Synthesis and Biological Activity of Some Aminothiazole Derivatives as Antileishmanial Agents

Author(s): Zahra Rezaei*, Bahador Sarkari, Soghra Khabnadideh, Mahbobeh Farjami, Mahsa Mehrjou, Atefeh Yazdi, Elham Riazimontazer, Mohammad Fararouei

Journal Name: Anti-Infective Agents
Anti-Infective Agents in Medicinal Chemistry

Volume 18 , Issue 2 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Leishmaniasis is a major health problem which is caused by the protozoan parasite of the genus Leishmania. Cutaneous leishmaniasis is one type of leishmaniasis and selflimited in most of the cases. However, when the lesions come with scars, they make a deep lifelong stigma. Despite being WHO's research priority, the optimum treatment for this disease has not been found yet. The current study aimed to synthesize and assess the activity of some new aminothiazole compounds against Leishmania major-induced cutaneous leishmaniasis in BALB/c mice.

Methods: Eight new aminothiazole derivatives were synthesized and their chemical structures were characterized by spectral data 1H-NMR spectroscopy, Mass spectrophotometry and elemental analysis. L. major parasites were inoculated into the tail base of BALB/c mice and the induced lesions were treated every other day with three different doses of the synthesized compounds against meglumine antimoniate as the drug reference for two weeks. Size of the lesions was observed for three weeks and the collected data were analyzed by SPSS software. Also, these compounds are docked into the active site of 14- α-demethylase as the targets in the treatment of leishmaniasis.

Results: Among the synthesized aminothiazole derivatives, compounds 1, 2, 3, 4, and 7 had good leishmanicidal effects. Docking binding energies showed that the synthesized compounds could act as inhibitors for 14- α-demethylase.

Conclusion: Among the synthesized compounds, compound 3, (N-((4-chlorophenyl)(phenyl) methyl)thiazol-2-amine) was the most promising one which deserves future studies for the treatment of leishmaniasis.

Keywords: Aminothiazole, cutaneous leishmaniasis, in vivo, 14-α-Demethylase, 1H-NMR spectroscopy, L. major parasites.

[1]
Desjeux, P. Leishmaniasis: current situation and new perspectives. Comp. Immunol. Microbiol. Infect. Dis., 2004, 27(5), 305-318.
[http://dx.doi.org/10.1016/j.cimid.2004.03.004] [PMID: 15225981]
[2]
Sarkari, B.; Ahmadpour, N.B.; Motazedian, M.H.; Mirjalali, H.; Akhoundi, M.; Mohebali, M.; Hajjaran, H. Inter-and intraspecific variations of Leishmania strains isolated from patients with cutaneous and visceral leishmaniases in Fars Province, South of Iran. Iran. J. Med. Sci., 2016, 41(3), 209-216.
[PMID: 27217605]
[3]
Sarkari, B.; Hatam, G.; Ghatee, M. Epidemiological features of visceral leishmaniasis in fars province, southern iran. Iran. J. Public Health, 2012, 41(4), 94-99.
[PMID: 23113170]
[4]
Sarkari, B.; Naraki, T.; Ghatee, M.A.; Abdolahi Khabisi, S.; Davami, M.H. Visceral leishmaniasis in Southwestern Iran: A retrospective clinico-hematological analysis of 380 consecutive hospitalized cases (1999-2014). PLoS One, 2016, 11(3)e0150406
[http://dx.doi.org/10.1371/journal.pone.0150406] [PMID: 26942443]
[5]
Ouellette, M.; Drummelsmith, J.; Papadopoulou, B. Leishmaniasis: drugs in the clinic, resistance and new developments. Drug Resist. Updat., 2004, 7(4-5), 257-266.
[http://dx.doi.org/10.1016/j.drup.2004.07.002] [PMID: 15533763]
[6]
Murray, H.W. Clinical and experimental advances in treatment of visceral leishmaniasis. Antimicrob. Agents Chemother., 2001, 45(8), 2185-2197.
[http://dx.doi.org/10.1128/AAC.45.8.2185-2197.2001] [PMID: 11451673]
[7]
Pourmohammadi, B.; Motazedian, M.H.; Handjani, F.; Hatam, G.H.; Habibi, S.; Sarkari, B. Glucantime efficacy in the treatment of zoonotic cutaneous leishmaniasis. Southeast Asian J. Trop. Med. Public Health, 2011, 42(3), 502-508.
[PMID: 21706927]
[8]
Sundar, S.; Chatterjee, M. Visceral leishmaniasis - current therapeutic modalities. Indian J. Med. Res., 2006, 123(3), 345-352.
[PMID: 16778315]
[9]
Alrajhi, A.A.; Ibrahim, E.A.; De Vol, E.B.; Khairat, M.; Faris, R.M.; Maguire, J.H. Fluconazole for the treatment of cutaneous leishmaniasis caused by Leishmania major. N. Engl. J. Med., 2002, 346(12), 891-895.
[http://dx.doi.org/10.1056/NEJMoa011882] [PMID: 11907288]
[10]
Croft, S.L.; Sundar, S.; Fairlamb, A.H. Drug resistance in leishmaniasis. Clin. Microbiol. Rev., 2006, 19(1), 111-126.
[http://dx.doi.org/10.1128/CMR.19.1.111-126.2006] [PMID: 16418526]
[11]
Consigli, J.; Danielo, C.; Gallerano, V.; Papa, M.; Guidi, A. Cutaneous leishmaniasis: successful treatment with itraconazole. Int. J. Dermatol., 2006, 45(1), 46-49.
[http://dx.doi.org/10.1111/j.1365-4632.2004.02429.x] [PMID: 16426375]
[12]
Ferreira, S.B.; Costa, M.S.; Boechat, N.; Bezerra, R.J.; Genestra, M.S.; Canto-Cavalheiro, M.M.; Kover, W.B.; Ferreira, V.F. Synthesis and evaluation of new difluoromethyl azoles as antileishmanial agents. Eur. J. Med. Chem., 2007, 42(11-12), 1388-1395.
[http://dx.doi.org/10.1016/j.ejmech.2007.02.020] [PMID: 17445951]
[13]
Amnerkar, N.D.; Bhongade, B.A.; Bhusari, K.P. Synthesis and biological evaluation of some 4-(6-substituted-1, 3-benzothiazol-2-yl) amino-1, 3-thiazole-2-amines and their Schiff bases. Arab. J. Chem., 2015, 8(4), 545-552.
[http://dx.doi.org/10.1016/j.arabjc.2014.11.034]
[14]
Prajapati, A.K.; Modi, V.P. Synthesis and biological activity of n-5-(4-methylphenyl) diazenyl-4-phenyl-1, 3-thiazol-2-yl benzamide derivatives. Quim. Nova, 2011, 34(5), 771-774.
[15]
Wagner, S.J.; Skripchenko, A.; Salata, J.; O’Sullivan, A.M.; Cardo, L.J. Inactivation of Leishmania donovani infantum and Trypanosoma cruzi in red cell suspensions with thiazole orange. Transfusion, 2008, 48(7), 1363-1367.
[http://dx.doi.org/10.1111/j.1537-2995.2008.01712.x] [PMID: 18422841]
[16]
Rezaei, Z.; Khabnadideh, S.; Pakshir, K.; Hossaini, Z.; Amiri, F.; Assadpour, E. Design, synthesis, and antifungal activity of triazole and benzotriazole derivatives. Eur. J. Med. Chem., 2009, 44(7), 3064-3067.
[http://dx.doi.org/10.1016/j.ejmech.2008.07.012] [PMID: 18760508]
[17]
Emami, S.; Tavangar, P.; Keighobadi, M. An overview of azoles targeting sterol 14α-demethylase for antileishmanial therapy. Eur. J. Med. Chem., 2017, 135, 241-259.
[http://dx.doi.org/10.1016/j.ejmech.2017.04.044] [PMID: 28456033]
[18]
Sarkari, B.; Sattari, H.; Moein, M.R.; Tamadon, A.M.; Rad, R.S.; Asgari, Q. Effect of topical gel prepared with hydroalcoholic extract of Echinacea purpurea on treatment of Leishmania major-induced cutaneous leishmaniasis in BALB/C mice. J. Pharm. Negat. Results, 2016, 7(1), 12.
[http://dx.doi.org/10.4103/0976-9234.177054]
[19]
Nakayama, H.; Loiseau, P.M.; Bories, C.; Torres de Ortiz, S.; Schinini, A.; Serna, E.; Rojas de Arias, A.; Fakhfakh, M.A.; Franck, X.; Figadère, B.; Hocquemiller, R.; Fournet, A. Efficacy of orally administered 2-substituted quinolines in experimental murine cutaneous and visceral leishmaniases. Antimicrob. Agents Chemother., 2005, 49(12), 4950-4956.
[http://dx.doi.org/10.1128/AAC.49.12.4950-4956.2005] [PMID: 16304157]
[20]
Fournet, A.; Ferreira, M.E.; Rojas De Arias, A.; Torres De Ortiz, S.; Fuentes, S.; Nakayama, H.; Schinini, A.; Hocquemiller, R. In vivo efficacy of oral and intralesional administration of 2-substituted quinolines in experimental treatment of new world cutaneous leishmaniasis caused by Leishmania amazonensis. Antimicrob. Agents Chemother., 1996, 40(11), 2447-2451.
[http://dx.doi.org/10.1128/AAC.40.11.2447] [PMID: 8913444]
[21]
Fereidoonnezhad, M.; Faghih, Z.; Mojaddami, A.; Sakhteman, A.; Rezaei, Z. A Comparative Docking Studies of Dichloroacetate Analogues on Four Isozymes of Pyruvate Dehydrogenase Kinase in Humans. Indian Journal of Pharmaceutical Education and Research, 2016, 50(2), s32-s38.
[22]
Davami, M.H.; Motazedian, M.H.; Sarkari, B. The changing profile of cutaneous leishmaniasis in a focus of the disease in Jahrom district, southern Iran. Ann. Trop. Med. Parasitol., 2010, 104(5), 377-382.
[http://dx.doi.org/10.1179/136485910X12786389891083] [PMID: 20819305]
[23]
Azizi, K.; Badzohreh, A.; Sarkari, B.; Fakoorziba, M.R.; Kalantari, M.; Moemenbellah-Fard, M.D.; Ali-Akbarpour, M. Nested polymerase chain reaction and sequence- based detection of leishmania infection of sand flies in recently emerged endemic focus of zoonotic cutaneous leishmaniasis, southern iran. Iran. J. Med. Sci., 2013, 38(2)(Suppl.), 156-162.
[PMID: 24031105]
[24]
Berman, J.D.; Gallalee, J.V. In vitro antileishmanial activity of inhibitors of steroid biosynthesis and combinations of antileishmanial agents. J. Parasitol., 1987, 73(3), 671-673.
[http://dx.doi.org/10.2307/3282158] [PMID: 3037057]
[25]
Berman, J.D. Activity of imidazoles against Leishmania tropica in human macrophage cultures. Am. J. Trop. Med. Hyg., 1981, 30(3), 566-569.
[http://dx.doi.org/10.4269/ajtmh.1981.30.566] [PMID: 6266261]
[26]
Hart, D.T.; Lauwers, W.J.; Willemsens, G.; Vanden Bossche, H.; Opperdoes, F.R. Perturbation of sterol biosynthesis by itraconazole and ketoconazole in Leishmania mexicana mexicana infected macrophages. Mol. Biochem. Parasitol., 1989, 33(2), 123-134.
[http://dx.doi.org/10.1016/0166-6851(89)90026-1] [PMID: 2542790]
[27]
Navin, T.R.; Arana, B.A.; Arana, F.E.; Berman, J.D.; Chajón, J.F. Placebo-controlled clinical trial of sodium stibogluconate (Pentostam) versus ketoconazole for treating cutaneous leishmaniasis in Guatemala. J. Infect. Dis., 1992, 165(3), 528-534.
[http://dx.doi.org/10.1093/infdis/165.3.528] [PMID: 1311351]
[28]
Saenz, R.E.; Paz, H.; Berman, J.D. Efficacy of ketoconazole against Leishmania braziliensis panamensis cutaneous leishmaniasis. Am. J. Med., 1990, 89(2), 147-155.
[http://dx.doi.org/10.1016/0002-9343(90)90292-L] [PMID: 2166429]
[29]
Momeni, A.Z.; Jalayer, T.; Emamjomeh, M.; Bashardost, N.; Ghassemi, R.L.; Meghdadi, M.; Javadi, A.; Aminjavaheri, M. Treatment of cutaneous leishmaniasis with itraconazole. Randomized double-blind study. Arch. Dermatol., 1996, 132(7), 784-786.
[http://dx.doi.org/10.1001/archderm.1996.03890310070009] [PMID: 8678570]
[30]
Palumbo, E. Treatment strategies for mucocutaneous leishmaniasis. J. Glob. Infect. Dis., 2010, 2(2), 147-150.
[http://dx.doi.org/10.4103/0974-777X.62879] [PMID: 20606970]
[31]
Siddiqui, M.; Ai-Mofadhi, A.; Ai-Reshaid, A.; Ai-Rakban, A.; Ai-Jarba, A.; Kahtani, H.; Abdul-Aziz, A.; Al-Johani, H. Treatment of cutaneous leishmaniasis with itraconazole. J. Dermatolog. Treat., 1998, 9(4), 235-238.
[http://dx.doi.org/10.3109/09546639809160701]
[32]
Hargrove, T.Y.; Wawrzak, Z.; Liu, J.; Nes, W.D.; Waterman, M.R.; Lepesheva, G.I. Substrate preferences and catalytic parameters determined by structural characteristics of sterol 14α-demethylase (CYP51) from Leishmania infantum. J. Biol. Chem., 2011, 286(30), 26838-26848.
[http://dx.doi.org/10.1074/jbc.M111.237099] [PMID: 21632531]
[33]
Das, D.; Sikdar, P.; Bairagi, M. Recent developments of 2-aminothiazoles in medicinal chemistry. Eur. J. Med. Chem., 2016, 109, 89-98.
[http://dx.doi.org/10.1016/j.ejmech.2015.12.022] [PMID: 26771245]
[34]
Ghaemmaghami, S.; May, B.C.; Renslo, A.R.; Prusiner, S.B. Discovery of 2-aminothiazoles as potent antiprion compounds. J. Virol., 2010, 84(7), 3408-3412.
[http://dx.doi.org/10.1128/JVI.02145-09] [PMID: 20032192]
[35]
de Toledo, J.S.; Junior, P.E.; Manfrim, V.; Pinzan, C.F.; de Araujo, A.S.; Cruz, A.K.; Emery, F.S. Synthesis, cytotoxicity and in vitro antileishmanial activity of naphthothiazoles. Chem. Biol. Drug Des., 2013, 81(6), 749-756.
[http://dx.doi.org/10.1111/cbdd.12123] [PMID: 23421616]
[36]
Poorrajab, F.; Ardestani, S.K.; Emami, S.; Behrouzi-Fardmoghadam, M.; Shafiee, A.; Foroumadi, A. Nitroimidazolyl-1,3,4-thiadiazole-based anti-leishmanial agents: synthesis and in vitro biological evaluation. Eur. J. Med. Chem., 2009, 44(4), 1758-1762.
[http://dx.doi.org/10.1016/j.ejmech.2008.03.039] [PMID: 18485538]
[37]
Pourrajab, F.; Forouzannia, S.K.; Tabatabaee, S.A. Novel immunomodulatory function of 1,3,4-thiadiazole derivatives with leishmanicidal activity. J. Antimicrob. Chemother., 2012, 67(8), 1968-1978.
[http://dx.doi.org/10.1093/jac/dks144] [PMID: 22581907]
[38]
Borelli, C.; Schaller, M.; Niewerth, M.; Nocker, K.; Baasner, B.; Berg, D.; Tiemann, R.; Tietjen, K.; Fugmann, B.; Lang-Fugmann, S.; Korting, H.C. Modes of action of the new arylguanidine abafungin beyond interference with ergosterol biosynthesis and in vitro activity against medically important fungi. Chemotherapy, 2008, 54(4), 245-259.
[http://dx.doi.org/10.1159/000142334] [PMID: 18587237]
[39]
Rezaei, Z.; Khabnadideh, S.; Zomorodian, K.; Pakshir, K.; Kashi, G.; Sanagoei, N.; Gholami, S. Design, synthesis and antifungal activity of some new imidazole and triazole derivatives. Arch. Pharm. (Weinheim), 2011, 344(10), 658-665.
[http://dx.doi.org/10.1002/ardp.201000357] [PMID: 21984016]
[40]
Scarim, C.B.; Jornada, D.H.; Machado, M.G.M.; Ferreira, C.M.R.; Dos Santos, J.L.; Chung, M.C. Thiazole, thio and semicarbazone derivatives against tropical infective diseases: Chagas disease, human African trypanosomiasis (HAT), leishmaniasis, and malaria. Eur. J. Med. Chem., 2019, 162, 378-395.
[http://dx.doi.org/10.1016/j.ejmech.2018.11.013] [PMID: 30453246]
[41]
Papadopoulou, M.V.; Bloomer, W.D.; Rosenzweig, H.S.; Wilkinson, S.R.; Szular, J.; Kaiser, M. Antitrypanosomal activity of 5-nitro-2-aminothiazole-based compounds. Eur. J. Med. Chem., 2016, 117, 179-186.
[http://dx.doi.org/10.1016/j.ejmech.2016.04.010] [PMID: 27092415]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 18
ISSUE: 2
Year: 2020
Page: [178 - 189]
Pages: 12
DOI: 10.2174/2211352517666190527112955

Article Metrics

PDF: 17
HTML: 1