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Synthesis of new quinazolin-2,4-diones as anti-Leishmania mexicana agents

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Abstract

The quinazolin-2,4-dione moiety is found in many compounds with important biological activities making it a target for its synthesis. In this work, a one-pot three-step synthesis of new quinazolin-2,4-diones from phthalic anhydrides and their activity against Leishmania mexicana are described. The new quinazolin-2,4-diones were isolated with yields in the range of 32–70 %. All compounds displayed lower cytotoxicity in RAW 264.7 macrophage over miltefosine. Compound 6,7-dichloro-3-phenylquinazoline-2,4(1H,3H)-dione (6e) displayed an attractive profile which includes anti-Leishmania mexicana activity (\(\hbox {IC}_{50} = 6.05\) \(\upmu \)M), much lower cytotoxic activity (\(\hbox {CC}_{50} = 111\) \(\upmu \)M) and a high selective index (\(\text {SI} = 18.35\)) proving to be superior to miltefosine.

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References

  1. Smith AL, Thomson CG, Leeson PD (1996) An efficient solid phase synthetic route to 1,3-disubstituted 2,4(1H,3H)-quinazolinediones suitable for combinatorial synthesis. Bioorg Med Chem Lett 6:1483–1486. doi:10.1016/s0960-894x(96)00253-3

    Article  CAS  Google Scholar 

  2. Brogden RN, Sorkin EM (1990) Ketanserin. Drugs 40:903–949. doi:10.2165/00003495-199040060-00010

    Article  CAS  PubMed  Google Scholar 

  3. Hayao S, Havera HJ, Strycker WG, Leipzig TJ, Kulp RA, Hartzler HE (1965) New sedative and hypotensive 3-substituted 2,4(1H,3H)-quinazolinediones. J Med Chem 8:807–811. doi:10.1021/jm00330a017

    Article  CAS  PubMed  Google Scholar 

  4. Hassan MA, Younes AMM, Taha MM, Abdel-Monsef A-BH (2011) Synthesis and reactions of 3-aminotetrachloroquinazolin-2,4-dione. Eur J Chem 2:514–518. doi:10.5155/eurjchem.2.4.514-518.479

    Article  CAS  Google Scholar 

  5. Hassan MA, Seleem MA, Younes AMM, Taha MM, Abdel-Monsef A-BH (2013) Synthesis and spectral characterization of some heterocyclic nitrogen compounds. Eur J Chem 4:121–123. doi:10.5155/eurjchem.4.2.121-123.740

    Article  CAS  Google Scholar 

  6. Choo HY, Kim M, Lee SK, Kim SW, Chung IK (2002) Solid-phase combinatorial synthesis and cytotoxicity of 3-aryl-2,4-quinazolinediones. Bioorg Med Chem 10:517–523. doi:10.1016/S0968-0896(01)00299-1

    Article  PubMed  Google Scholar 

  7. Li Z, Huang H, Sun H, Jiang H, Liu H (2008) Microwave-assisted efficient and convenient synthesis of 2,4(1H,3H)-quinazolinediones and 2-thioxoquinazolines. J Comb Chem 10:484–486. doi:10.1021/cc800040z

    Article  CAS  PubMed  Google Scholar 

  8. Yalysheva NZ, Granik VG (1984) Unexpected formation of 2,4-quinazolinedione in the reaction of \(\alpha \)-cyano-\(\beta \)-dimethylaminocrotonamide with ethyl anthranilate. Chem Heterocycl Compd 20:1186–1186. doi:10.1007/BF00503620

    Article  Google Scholar 

  9. Rayat S, Qian M, Glaser R (2005) Nitrosative cytosine deamination. An exploration of the chemistry emanating from deamination with pyrimidine ring-opening. Chem Res Toxicol 18:1211–1218. doi:10.1021/tx050082a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Gao J, He L-N, Miao C-X, Chanfreau S (2010) Chemical fixation of CO\(_2\): efficient synthesis of quinazoline-2,4(1H,3H)-diones catalyzed by guanidines under solvent-free conditions. Tetrahedron 66:4063–4067. doi:10.1016/j.tet.2010.04.011

    Article  CAS  Google Scholar 

  11. Willis MC, Snell RH, Fletcher AJ, Woodward RL (2006) Tandem palladium-catalyzed urea arylation-intramolecular ester amidation? Regioselective synthesis of 3-alkylated 2,4-quinazolinediones. Org Lett 8:5089–5091. doi:10.1021/ol062009x

    Article  CAS  PubMed  Google Scholar 

  12. Beylin V, Boyles DC, Curran TT, Macikenas D, Parlett Vrieze D (2007) The preparation of two, preclinical amino-quinazolinediones as antibacterial agents. Org Process Res Dev 11:441–449. doi:10.1021/op7000639

    Article  CAS  Google Scholar 

  13. Davidson JS (1984) The preparation of 5-(2-aminophenyl)-1,3,4-oxadiazole-2(3H)-one and its rearrangement to 3-amino-2,4(1H,3H)-quinazolinedione. Monatsh Chem Chem Mon 115:565–571. doi:10.1007/bf00799164

    Article  CAS  Google Scholar 

  14. Ryu C-K, Shin K-H, Seo J-H, Kim H-J (2002) 6-Arylamino-5,8-quinazolinediones as potent inhibitors of endothelium-dependent vasorelaxation. Eur J Med Chem 37:77–82. doi:10.1016/s0223-5234(01)01290-9

    Article  CAS  PubMed  Google Scholar 

  15. Havera HJ (1979) Derivatives of 1,3-disubstituted 2,4(1H,3H)-quinazolinediones as possible peripheral vasodilators or antihypertensive agents. J Med Chem 22:1548–1550. doi:10.1021/jm00198a024

    Article  CAS  PubMed  Google Scholar 

  16. Usifoh CO, Scriba GKE (2000) Synthesis and anticonvulsant activity of acetylenic quinazolinone derivatives. Arch Pharm 333:261–266. doi:10.1002/1521-4184(20008)333:8<261:aid-ardp261>3.0.co;2-o

  17. Lowe JA, Archer RL, Chapin DS, Cheng JB, Helweg D, Johnson JL, Koe BK, Lebel LA, Moore PF (1991) Structure–activity relationship of quinazolinedione inhibitors of calcium-independent phosphodiesterase. J Med Chem 34:624–628. doi:10.1021/jm00106a024

    Article  CAS  PubMed  Google Scholar 

  18. Fujimori H, Cobb DP (1965) Central nervous system depressant activity of Ma1337, 3-(3-(4-M-chlorophenyl-1-piperazyl)propyl)-2,4(1h,3h)quinazolinedione hydrochloride. J Pharmacol Exp Ther 148:151–157

    CAS  PubMed  Google Scholar 

  19. Tran TP, Ellsworth EL, Stier MA, Domagala JM, Hollis Showalter HD, Gracheck SJ, Shapiro MA, Joannides TE, Singh R (2004) Synthesis and structural–activity relationships of 3-hydroxyquinazoline-2,4-dione antibacterial agents. Bioorg Med Chem Lett 14:4405–4409. doi:10.1016/j.bmcl.2004.06.063

  20. Hassan MA, Younes AMM, Taha MM, Abdel-Monsef A (2012) Synthesis and reactions of 3-(2-chloromethyl-carbonylamino)tetrachloroquinazolin-2,4-dione. Org Chem Int 2012:1–4. doi:10.1155/2012/284947

  21. Ryu CK, Shim JY, Yi YJ, Choi IH, Chae MJ, Han JY, Jung OJ (2004) Synthesis and antifungal activity of 5,8-quinazolinedione derivatives modified at positions 6 and 7. Arch Pharmacal Res 27:990–996. doi:10.1007/BF02975419

    Article  CAS  Google Scholar 

  22. Elansary AK, Kadry HH, Ahmed EM, Sonousi ASM (2011) Design, synthesis, and biological activity of certain quinazolinedione derivatives as potent phosphodiestrase4 inhibitors. Med Chem Res 21:3557–3567. doi:10.1007/s00044-011-9892-x

    Article  Google Scholar 

  23. Kirincich SJ, Xiang J, Green N, Tam S, Yang HY, Shim J, Shen MWH, Clark JD, McKew JC (2009) Benzhydrylquinazolinediones: novel cytosolic phospholipase A2\(\alpha \) inhibitors with improved physicochemical properties. Bioorg Med Chem 17:4383–4405. doi:10.1016/j.bmc.2009.05.027

    Article  CAS  PubMed  Google Scholar 

  24. Lansdon EB, Liu Q, Leavitt SA, Balakrishnan M, Perry JK, Lancaster-Moyer C, Kutty N, Liu X, Squires NH, Watkins WJ, Kirschberg TA (2011) Structural and binding analysis of pyrimidinol carboxylic acid and N-hydroxy quinazolinedione HIV-1 RNase H inhibitors. Antimicrob Agents Chemother 55:2905–2915. doi:10.1128/aac.01594-10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Malik M, Marks KR, Mustaev A, Zhao X, Chavda K, Kerns RJ, Drlica K (2011) Fluoroquinolone and quinazolinedione activities against wild-type and gyrase mutant strains of Mycobacterium smegmatis. Antimicrob Agents Chemother 55:2335–2343. doi:10.1128/aac.00033-11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kakuta H, Tanatani A, Nagasawa K, Hashimoto Y (2003) Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1H,3H)-quinazolinedione skeleton. Chem Pharm Bull 51:1273–1282. doi:10.1248/cpb.51.1273

    Article  CAS  PubMed  Google Scholar 

  27. Ochoa-Diaz YO, Lopez-Moreno CY, Rendon-Maldonado JG, Lopez-Moreno HS (2012) Molecular diagnosis of Leishmania mexicana in a Cutaneous Leishmaniasis case in Sinaloa, Mexico. Vector-Borne Zoonotic Dis 12:78–80. doi:10.1089/vbz.2011.0688

    Article  PubMed  Google Scholar 

  28. Arguello-Garcia R, Cruz-Soto M, Romero-Montoya L, Ortega-Pierres G (2009) In vitro resistance to 5-nitroimidazoles and benzimidazoles in Giardia duodenalis: variability and variation in gene expression. Infect Genet Evol 9:1057–1064. doi:10.1016/j.meegid.2009.05.015

    Article  PubMed  Google Scholar 

  29. Navarrete-Vazquez G, Chavez-Silva F, Argotte-Ramos R, Rodriguez-Gutierrez Mdel C, Chan-Bacab MJ, Cedillo-Rivera R, Moo-Puc R, Hernandez-Nunez E (2011) Synthesis of benzologues of Nitazoxanide and Tizoxanide: a comparative study of their in vitro broad-spectrum antiprotozoal activity. Bioorg Med Chem Lett 21:3168–3171. doi:10.1016/j.bmcl.2011.02.100

    Article  CAS  PubMed  Google Scholar 

  30. Minodier P, Parola P (2007) Cutaneous leishmaniasis treatment. Travel Med Infect Dis 5:150–158. doi:10.1016/j.tmaid.2006.09.004

    Article  PubMed  Google Scholar 

  31. Sindermann H, Engel J (2006) Development of miltefosine as an oral treatment for leishmaniasis. Trans R Soc Trop Med Hyg 100:S17–S20. doi:10.1016/j.trstmh.2006.02.010

    Article  CAS  PubMed  Google Scholar 

  32. Sundar S, Jha TK, Thakur CP, Engel J, Sindermann H, Fischer C, Junge K, Bryceson A, Berman J (2002) Oral miltefosine for Indian visceral leishmaniasis. N Engl J Med 347:1739–1746. doi:10.1056/NEJMoa021556

    Article  CAS  PubMed  Google Scholar 

  33. Paris C, Loiseau PM, Bories C, Breard J (2004) Miltefosine induces apoptosis-like death in Leishmania donovani promastigotes. Antimicrob Agents Chemother 48:852–859. doi:10.1128/aac.48.3.852-859.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Soto J, Arana BA, Toledo J, Rizzo N, Vega JC, Diaz A, Luz M, Gutierrez P, Arboleda M, Berman JD, Junge K, Engel J, Sindermann H (2004) Miltefosine for new world Cutaneous Leishmaniasis. Clin Infect Dis 38:1266–1272. doi:10.1086/383321

  35. Torres-Gomez H, Hernandez-Nunez E, Leon-Rivera I, Guerrero-Alvarez J, Cedillo-Rivera R, Moo-Puc R, Argotte-Ramos R, Rodriguez-Gutierrez Mdel C, Chan-Bacab MJ, Navarrete-Vazquez G (2008) Design, synthesis and in vitro antiprotozoal activity of benzimidazole-pentamidine hybrids. Bioorg Med Chem Lett 18:3147–3151. doi:10.1016/j.bmcl.2008.05.009

    Article  CAS  PubMed  Google Scholar 

  36. Bolivar P, Cruz-Paredes C, Hernández LR, Juárez ZN, Sánchez-Arreola E, Av-Gay Y, Bach H (2011) Antimicrobial, anti-inflammatory, antiparasitic, and cytotoxic activities of Galium mexicanum. J Ethnopharmacol 137:141–147. doi:10.1016/j.jep.2011.04.069

    Article  CAS  PubMed  Google Scholar 

  37. Martin-Quintal Z, Moo-Puc R, Gonzalez-Salazar F, Chan-Bacab MJ, Torres-Tapia LW, Peraza-Sanchez SR (2009) In vitro activity of Tridax procumbens against promastigotes of Leishmania mexicana. J Ethnopharmacol 122:463–467. doi:10.1016/j.jep.2009.01.037

    Article  CAS  PubMed  Google Scholar 

  38. Sarmiento-Sánchez JI, Montes-Avila J, Ochoa-Terán A, Delgado-Vargas F, Wilson-Corral V, Díaz-Camacho SP, García-Páez F, Bastidas-Bastidas P (2014) Synthesis of 1\(H\)-benzoxazine-2,4-diones from heterocyclic anhydrides: evaluation of antioxidant and antimicrobial activities. Quim Nova 37:1297–1301. doi:10.5935/0100-4042.20140201

  39. Sarmiento-Sánchez JI, Ochoa-Terán A, Rivero IA (2014) Synthesis and antioxidant evaluation of enantiomerically pure bis-(1,2,3-triazolylmethyl)amino esters from modified\(\alpha \)-amino acids. Sci World J 2014:1–7. doi:10.1155/2014/264762

    Article  Google Scholar 

  40. Washburne SS, Peterson WR Jr, Berman DA (1972) Reaction of trimethylsilyl azide with anhydrides and imides. A new uracil synthesis via nitrogen insertion. J Org Chem 37:1738–1742. doi:10.1021/jo00976a015

    Article  CAS  PubMed  Google Scholar 

  41. Nakagawa A, Uno S, Makishima M, Miyachi H, Hashimoto Y (2008) Progesterone receptor antagonists with a 3-phenylquinazoline-2,4-dione/2-phenylisoquinoline-1,3-dione skeleton. Bioorg Med Chem 16:7046–7054. doi:10.1016/j.bmc.2008.05.016

  42. Papadopoulos EP, Torres CD (1982) Convenient preparation ofN-substituted 2-amino-4H-3, l-benzoxazin-4-ones and 3-substituted 2,4(1H,3H)-quinazolinediones. J Heterocycl Chem 19:269–272. doi:10.1002/jhet.5570190209

    Article  CAS  Google Scholar 

  43. Steiger W, Kappe T, Ziegler E (1969) Synthesen von Heterocyclen, 123. Mitt.: Über Reaktionen des Isatosäureanhydrids mit Anilen. Monatsh Chem 100:146–149. doi:10.1007/bf00938250

    Article  CAS  Google Scholar 

  44. Garin J, Melendez E, Merchán FL, Tejero T, Villarroya E (1983) Synthesis of 3-aryl-2,4-dioxo-1,2,3,4-tetrahydroquinazolines and 2-arylamino-4-oxo-4H-3,1-benzoxazines from methyl N-aryldithiocarbamates. Synthesis 1983:406–408. doi:10.1055/s-1983-30357

  45. Horiie S, Murahashi S (1960) Studies on the high pressure reaction of carbon monoxide. III. Reaction between azocompounds and carbon monoxide. Bull Chem Soc Jpn 33:88–94. doi:10.1246/bcsj.33.88

    Article  Google Scholar 

  46. Lanone S, Rogerieux F, Geys J, Dupont A, Maillot-Marechal E, Boczkowski J, Lacroix G, Hoet P (2009) Comparative toxicity of 24 manufactured nanoparticles in human alveolar epithelial and macrophage cell lines. Part Fibre Toxicol 6:14. doi:10.1186/1743-8977-6-14

    Article  PubMed  PubMed Central  Google Scholar 

  47. Schoen J (1995) The condensation of \(N, N^{\prime }\)-diaryl derivatives of thiourea with cyclohexanone. Synthesis of new compounds of the type 1,3-diaryl-2,4-dithioxo.ovrddot.octahydroquinazoline. Rocz Chem 29:549–566

    Google Scholar 

  48. Khademvatan S, Gharavi MJ, Akhlaghi L, Samadikuchaksaraei A, Oormazdi H, Mousavizadeh K, Hadighi R, Saki J (2009) Induction of apoptosis by miltefosine in iranian strain of Leishmania infantum promastigotes. Iran J Parasitol 4:23–31

    CAS  Google Scholar 

  49. Saibu GM, Katerere DR, Rees DJG, Meyer M (2015) In vitro cytotoxic and pro-apoptotic effects of water extracts of Tulbaghia violacea leaves and bulbs. J Ethnopharmacol 164:203–209. doi:10.1016/j.jep.2015.01.040

    Article  CAS  PubMed  Google Scholar 

  50. Lizarazo-Jaimes EH, Reis PG, Bezerra FM, Rodrigues BL, Monte-Neto RL, Melo MN, Frézard F, Demicheli C (2014) Complexes of different nitrogen donor heterocyclic ligands with SbCl\(_{3}\) and PhSbCl\(_{2}\) as potential antileishmanial agents against Sb\(^{III}\)-sensitive and -resistant parasites. J Inorg Biochem 132:30–36. doi:10.1016/j.jinorgbio.2013.12.001

    Article  CAS  PubMed  Google Scholar 

  51. Savoia D, Allice T, Tovo PA (2005) Antileishmanial activity of HIV protease inhibitors. Int J Antimicrob Agents 26:92–94. doi:10.1016/j.ijantimicag.2005.04.003

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We gratefully acknowledge the support for this project by Consejo Nacional de Ciencia y Tecnología (SEP-CONACyT, GRANT No CB-2012-178266-Q) and Secretaría de Educación Pública (Nuevo PTC UAS-061, PROMEP/103.5/12/3360).

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    Authors and Affiliations

    1. Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Blvd. de las Ámericas S/N, C.P. 80040, Culiacán Rosales, Sinaloa, Mexico

      Eduardo Enciso, Héctor S. López-Moreno, Ulises Osuna-Martínez & Evangelina Beltrán-López

    2. Facultad de Ingeniería Culiacán, Universidad Autónoma de Sinaloa, Blvd. de las Ámericas S/N, C.P. 80040, Culiacán Rosales, Sinaloa, Mexico

      Juan I. Sarmiento-Sánchez

    3. Centro de Graduados e Investigación en Química, Instituto Tecnológico de Tijuana, Blvd. Alberto Limón Padilla S/N, Mesa de Otay, 22500, Tijuana, B.C., Mexico

      Adrián Ochoa-Terán

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    1. Eduardo Enciso
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    Correspondence to Juan I. Sarmiento-Sánchez.

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    Juan I. Sarmiento-Sánchez and Héctor S. López-Moreno have contributed equally to this study.

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    11030_2016_9693_MOESM1_ESM.docx

    Supplementary data Available at http:// in the form of a PDF file, with free access: the 1H-NMR, 13C-NMR, and HRMS-ESI spectra for novel compounds (6c, 6e, and 6g). Graphs of percentage viabilities (promastigotes and macrophage cell) versus logarithmic concentrations are shown.

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    Enciso, E., Sarmiento-Sánchez, J.I., López-Moreno, H.S. et al. Synthesis of new quinazolin-2,4-diones as anti-Leishmania mexicana agents. Mol Divers 20, 821–828 (2016). https://doi.org/10.1007/s11030-016-9693-8

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