Abstract
Background: Infections caused by helminth parasites are the main cause of economic losses in the livestock industry worldwide. The rapid resistance acquired by different parasites against commercially available drugs motivates the search, design, and development of new compounds capable of overcoming this situation. Previously, our group reported the novel hybrid valerolactam-fenbendazole (VALFBZ) compound with in vitro anthelmintic activity and good ex vivo parasite permeation.
Objective: This study aimed at optimizing the novel hybrid VAL-FBZ compound synthesis and scaling up to the multigram order necessary for in vivo assays.
Methods: For the hybrid VAL-FBZ synthesis, a convergent strategy was utilized. To obtain the benzimidazole core, widely available fenbendazole and L-Ornithine hydrochloride synthesis were used. The key step was the coupling reaction, for which an inexpensive coupling agent of the uronium salt family was used. Optimization was carried out by minimizing the risks and costs of upscaling at the multigram level.
Results: In the first stage, the precursors of Valerolactam and Benzimidazole cores were synthesized on a decagram scale to obtain better results than previous reports. Also, the coupling reaction was carried out using HBTU to obtain VAL-FBZ with above 99% HPLC purity, and an overall yield of 48%. The successful synthesis was carried out without performing chromatographic purification in any step to minimize a few risks for the operator.
Conclusion: Successfully, an efficient multigram and economic process is developed.
Keywords: Anthelmintic compounds, Resistance, Hybrids, Valerolactam-Benzimidazoles, Multigram synthesis, Scale-up
Graphical Abstract
[1]
Euzen, J.-P.; Trambouze, P.; Wauquier, J.-P. Scale-up methodology for chemical processes; Editions Technip: Paris, France, 1993.
[2]
Waller, P.J. From discovery to development: Current industry perspectives for the development of novel methods of helminth control in livestock. Vet. Parasitol., 2006, 139(1-3), 1-14.
[http://dx.doi.org/10.1016/j.vetpar.2006.02.036] [PMID: 16675128]
[http://dx.doi.org/10.1016/j.vetpar.2006.02.036] [PMID: 16675128]
[3]
Torres-Acosta, J.F.; Mendoza-de-Gives, P.; Aguilar-Caballero, A.J.; Cuéllar-Ordaz, J.A. Anthelmintic resistance in sheep farms: Update of the situation in the American continent. Vet. Parasitol., 2012, 189(1), 89-96.
[http://dx.doi.org/10.1016/j.vetpar.2012.03.037] [PMID: 22520233]
[http://dx.doi.org/10.1016/j.vetpar.2012.03.037] [PMID: 22520233]
[4]
Martin, R.J.; Wolstenholme, A.J.; Caffrey, C.R. Anthelmintics: From discovery to resistance II (San Diego, 2016). Int. J. Parasitol. Drugs Drug Resist., 2016, 6(3), 297-298.
[http://dx.doi.org/10.1016/j.ijpddr.2016.09.002] [PMID: 27814986]
[http://dx.doi.org/10.1016/j.ijpddr.2016.09.002] [PMID: 27814986]
[5]
Kotze, A.; Prichard, R. Anthelmintic resistance in Haemonchus contortus: History, mechanisms and diagnosis. Adv. Parasitol., 2016, 93, 397-428.
[6]
Lambert, S.M.; Nishi, S.M.; Mendonça, L.R.; da Silva Souza, B.M.P.; da Silva Julião, F.; da Silva Gusmão, P.; de Almeida, M.A.O. Genotypic profile of benzimidazole resistance associated with SNP F167Y and F200Y beta-tubulin gene in Brazilian populations of Haemonchus contortus of goats. Vet. Parasitol. Reg. Stud. Rep., 2017, 8, 28-34.
[http://dx.doi.org/10.1016/j.vprsr.2017.01.006] [PMID: 31014633]
[http://dx.doi.org/10.1016/j.vprsr.2017.01.006] [PMID: 31014633]
[7]
Nari, A.; Salles, J.; Gil, A.; Waller, P.J.; Hansen, J.W. The prevalence of anthelmintic resistance in nematode parasites of sheep in southern Latin America: Uruguay. Vet. Parasitol., 1996, 62(3-4), 213-222.
[http://dx.doi.org/10.1016/0304-4017(95)00908-6] [PMID: 8686167]
[http://dx.doi.org/10.1016/0304-4017(95)00908-6] [PMID: 8686167]
[8]
Mederos, A.; Carracelas, B.; Lara, S.; Pimentel, S.; Banchero, G. Situación actual de la resistencia a las drogas antihelmínticas en ovinos en Uruguay. Rev. INIA Urug., 2016, 44, 10-12.
[9]
Melian, M.E.; Munguía, A.B.; Faccio, R.; Palma, S.; Domínguez, L. The impact of solid dispersion on formulation, using confocal micro raman spectroscopy as tool to probe distribution of components. J. Pharm. Innov., 2018, 13(1), 58-68.
[http://dx.doi.org/10.1007/s12247-017-9306-9]
[http://dx.doi.org/10.1007/s12247-017-9306-9]
[10]
Kaplan, R.M. Drug resistance in nematodes of veterinary importance: A status report. Trends Parasitol., 2004, 20(10), 477-481.
[http://dx.doi.org/10.1016/j.pt.2004.08.001] [PMID: 15363441]
[http://dx.doi.org/10.1016/j.pt.2004.08.001] [PMID: 15363441]
[11]
Besier, B. New anthelmintics for livestock: The time is right. Trends Parasitol., 2007, 23(1), 21-24.
[http://dx.doi.org/10.1016/j.pt.2006.11.004] [PMID: 17118708]
[http://dx.doi.org/10.1016/j.pt.2006.11.004] [PMID: 17118708]
[12]
Munguía, B.; Michelena, M.; Melian, E.; Saldaña, J.; Ures, X.; Manta, E.; Domínguez, L. Development of novel valerolactam-benzimidazole hybrids anthelmintic derivatives: Diffusion and bio-transformation studies in helminth parasites. Exp. Parasitol., 2015, 153, 75-80.
[http://dx.doi.org/10.1016/j.exppara.2015.03.013] [PMID: 25816976]
[http://dx.doi.org/10.1016/j.exppara.2015.03.013] [PMID: 25816976]
[13]
Munguía, B.; Mendina, P.; Espinosa, R.; Lanz, A.; Saldaña, J.J.; Andina, M.; Ures, X.; López, A.; Manta, E.; Domínguez, L. Synthesis and anthelmintic evaluation of novel valerolactam-benzimidazole hybrids. Lett. Drug Des. Discov., 2013, 10(10), 1007-1014.
[http://dx.doi.org/10.2174/15701808113109990028]
[http://dx.doi.org/10.2174/15701808113109990028]
[14]
Mendina, P.; Munguía, B.; Espinosa, R.; Saldaña, J.; Domínguez, L.; Manta, E. Derivados de la 2-amino-δ-valerolactama y bencimidazoles que presentan actividad antiparasitaria y en particular antihelmíntica de amplio espectro. UY Patent, DNPI-n°14424, 2014, 2014, 14424.
[15]
Melian, M.E.; Paredes, A.; Munguía, B.; Colobbio, M.; Ramos, J.C.; Teixeira, R.; Manta, E.; Palma, S.; Faccio, R.; Domínguez, L. Nanocrystals of novel valerolactam-fenbendazole hybrid with improved in vitro dissolution performance. AAPS PharmSciTech, 2020, 21(237), 14424.
[http://dx.doi.org/10.1208/s12249-020-01777-y] [PMID: 32808055]
[http://dx.doi.org/10.1208/s12249-020-01777-y] [PMID: 32808055]
[16]
Hutchinson, I.S.; Matlin, S.A.; Mete, A. The synthesis and chemistry of 3-diazo-piperidin-2-one. Tetrahedron, 2002, 58(16), 3137-3143.
[http://dx.doi.org/10.1016/S0040-4020(02)00278-8]
[http://dx.doi.org/10.1016/S0040-4020(02)00278-8]
[17]
Ji, J.; Chen, C.; Cai, J.; Wang, X.; Zhang, K.; Shi, L.; Lv, H.; Zhang, X. Highly enantioselective synthesis of non-natural aliphatic α-amino acids via asymmetric hydrogenation. Org. Biomol. Chem., 2015, 13(28), 7624-7627.
[http://dx.doi.org/10.1039/C5OB01111F] [PMID: 26103461]
[http://dx.doi.org/10.1039/C5OB01111F] [PMID: 26103461]
[18]
Blade-Font, A. Facile synthesis of γ-, α-, and ε-lactams by cyclodehydration of ω-amino acids on alumina or silica gel. Tetrahedron Lett., 1980, 21(25), 2443-2446.
[http://dx.doi.org/10.1016/S0040-4039(00)93171-X]
[http://dx.doi.org/10.1016/S0040-4039(00)93171-X]
[19]
Pellegata, R.; Pinza, M.; Pifferi, G. An improved synthesis of γ-, δ-, and ε-Lactams. Synthesis, 1978, 1978(08), 614-616.
[http://dx.doi.org/10.1055/s-1978-24834]
[http://dx.doi.org/10.1055/s-1978-24834]
[20]
Phi, T.D.; Mai, H.D.T.; Tran, V.H.; Truong, B.N.; Tran, T.A.; Pham, V.C. Synthesis of bengamide E analogues and their cytotoxic activity. Tetrahedron Lett., 2017, 58(19), 1830-1833.
[http://dx.doi.org/10.1016/j.tetlet.2017.03.077]
[http://dx.doi.org/10.1016/j.tetlet.2017.03.077]
[21]
Gordon, S.; Costa, L.; Incerti, M.; Manta, E.; Saldaña, J.; Domínguez, L.; Mariezcurrena, R.; Suescun, L. Synthesis and in vitro anthelmintic activity against Nippostrongylus brasiliensis of new 2-amino-4-hydroxy-delta-valerolactam derivatives. Farmaco, 1997, 52(10), 603-608.
[PMID: 9580122]
[PMID: 9580122]
[22]
Reaction studies and HPLC´s analysis are provided in supplementary data. 2014. Available from: https://drive.google.com/file/d/1QgptOiPXc12KjxNt WbfekGS8BCYIPUoU/view?usp=sharing
[23]
Grillot, A-L.; Le Tiran, A.; Shannon, D.; Krueger, E.; Liao, Y.; O’Dowd, H.; Tang, Q.; Ronkin, S.; Wang, T.; Waal, N.; Li, P.; Lauffer, D.; Sizensky, E.; Tanoury, J.; Perola, E.; Grossman, T.H.; Doyle, T.; Hanzelka, B.; Jones, S.; Dixit, V.; Ewing, N.; Liao, S.; Boucher, B.; Jacobs, M.; Bennani, Y.; Charifson, P.S. Second-generation antibacterial benzimidazole ureas: Discovery of a preclinical candidate with reduced metabolic liability. J. Med. Chem., 2014, 57(21), 8792-8816.
[http://dx.doi.org/10.1021/jm500563g] [PMID: 25317480]
[http://dx.doi.org/10.1021/jm500563g] [PMID: 25317480]
[24]
Freidinger, R.M.; Perlow, D.S.; Veber, D.F. Protected lactam-bridged dipeptides for use as conformational constraints in peptides. J. Org. Chem., 1982, 47(1), 104-109.
[http://dx.doi.org/10.1021/jo00340a023]
[http://dx.doi.org/10.1021/jo00340a023]
[25]
Inoue, S.; Ikeda, J.-E.; Hirayama, N.; Tanaka, K.; Kanno, T. Preparation of acylaminoimidazole derivatives as therapeutic agents for neurological diseases. Patent WO2012014699, 2012.
[26]
Hasegawa, M.; Takada, M.; Washio, Y. Preparation of 2-aminopyrimidinones for inhibiting hYAK3 proteins. Patent WO2005076854, 2005.
[27]
Tehim, A.; Hopper, A.; Liu, R.; Kuester, E.; Dunn, R.F.; Renau, T.E. Preparation of 4-(substituted-phenyl)-2-pyrrolidinone derivatives as selective phosphodiesterase 4 inhibitors. Patent WO2004094375, 2004.
[28]
Cheung, M.; Harris, P.A.; Hasegawa, M.; Ida, S.; Kano, K.; Nishigaki, N.; Sato, H.; Veal, J.M.; Washio, Y.; West, R.I. Preparation of benzimidazoles as TIE-2 and/or VEGFR2 inhibitors. Patent WO2002044156, 2002.
[29]
Michardy, S.F.; Lowe, J.A. III Preparation of bicyclic [3.1.0] heteroaryl amides as type 1 glycine transport inhibitors. Patent WO2006106425, 2006.
[30]
Dhanak, D.; Knight, S.D. Preparation of thiazolones for use as PI3 kinase inhibitors. Patent WO2007103755, 2007.
[31]
Guertin, K.R. Isoindolin-1-one glucokinase activators, and their pharmaceutical compositions, preparation, and use in the treatment or prophylaxis of type II diabetes. Patent WO2002048106, 2002.
[32]
Beke, G.; Bozo, E.; Farkas, S.; Hornok, K.; Keseru, G.; Schmidt, E.; Szentirmay, E.; Vago, I.; Vastag, M. Preparation of phenylsulfamoyl benzamide derivatives as bradykinin antagonists. Patent WO2008050167, 2008.
[33]
Remarchuk, T.; St-Jean, F.; Carrera, D.; Savage, S.; Yajima, H.; Wong, B.; Babu, S.; Deese, A.; Stults, J.; Dong, M.W. Synthesis of Akt inhibitor ipatasertib. Part 2. Total synthesis and first kilogram scale-up. Org. Process Res. Dev., 2014, 18(12), 1652-1666.
[http://dx.doi.org/10.1021/op500270z]
[http://dx.doi.org/10.1021/op500270z]
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