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Medicinal Chemistry

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

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Research Article

Synthesis and In vitro Efficacy of Tetracyclic Benzothiazepines Against Blood-Stage Plasmodium falciparum and Liver-Stage P. berghei

Author(s): Clare E. Gutteridge*, Brett W. Sadowski, Stephen M. Hughes, J. Alan Friedlander, Alicia D. Gaidry, Michael C. Baxter, Matthew B. Smith, Leighton G. Rodrigo, Michael T. O'Neil, Lucia Gerena, Patricia J. Lee, Ramadas Sathunuru and Montip Gettayacamin

Volume 19, Issue 5, 2023

Published on: 21 October, 2022

Page: [478 - 484] Pages: 7

DOI: 10.2174/1573406418666220820112324

Price: $65

Abstract

Objective: A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize the potency of this chemical class against drug-resistant strains of the malaria parasite.

Methods: Tetracyclic benzothiazepines bearing structural modification at seven distinct positions within the structure were synthesized in Knoevenagel condensation reactions followed by sequential intermolecular thio-Michael and then intramolecular imine formation reactions. Following purification and chemical characterization, the novel compounds were tested for in vitro efficacy against blood-stage P. falciparum and liver-stage P. berghei and also for in vivo efficacy against P. berghei.

Results: Benzothiazepines bearing structural modification at the sulfur atom and at the three carbocycles within the molecule were successfully synthesized. The majority of analogs inhibited bloodstage P. falciparum with submicromolar IC50 values. The potency of an 8-methoxy-substituted analog 12 exceeded that of chloroquine in all three P. falciparum strains tested. The parent benzothiazepine 1 possessed liver-stage activity, inhibiting P. berghei sporozoites infecting HepG2 cells with an IC50 of 106.4 nM and an IC90 of 408.9 nM, but failed to enhance the longevity of P. berghei infected mice compared to the controls. Compounds displayed modest toxicity toward HepG2 cells and were tolerated by mice at the highest dose tested, 640 mg/kg/dose once daily for three days.

Conclusion: The tetracyclic benzothiazepine described, which inhibits P. berghei infected hepatic cells with an IC50 of 106.4 nM, would appear to warrant further investigation. Optimization of ADME properties may be required since the most active analogs are probably excessively lipophilic.

Keywords: benzothiazepines, benzoindenothiazepines, drug resistance, malaria, Plasmodium falciparum, structure activity relationship

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[1]
World Health Organization, World Malaria Report. 2021. 2021. Available from: who.int/teams/global-malaria-programme/reports/ world-malaria-report-2021 (Accessed on Mar 01, 2022).
[2]
Sá, J.M.; Chong, J.L.; Wellems, T.E. Malaria drug resistance: New observations and developments. Essays Biochem., 2011, 51, 137-160.
[http://dx.doi.org/10.1042/bse0510137] [PMID: 22023447]
[3]
Maqbool, M.; Dar, M.A.; Rasool, S.; Khan, M. Curious case of drug resistant malaria and artemisinin compounds in the modern era. J. Appl. Pharm. Sci. Res., 2019, 2(2), 1-4.
[http://dx.doi.org/10.31069/japsr.v2i2.1]
[4]
The World Health Organization Guidelines for malaria. Available from:. who.int/publications/i/item/guidelines-for-malaria(Accessed on Mar 01, 2022).
[5]
Noedl, H.; Se, Y.; Schaecher, K.; Smith, B.L.; Socheat, D.; Fukuda, M.M. Evidence of artemisinin-resistant malaria in western Cambodia. N. Engl. J. Med., 2008, 359(24), 2619-2620.
[http://dx.doi.org/10.1056/NEJMc0805011] [PMID: 19064625]
[6]
Wells, T.N.C.; Hooft van Huijsduijnen, R.; Van Voorhis, W.C. Malaria medicines: A glass half full? Nat. Rev. Drug Discov., 2015, 14(6), 424-442.
[http://dx.doi.org/10.1038/nrd4573] [PMID: 26000721]
[7]
Delves, M.; Plouffe, D.; Scheurer, C.; Meister, S.; Wittlin, S.; Winzeler, E.A.; Sinden, R.E.; Leroy, D. The activities of current antimalarial drugs on the life cycle stages of Plasmodium: A comparative study with human and rodent parasites. PLoS Med., 2012, 9(2)e1001169
[http://dx.doi.org/10.1371/journal.pmed.1001169] [PMID: 22363211]
[8]
Chaffman, M.; Brogden, R.N. Diltiazem. A review of its pharmacological properties and therapeutic efficacy. Drugs, 1985, 29(5), 387-454.
[http://dx.doi.org/10.2165/00003495-198529050-00001] [PMID: 3891302]
[9]
Dong, C.K.; Urgaonkar, S.; Cortese, J.F.; Gamo, F.J.; Garcia-Bustos, J.F.; Lafuente, M.J.; Patel, V.; Ross, L.; Coleman, B.I.; Derbyshire, E.R.; Clish, C.B.; Serrano, A.E.; Cromwell, M.; Barker, R.H., Jr; Dvorin, J.D.; Duraisingh, M.T.; Wirth, D.F.; Clardy, J.; Mazitschek, R. Identification and validation of tetracyclic benzothiazepines as Plasmodium falciparum cytochrome bc1 inhibitors. Chem. Biol., 2011, 18(12), 1602-1610.
[http://dx.doi.org/10.1016/j.chembiol.2011.09.016] [PMID: 22195562]
[10]
Fry, M.; Pudney, M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4′-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem. Pharmacol., 1992, 43(7), 1545-1553.
[http://dx.doi.org/10.1016/0006-2952(92)90213-3] [PMID: 1314606]
[11]
Goodman, C.D.; Siregar, J.E.; Mollard, V.; Vega-Rodríguez, J.; Syafruddin, D.; Matsuoka, H.; Matsuzaki, M.; Toyama, T.; Sturm, A.; Cozijnsen, A.; Jacobs-Lorena, M.; Kita, K.; Marzuki, S.; McFadden, G.I. Parasites resistant to the antimalarial atovaquone fail to transmit by mosquitoes. Science, 2016, 352(6283), 349-353.
[http://dx.doi.org/10.1126/science.aad9279] [PMID: 27081071]
[12]
Fetzer, C.; Korotkov, V.S.; Thänert, R.; Lee, K.M.; Neuenschwander, M.; von Kries, J.P.; Medina, E.; Sieber, S.A. A chemical disruptor of the CLPX chaperone complex attenuates the virulence of multidrug-resistant Staphylococcus aureus. Angew. Chem. Int. Ed. Engl., 2017, 56(49), 15746-15750.
[http://dx.doi.org/10.1002/anie.201708454] [PMID: 28906057]
[13]
Boyom, F.F.; Fokou, P.V.T.; Tchokouaha, L.R.Y.; Spangenberg, T.; Mfopa, A.N.; Kouipou, R.M.T.; Mbouna, C.J.; Donfack, V.F.; Zollo, P.H.A. Repurposing the open access malaria box to discover potent inhibitors of Toxoplasma gondii and Entamoeba histolytica. Antimicrob. Agents Chemother., 2014, 58(10), 5848-5854.
[http://dx.doi.org/10.1128/AAC.02541-14] [PMID: 25049259]
[14]
Crane, S. Inhibitors of polynucleotide repeat-associated RNA foci and uses thereof for treating diseases. Can. Pat. Appl. C.A. Patent, 2984073A1, 201904272019.
[15]
Krysin, M.Y.; Petrov, V.V.; Shikhaliev, K.S.; Gozhina, O.V.; Trefilova, I.N. New fused thiazepines, Izvestiya Vysshikh Uchebnykh Zavedenii. Khimiya i Khimicheskaya Tekhnologiya, 2003, 46, 12-14.
[16]
Gutteridge, C.E.; Sadowski, B.W.; Hughes, S.M.; Friedlander, J.A.; Rodrigo, L.G.; Baxter, M.C.; Lorei, N.C.; Harrell, J.; O’Neil, M.T. Synthesis of substituted benzothiazepine compounds with medicinal potential. Int. J. Org. Chem. (Irvine), 2020, 10(3), 123-134.
[http://dx.doi.org/10.4236/ijoc.2020.103009]
[17]
Cema, G.; Rotbergs, J.; Oskaja, V. Condensation of dicarboxylic acid anhydrides containing active methylene groups.VII. 5-Chloroind-1,3-dione and its derivatives. Latvijas PSR Zinātnu akadēmijas vēstis. Kimijas sērija 1968, 4, 466-470.
[18]
Cema, G.; Rotbergs, J.; Oskaja, V. 5-Methoxyind-1,3-dione. Latvijas PSR Zinātnu akadēmijas vēstis. Kimijas sērija 1967, 6, 717-722.
[19]
Lusis, V.; Muceniece, D.; Zandersons, A.; Mazeika, I.; Duburs, G. C- and N-alkylation of 4,5-dihydro-1H-indeno[1,2-b]pyridine derivatives. Khimiya Geterotsiklicheskikh Soedinenii, 1984, 3, 393-398.
[20]
Oskaja, V. Synthesis of 4,6-and 5,6-dimethoxyindane-1,3-diones. Latvijas PSR Zinātnu akadēmijas vēstis. Kimijas sērija 1971, 6, 730-734.
[21]
Hodson, S.J.; Bishop, M.J.; Speake, J.D.; Navas, F., III; Garrison, D.T.; Bigham, E.C.; Saussy, D.L., Jr; Liacos, J.A.; Irving, P.E.; Gobel, M.J.; Sherman, B.W. 2-(Anilinomethyl)imidazolines as α1 adrenergic receptor agonists: the discovery of α1a subtype selective 2′-alkylsulfonyl-substituted analogues. J. Med. Chem., 2002, 45(11), 2229-2239.
[http://dx.doi.org/10.1021/jm000542r] [PMID: 12014961]
[22]
Mathis, C.A.; Wang, Y.; Holt, D.P.; Huang, G.F.; Debnath, M.L.; Klunk, W.E. Synthesis and evaluation of 11C-labeled 6-substituted 2-arylbenzothiazoles as amyloid imaging agents. J. Med. Chem., 2003, 46(13), 2740-2754.
[http://dx.doi.org/10.1021/jm030026b] [PMID: 12801237]
[23]
Lévai, A. Oxazepines and Thiazepines, XXV: Chemical transformations of 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones. Arch. Pharm. (Weinheim), 1992, 325(11), 721-726.
[http://dx.doi.org/10.1002/ardp.19923251108]
[24]
Milner, E.; Gardner, S.; Moon, J.; Grauer, K.; Auschwitz, J.; Bathurst, I.; Caridha, D.; Gerena, L.; Gettayacamin, M.; Johnson, J.; Kozar, M.; Lee, P.; Leed, S.; Li, Q.; McCalmont, W.; Melendez, V.; Roncal, N.; Sciotti, R.; Smith, B.; Sousa, J.; Tungtaeng, A.; Wipf, P.; Dow, G. Structure-activity relationships of 4-position diamine quinoline methanols as intermittent preventative treatment (IPT) against Plasmodium falciparum. J. Med. Chem., 2011, 54(18), 6277-6285.
[http://dx.doi.org/10.1021/jm200647u] [PMID: 21854078]
[25]
Milhous, W.K.; Weatherly, N.F.; Bowdre, J.H.; Desjardins, R.E. In vitro activities of and mechanisms of resistance to antifol antimalarial drugs. Antimicrob. Agents Chemother., 1985, 27(4), 525-530.
[http://dx.doi.org/10.1128/AAC.27.4.525] [PMID: 3890727]
[26]
Johnson, J.D.; Dennull, R.A.; Gerena, L.; Lopez-Sanchez, M.; Roncal, N.E.; Waters, N.C. Assessment and continued validation of the malaria SYBR green I-based fluorescence assay for use in malaria drug screening. Antimicrob. Agents Chemother., 2007, 51(6), 1926-1933.
[http://dx.doi.org/10.1128/AAC.01607-06] [PMID: 17371812]
[27]
Hughes, L.M.; Lanteri, C.A.; O’Neil, M.T.; Johnson, J.D.; Gribble, G.W.; Trumpower, B.L. Design of anti-parasitic and anti-fungal hydroxy-naphthoquinones that are less susceptible to drug resistance. Mol. Biochem. Parasitol., 2011, 177(1), 12-19.
[http://dx.doi.org/10.1016/j.molbiopara.2011.01.002] [PMID: 21251932]
[28]
Sacci, J.B. Inhibition of liver-stage development assay. In: Malaria Methods and Protocols. Methods in Molecular Medicine; Doolan, D.L., Ed.; Humana Press: New Jersey, 2002; Vol. 72, pp. 517-520.
[29]
Jiang, S.; Zeng, Q.; Gettayacamin, M.; Tungtaeng, A.; Wannaying, S.; Lim, A.; Hansukjariya, P.; Okunji, C.O.; Zhu, S.; Fang, D. Antimalarial activities and therapeutic properties of febrifugine analogs. Antimicrob. Agents Chemother., 2005, 49(3), 1169-1176.
[http://dx.doi.org/10.1128/AAC.49.3.1169-1176.2005] [PMID: 15728920]
[30]
Puri, S.K.; Dutta, G.P. Quinoline esters as potential antimalarial drugs: Effect on relapses of Plasmodium cynomolgi infections in monkeys. Trans. R. Soc. Trop. Med. Hyg., 1990, 84(6), 759-760.
[http://dx.doi.org/10.1016/0035-9203(90)90066-N] [PMID: 2096498]
[31]
Fukuda, M.M.; Krudsood, S.; Mohamed, K.; Green, J.A.; Warrasak, S.; Noedl, H.; Euswas, A.; Ittiverakul, M.; Buathong, N.; Sriwichai, S.; Miller, R.S.; Ohrt, C. A randomized, double-blind, active-control trial to evaluate the efficacy and safety of a three day course of tafenoquine monotherapy for the treatment of Plasmodium vivax malaria. PLoS One, 2017, 12(11)e0187376
[http://dx.doi.org/10.1371/journal.pone.0187376] [PMID: 29121061]
[32]
Lacerda, M.V.G.; Llanos-Cuentas, A.; Krudsood, S.; Lon, C.; Saunders, D.L.; Mohammed, R.; Yilma, D.; Batista Pereira, D.; Espino, F.E.J.; Mia, R.Z.; Chuquiyauri, R.; Val, F.; Casapía, M.; Monteiro, W.M.; Brito, M.A.M.; Costa, M.R.F.; Buathong, N.; Noedl, H.; Diro, E.; Getie, S.; Wubie, K.M.; Abdissa, A.; Zeynudin, A.; Abebe, C.; Tada, M.S.; Brand, F.; Beck, H-P.; Angus, B.; Duparc, S.; Kleim, J-P.; Kellam, L.M.; Rousell, V.M.; Jones, S.W.; Hardaker, E.; Mohamed, K.; Clover, D.D.; Fletcher, K.; Breton, J.J.; Ugwuegbulam, C.O.; Green, J.A.; Koh, G.C.K.W. Single-dose tafenoquine to prevent relapse of Plasmodium vivax malaria. N. Engl. J. Med., 2019, 380(3), 215-228.
[http://dx.doi.org/10.1056/NEJMoa1710775] [PMID: 30650322]

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