Anti-Toxoplasma gondii activity of 5-oxo-hexahydroquinoline derivatives: synthesis, in vitro and in vivo evaluations, and molecular docking analysis

Mohammadsaeid Zahedi , Qasem Asgari, Fatemeh Badakhshan, Amirhossein Sakhteman, Sara Ranjbar, Mehdi Khoshneviszadeh

Abstract


Background and purpose: The aim of this study was to evaluate the in vitro and in vivo anti-Toxoplasma gondii (T. gondii) effect of 5-oxo-hexahydroquinoline compounds. Moreover, molecular docking study of the compounds into the active site of enoyl-acyl carrier protein reductase (ENR) as a necessary enzyme for the vitality of apicoplast was carried out.

Experimental approach: A number of 5-oxo-hexahydoquinoline derivatives (Z1-Z4) were synthesized. The T. gondii tachyzoites of RH strain were treated by different concentrations (1-64 μg/mL) of the compounds. The viability of the encountered parasites with compounds was assessed using flow cytometry and propidium iodide (PI) staining. Due to the high mortality effect of Z3 and Z4in vitro, their chemotherapy effect was assessed by inoculation of tachyzoites to four BALB/c mice groups (n = 5), followed by the gavage of various concentrations of the compounds to the mice. Molecular docking was done to study the binding affinity of the synthesized 5-oxo-hexahydroquinolines into ENR enzyme active site byusing AutoDock Vina® software. Docking was performed by a Lamarckian Genetic Algorithm with 100 runs.

Findings / Results: Flow cytometry assay results indicated compounds Z3 and Z4 had relevant mortality effect on parasite tachyzoites. Besides, in vivo experiments were also performed and a partial increase of mice longevity between control and experiment groups was recorded. Molecular docking of Z3 and Z4 in the binding site of ENR enzyme indicated that the compounds were well accommodated within the binding site. Therefore, it could be suggested that these compounds may exert their anti-T. gondii activity through the inhibition of the ENR enzyme.

Conclusion and implications: Compounds Z3 and Z4 are good leads in order to develop better anti-T. gondii agents as they demonstrated both in vitro and in vivo inhibitory effects on tachyzoites viability and infection. Further studies on altering the route of administration along with additional pharmacokinetics evaluations are needed to improve the anti-T. gondii impacts of 5-oxo-hexahydroquinoline compounds.


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References


Dunay IR, Gajurel K, Dhakal R, Liesenfeld O, Montoya JG. Treatment of toxoplasmosis: historical perspective, animal models, and current clinical practice. Clin Microbiol Rev. 2018;31(4):e00057-17,1-33.

DOI: 10.1128/CMR.00057-17.

Hoffmann S, Batz MB, Morris JG. Annual cost of illness and quality-adjusted life year losses in the United States due to 14 foodborne pathogens. J Food Prot. 2012;75(7):1292-1302.

DOI: 10.4315/0362-028X.JFP-11-417.

Weiss LM, Dubey JP. Toxoplasmosis: A history of clinical observations. . Int J Parasitol. 2009;39(8):895-901.

DOI: 10.1016/j.ijpara.2009.02.004.

Carme B, Demar M, Ajzenberg D, Dardé ML. Severe acquired toxoplasmosis caused by wild cycle of Toxoplasma gondii, French Guiana. Emerg Infect Dis. 2009;15(4):656-658.

DOI: 10.3201/eid1504.081306.

Khan A, Ajzenberg D, Mercier A, Demar M, Simon S, Darde ML, et al. Geographic separation of domestic and wild strains of Toxoplasma gondii in French Guiana correlates with a monomorphic version of chromosome1a. PLOS Neglect Trop Dis. 2014;8(9):e3182,1-12.

DOI: 10.1371/journal.pntd.0003182.

Freppel W, Ferguson DJ, Shapiro K, Dubey JP, Puech P-H, Dumètre A. Structure, composition, and roles of the Toxoplasma gondii oocyst and sporocyst walls. Cell Surf. 2019;5:100016-100026.

DOI: 10.1016/j.tcsw.2018.100016.

Dubey JP. The history and life cycle of Toxoplasma gondii. In: Weiss LM, Kim K, editors. The model Apicomplexan-perspectives and methods. 3th ed. New York: Academic Press; 2020. pp. 1-19.

DOI: 10.1016/C2011-0-07157-0.

Ramakrishnan C, Maier S, Walker RA, Rehrauer H, Joekel DE, Winiger RR, et al. An experimental genetically attenuated live vaccine to prevent transmission of Toxoplasma gondii by cats. Sci Rep. 2019;9(1):1474-1487.

DOI: 10.1038/s41598-018-37671-8.

Saraf P, Shwab EK, Dubey JP, Su C. On the determination of Toxoplasma gondii virulence in mice. Exp Parasitol. 2017;174:25-30.

DOI: 10.1016/j.exppara.2017.01.009.

Konstantinovic N, Guegan H, Stäjner T, Belaz S, Robert-Gangneux F. Treatment of toxoplasmosis: current options and future perspectives. Food Waterborne Parasitol. 2019;15:e00036,1-15.

DOI: 10.1016/j.fawpar.2019.e00036.

Murata Y, Sugi T, Weiss LM, Kato K. Identification of compounds that suppress Toxoplasma gondii tachyzoites and bradyzoites. PloS One. 2017;12(6):e0178203,1-14.

DOI: 10.1371/journal.pone.0178203

Kumari L, Mazumder A, Pandey D, Yar MS, Kumar R, Mazumder R, et al. Synthesis and biological potentials of quinoline analogues: A review of literature. Mini-Rev Org Chem. 2019;16:653-88.

DOI: 10.2174/1570193X16666190213105146

Ranjbar S, Edraki N, Firuzi O, Khoshneviszadeh M, Miri R. 5-Oxo-hexahydroquinoline: An attractive scaffold with diverse biological activities. Mol. Divers. 2019;23:471-508.

DOI: 10.1007/s11030-018-9886-4

Ranjbar S, Khonkarn R, Moreno A, Baubichon-Cortay H, Miri R, Khoshneviszadeh M, et al. 5-Oxo-hexahydroquinoline derivatives as modulators of P-gp, MRP1 and BCRP transporters to overcome multidrug resistance in cancer cells. Toxicol Appl Pharm. 2019;362:136-49.

DOI: 10.1016/j.taap.2018.10.025

Ranjbar S, Firuzi O, Edraki N, Shahraki O, Saso L, Khoshneviszadeh M, et al. Tetrahydroquinolinone derivatives as potent P-glycoprotein inhibitors: design, synthesis, biological evaluation and molecular docking analysis. MedChemComm. 2017;8:1919-33.

DOI: 10.1039/C7MD00178A

Kadri D, Crater AK, Lee H, Solomon VR, Ananvoranich S. The potential of quinoline derivatives for the treatment of Toxoplasma gondii infection. Exp Parasitol. 2014;145:135-144.

DOI: 10.1016/j.exppara.2014.08.008.

Brinster S, Lamberet G, Staels B, Trieu-Cuot P, Gruss A, Poyart C. Type II fatty acid synthesis is not a suitable antibiotic target for Gram-positive pathogens. Nature. 2009;458(7234):83-86.

DOI: 10.1038/nature07772.

Salas-Navarrete C, Hernández-Chávez G, Flores N, Martínez LM, Martinez A, Bolívar F, et al. Increasing pinosylvin production in Escherichia coli by reducing the expression level of the gene fabI-encoded enoyl-acyl carrier protein reductase. Electron J Biotechnol. 2018;33:11-16.

DOI: 10.1016/j.ejbt.2018.03.001.

Anquetin G, Greiner J, Vierling P. Quinolone-based drugs against Toxoplasma gondii and Plasmodium spp. Curr Drug Targets Infect Disord. 2005;5(3):227-245.

DOI: 10.2174/1568005054880172.

McLeod R, Muench SP, Rafferty JB, Kyle DE, Mui EJ, Kirisits MJ, et al. Triclosan inhibits the growth of Plasmodium falciparum and Toxoplasma gondii by inhibition of apicomplexan Fab I. Int J Parasitol. 2001;31(2):109-113.

DOI: 10.1016/s0020-7519(01)00111-4.

Radke JB, Burrows JN, Goldberg DE, Sibley LD. Evaluation of current and emerging antimalarial medicines for inhibition of Toxoplasma gondii growth in vitro. Int J Parasitol. 2001;31(2):109-113.

DOI: 10.1016/s0020-7519(01)00111-4.

Doggett JS, Nilsen A, Forquer I, Wegmann KW, Jones-Brando L, Yolken RH, et al. Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis. Proc Natl Acad Sci U S A. 2012;109(39):15936-15941.

DOI: 10.1073/pnas.1208069109.

Smith AT, Livingston MR, Mai A, Filetici P, Queener SF, Sullivan WJ. Quinoline derivative MC1626, a putative GCN5 histone acetyltransferase (HAT) inhibitor, exhibits HAT-independent activity against Toxoplasma gondii. Antimicrob Agents Chemother. 2007;51(3):1109-1111.

DOI: 10.1128/AAC.01256-06.

Akins CK, Panicker SE, Cunningham CL. Laboratory animals in research and teaching: Ethics, care, and methods: Am Psychol Assoc. 2005.

Asgari Q, Keshavarz H, Rezaeian M, Motazedian MH, Shojaee S, Mohebali M, et al. Direct effect of two naphthalene-sulfonyl-indole compounds on Toxoplasma gondii tachyzoite. J Parasitol Res. 2013;2013,1-8.

DOI: 10.1155/2013/716976.

Buntrock RE. ChemOffice Ultra 7.0. J Chem Inf Model Comput Sci. 2002;42(6):1505-1506.

DOI: 10.1021/ci025575p.

Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455-461.

DOI: 10.1002/jcc.21334.

Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and an empirical binding free energy function. J Comput Chem. 1998;19(14):1639-1662.

DOI: 10.1002/(SICI)1096.

Hegewald J, Gross U, Bohne W. Identification of dihydroorotate dehydrogenase as a relevant drug target for 1-hydroxyquinolones in Toxoplasma gondii. Mol Biochem Parasitol. 2013;190(1):6-15.

DOI: 10.1016/j.molbiopara.2013.05.008.

Barbosa BF, Gomes AO, Ferro EAV, Napolitano DR, Mineo JR, Silva NM. Enrofloxacin is able to control Toxoplasma gondii infection in both in vitro and in vivo experimental models. Vet Parasitol. 2012;187(1-2):44-52.

DOI: 10.1016/j.vetpar.2011.12.039.

da Silva RJ, Gomes AO, Franco PS, Pereira AS, Milian IC, Ribeiro M, et al. Enrofloxacin and toltrazuril are able to reduce Toxoplasma gondii growth in human BeWo trophoblastic cells and villous explants from human third trimester pregnancy. Front Cell Infect Microbiol. 2017;7:340-360.

DOI: 10.3389/fcimb.2017.00340.

Khan AA, Slifer TR, Araujo FG, Remington JS. Activity of gatifloxacin alone or in combination with pyrimethamine or gamma interferon against Toxoplasma gondii. Antimicrob Agents Chemother. 2001;45(1):48-51.

DOI: 10.1128/AAC.45.1.48-51.2001.

McPhillie M, Zhou Y, El Bissati K, Dubey J, Lorenzi H, Capper M, et al. New paradigms for understanding and step changes in treating active and chronic, persistent apicomplexan infections. S Sci Rep. 2016;6:29179-29202.

DOI: 10.1038/srep29179.

Burrows JN, Burlot E, Campo B, Cherbuin S, Jeanneret S, Leroy D, et al. Antimalarial drug discovery–the path towards eradication. Parasitol. 2014;141(1):128-139.

DOI: 10.1017/S0031182013000826.

Parsons JB, Frank MW, Subramanian C, Saenkham P, Rock CO. Metabolic basis for the differential susceptibility of Gram-positive pathogens to fatty acid synthesis inhibitors. Proc Natl Acad Sci U S A. 2011;108(37):15378-15383.

DOI: 10.1073/pnas.1109208108.

Yao J, Rock CO. How bacterial pathogens eat host lipids: implications for the development of fatty acid synthesis therapeutics. J J Biol Chem. 2015;290(10):5940-5946.

DOI: 10.1074/jbc.R114.636241.

Vaughan AM, O'Neill MT, Tarun AS, Camargo N, Phuong TM, Aly AS, et al. Type II fatty acid synthesis is essential only for malaria parasite late liver stage development. Cell Microbiol. 2009;11(3):506-520.

DOI: 10.1111/j.1462-5822.2008.01270.x.

Goodman C, McFadden G. Fatty acid biosynthesis as a drug target in apicomplexan parasites. Current drug targets. 2007;8:15-30.

Surolia N, Surolia A. Triclosan offers protection against blood stages of malaria by inhibiting enoyl-ACP reductase of Plasmodium falciparum. Nat Med. 2001;7(2):167-173.

DOI: 10.1038/84612.


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