticidal effects at 50 μM concentration, whereas, two of the DHP derivatives also significantly reduced Acanthamoebamediated host cell cytotoxicity. Moreover, these DHPs were found to have low cytotoxicity against human cells suggesting a good safety profile.

Conclusion: The results suggest that DHPs have potential against Acanthamoeba especially against the more resistant cyst stage and can be assessed further for drug development.

Keywords: Acanthamoeba, amoebicidal, cysticidal, dihydropyridine, synthesis, host cells cytotoxicity.

Next »
Graphical Abstract
[1]
Marciano-Cabral, F.; Cabral, G. Acanthamoeba spp. as agents of disease in humans. Clin. Microbiol. Rev., 2003, 16(2), 273-307.
[http://dx.doi.org/10.1128/CMR.16.2.273-307.2003] [PMID: 12692099]
[2]
Khan, N.A. Acanthamoeba: biology and increasing importance in human health. FEMS Microbiol. Rev., 2006, 30(4), 564-595.
[http://dx.doi.org/10.1111/j.1574-6976.2006.00023.x] [PMID: 16774587]
[3]
Dudley, R.; Jarroll, E.L.; Khan, N.A. Carbohydrate analysis of Acanthamoeba castellanii. Exp. Parasitol., 2009, 122(4), 338-343.
[http://dx.doi.org/10.1016/j.exppara.2009.04.009] [PMID: 19389397]
[4]
Lorenzo-Morales, J.; Martín-Navarro, C.M.; López-Arencibia, A.; Arnalich-Montiel, F.; Piñero, J.E.; Valladares, B. Acanthamoeba keratitis: an emerging disease gathering importance worldwide? Trends Parasitol., 2013, 29(4), 181-187.
[http://dx.doi.org/10.1016/j.pt.2013.01.006] [PMID: 23433689]
[5]
Knickelbein, J.E.; Kovarik, J.; Dhaliwal, D.K.; Chu, C.T. Acanthamoeba keratitis: a clinicopathologic case report and review of the literature. Hum. Pathol., 2013, 44(5), 918-922.
[http://dx.doi.org/10.1016/j.humpath.2012.10.007] [PMID: 23332929]
[6]
Lorenzo-Morales, J.; Khan, N.A.; Walochnik, J. An update on Acanthamoeba keratitis: diagnosis, pathogenesis and treatment. Parasite, 2015, 22, 10.
[http://dx.doi.org/10.1051/parasite/2015010] [PMID: 25687209]
[7]
Altaf, A.A.; Shahzad, A.; Gul, Z.; Rasool, N.; Badshah, A.; Lal, B.; Khan, E. A review on the medicinal importance of pyridine derivatives. J. Drug Design Med. Chem., 2015, 1, 1-11.
[8]
Chaubey, A.; Pandeya, S. Pyridine: a versatile nucleuse in pharmaceutical field. Asian J. Pharm. Clin. Res., 2011, 4, 5-8.
[9]
Abadi, A.H.; Ibrahim, T.M.; Abouzid, K.M.; Lehmann, J.; Tinsley, H.N.; Gary, B.D.; Piazza, G.A. Design, synthesis and biological evaluation of novel pyridine derivatives as anticancer agents and phosphodiesterase 3 inhibitors. Bioorg. Med. Chem., 2009, 17(16), 5974-5982.
[http://dx.doi.org/10.1016/j.bmc.2009.06.063] [PMID: 19628397]
[10]
Hameed, A.; Anwar, A.; Khan, K.M.; Malik, R.; Shahab, F.; Siddiq, S.; Basha, F.Z.; Choudhary, M.I. Urease inhibition and anticancer activity of novel polyfunctional 5, 6-dihydropyridine derivatives and their structure-activity relationship. Eur. J. Chem., 2013, 4, 49-52.
[http://dx.doi.org/10.5155/eurjchem.4.1.49-52.701]
[11]
Messerli, F.H.; Noll, G.; Lindholm, L.H.; Haller, H.; Ruilope, L.M.; Volpe, M. The role of dihydropyridine calcium channel blockers in the treatment of hypertension and cardiovascular disease–An update. Eur. Cardiovasc. Dis., 2006, 1, 1-6.
[12]
Hameed, A.; Anwar, A.; Yousaf, S.; Khan, K.M.; Basha, F.Z. Tetra-n-butylammonium fluoride-mediated dimerization of (α-methylbenzylidene) malononitriles to form polyfunctional 5, 6-dihydropyridines derivatives under solvent-free conditions. Eur. J. Chem., 2012, 3, 179-185.
[http://dx.doi.org/10.5155/eurjchem.3.2.179-185.562]
[13]
Anwar, A.; Hameed, A.; Perveen, S.; Uroos, M.; Choudhary, M.I.; Basha, F.Z. 1, 1-Diphenyl-2-picrylhydrazyl radical scavenging activity of novel dihydropyridine derivatives. Eur. J. Chem., 2014, 5, 189-191.
[http://dx.doi.org/10.5155/eurjchem.5.1.189-191.916]
[14]
Sissons, J.; Alsam, S.; Stins, M.; Rivas, A.O.; Morales, J.L.; Faull, J.; Khan, N.A. Use of in vitro assays to determine effects of human serum on biological characteristics of Acanthamoeba castellanii. J. Clin. Microbiol., 2006, 44(7), 2595-2600.
[http://dx.doi.org/10.1128/JCM.00144-06] [PMID: 16825391]
[15]
Lakhundi, S.; Khan, N.A.; Siddiqui, R. Inefficacy of marketed contact lens disinfection solutions against keratitis-causing Acanthamoeba castellanii belonging to the T4 genotype. Exp. Parasitol., 2014, 141, 122-128.
[http://dx.doi.org/10.1016/j.exppara.2014.03.018] [PMID: 24657584]
[16]
Sissons, J.; Kim, K.S.; Stins, M.; Jayasekera, S.; Alsam, S.; Khan, N.A. Acanthamoeba castellanii induces host cell death via a phosphatidylinositol 3-kinase-dependent mechanism. Infect. Immun., 2005, 73(5), 2704-2708.
[http://dx.doi.org/10.1128/IAI.73.5.2704-2708.2005] [PMID: 15845472]
[17]
Anwar, A.; Siddiqui, R.; Hussain, M.A.; Ahmed, D.; Shah, M.R.; Khan, N.A. Silver nanoparticle conjugation affects antiacanthamoebic activities of amphotericin B, nystatin, and fluconazole. Parasitol. Res., 2018, 117(1), 265-271.
[http://dx.doi.org/10.1007/s00436-017-5701-x] [PMID: 29218442]
[18]
Siddiqui, R.; Aqeel, Y.; Khan, N.A. The development of drugs against Acanthamoeba infections. Antimicrob. Agents Chemother., 2016, 60(11), 6441-6450.
[http://dx.doi.org/10.1128/AAC.00686-16] [PMID: 27600042]
[19]
Vanden Eynde, J.J.; Mayence, A. Synthesis and aromatization of Hantzsch 1, 4-dihydropyridines under microwave irradiation. An overview. Molecules, 2003, 8, 381-391.
[http://dx.doi.org/10.3390/80400381]
[20]
Anwar, A.; Khan, N.A.; Siddiqui, R. Combating Acanthamoeba spp. cysts: what are the options? Parasit. Vectors, 2018, 11(1), 26.
[http://dx.doi.org/10.1186/s13071-017-2572-z] [PMID: 29316961]
[21]
Niaz, H.; Kashtoh, H.; Khan, J.A.; Khan, A.; Wahab, A.T.; Alam, M.T.; Khan, K.M.; Perveen, S.; Choudhary, M.I. Synthesis of diethyl 4-substituted-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylates as a new series of inhibitors against yeast α-glucosidase. Eur. J. Med. Chem., 2015, 95, 199-209.
[http://dx.doi.org/10.1016/j.ejmech.2015.03.018] [PMID: 25817770]
[22]
Martin, A.E.; Montgomery, P.A. Acarbose: an alpha-glucosidase inhibitor. Am. J. Health Syst. Pharm., 1996, 53(19), 2277-2290.
[http://dx.doi.org/10.1093/ajhp/53.19.2277] [PMID: 8893066]
[23]
Kim, B.G.; Sobota, A.; Bitonti, A.J.; McCann, P.P.; Byers, T.J. Polyamine metabolism in Acanthamoeba: polyamine content and synthesis of ornithine, putrescine, and diaminopropane. J. Protozool., 1987, 34(3), 278-284.
[http://dx.doi.org/10.1111/j.1550-7408.1987.tb03175.x] [PMID: 3656216]
[24]
Baig, A.M.; Rana, Z.; Waliani, N.; Karim, S.; Rajabali, M. Evidence of human-like Ca2+ channels and effects of Ca2+ channel blockers in Acanthamoeba castellanii. Chem. Biol. Drug Des., 2019, 93(3), 351-363.
[http://dx.doi.org/10.1111/cbdd.13421] [PMID: 30362253]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy