Synthesis, Plasmodium falciparum Inhibitory Activity, Cytotoxicity and Solubility of N2 ,N4 -Disubstituted Quinazoline-2,4-diamines.

Author(s): Nattakarn Pobsuk , Praphasri Suphakun , Supa Hannongbua , Chanin Nantasenamat , Kiattawee Choowongkomon , M. Paul Gleeson* .

Journal Name: Medicinal Chemistry

Volume 15 , Issue 6 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Despite the development of extensive control strategies and treatment options, approximately 200 million malaria cases, leading to approximately 450,000 deaths, were reported in 2015. Due to issue of disease resistance, additional drug development efforts are needed to produce new, more effective treatments. Quinazoline-2,4-diamines were identified as antiparasitic compounds over three decades ago and have remained of interest to date in industry and academia.

Objective: An anti-malarial SAR evaluation of previously unreported N2 ,N4 -disubstituted quinazoline- 2,4-diamines have been undertaken in this study. We have synthesized and evaluated new derivatives against P. falciparum in our attempt to better characterize their biological activity and overall physical properties.

Methods: The synthesis of N2 ,N4 -disubstituted quinazoline-2,4-diamines inhibitors is reported along with activities in a radioactive labeled hypoxanthine incorporation assay against the f Plasmodium falciparum (Pf.) K1 strain. In addition, cytotoxicity was determined in the A549 and Vero cell lines using an MTT based. The aqueous solubility of key compounds was assessed at pH 7.4 using a shake flask-based approach.

Results: We identified compounds 1 and 6p as sub µM inhibitors of P. falciparum, having equivalent anti-malarial activity to Chloroquine. Compounds 1 and 6m are low µM inhibitors of P. falciparum with improved cytotoxicity profiles. Compound 6m displayed the best balance between P. falciparum Inhibitory activity (2 µM) and cytotoxicity, displaying >49 fold selectivity over A549 and Vero cell lines.

Conclusion: Twenty one N2 ,N4 -Disubstituted Quinazoline-2,4-diamines have been prepared in our group and characterized in terms of their antimalarial activity, cytotoxicity and physical properties. Compounds with good activity and reasonable selectivity over mammalian cell lines have been identified. SAR analyses suggest further exploration is are necessary to improve the balance of P. falciparum Inhibitory activity, cytotoxicity and solubility.

Keywords: Plasmodium falciparum, quinazoline-2, 4-diamines K1 strain, cytotoxicity, A549, Vero, solubility.

[1]
Tripura, R.; Peto, T.J.; Chalk, J.; Lee, S.J.; Sirithiranont, P.; Nguon, C.; Dhorda, M.; von Seidlein, L.; Maude, R.J.; Day, N.P.J.; Imwong, M.; White, N.J.; Dondorp, A.M. Persistent Plasmodium falciparum and Plasmodium vivax infections in a western Cambodian population: Implications for prevention, treatment and elimination strategies. Malar. J., 2016, 15(1), 181.
[2]
Imwong, M.; Nguyen, T.N.; Tripura, R.; Peto, T.J.; Lee, S.J.; Lwin, K.M. The epidemiology of subclinical malaria infections in South-East Asia: Findings from cross-sectional surveys in Thailand-Myanmar border areas, Cambodia, and Vietnam. Malar. J., 2015, 14, 381.
[3]
Rich, S.M.; Leendertz, F.H.; Xu, G.; LeBreton, M.; Djoko, C.F.; Aminake, M.N.; Takang, E.E.; Diffo, J.L.D.; Pike, B.L.; Rosenthal, B.M.; Formenty, P.; Boesch, C.; Ayala, F.J.; Wolfe, N.D. The origin of malignant malaria. Proc. Natl. Acad. Sci. USA, 2009, 106(35), 14902-14907.
[4]
WHO, World Malaria Report 2015: http://www.who.int/malaria/ publications/world-malaria-report-2015/report/en/Geneva: World Health Organization:. 2015.
[5]
Sibley, C.H. Understanding artemisinin resistance. Science, 2015, 347(6220), 373-374.
[6]
Mbengue, A.; Bhattacharjee, S.; Pandharkar, T.; Liu, H.; Estiu, G.; Stahelin, R.V.; Rizk, S.S.; Njimoh, D.L.; Ryan, Y.; Chotivanich, K.; Nguon, C.; Ghorbal, M.; Lopez-Rubio, J-J.; Pfrender, M.; Emrich, S.; Mohandas, N.; Dondorp, A.M.; Wiest, O.; Haldar, K. A molecular mechanism of artemisinin resistance in Plasmodium falciparum malaria. Nature, 2015, 520(7549), 683-687.
[7]
Meister, S.; Plouffe, D.M.; Kuhen, K.L.; Bonamy, G.M.C.; Wu, T.; Barnes, S.W.; Bopp, S.E.; Borboa, R.; Bright, A.T.; Che, J.; Cohen, S.; Dharia, N.V.; Gagaring, K.; Gettayacamin, M.; Gordon, P.; Groessl, T.; Kato, N.; Lee, M.C.S.; McNamara, C.W.; Fidock, D.A.; Nagle, A.; Nam, T-G.; Richmond, W.; Roland, J.; Rottmann, M.; Zhou, B.; Froissard, P.; Glynne, R.J.; Mazier, D.; Sattabongkot, J.; Schultz, P.G.; Tuntland, T.; Walker, J.R.; Zhou, Y.; Chatterjee, A.; Diagana, T.T.; Winzeler, E.A. Imaging of Plasmodium liver stages to drive next-generation antimalarial drug discovery. Science, 2011, 334(6061), 1372-1377.
[8]
Gamo, F.; Sanz, L.; Vidal, J.; de Cozar, C.; Alvarez, E.; Lavandera, J.; Vanderwall, D.; Green, D.; Kumar, V.; Hasan, S.; Brown, J.; Peishoff, C.; Cardon, L.; Garcia-Bustos, J. Thousands of chemical starting points for antimalarial lead identification. Nature, 2010, 465, 305-310.
[9]
Guiguemde, W.; Shelat, A.; Bouck, D.; Duffy, S.; Crowther, G.; Davis, P.; Smithson, D.; Connelly, M.; Clark, J.; Zhu, F.; Jimenez-Diaz, M.; Martinez, M.; Wilson, E.; Tripathi, A.; Gut, J.; Sharlow, E.; Bathurst, I.; El Mazouni, F.; Fowble, J.; Forquer, I.; McGinley, P.; Castro, S.; Angulo-Barturen, I.; Ferrer, S.; Rosenthal, P.; Derisi, J.; Sullivan, D.; Lazo, J.; Roos, D.; Riscoe, M. Chemical genetics of Plasmodium falciparum. Nature, 2010, 465, 311-315.
[10]
Spangenberg, T.; Burrows, J.N.; Kowalczyk, P.; McDonald, S.; Wells, T.N.C.; Willis, P. The open access malaria box: A drug discovery catalyst for neglected diseases. PLoS One, 2013, 8e62906
[11]
Eggert, U.S. The why and how of phenotypic small-molecule screens. Nat. Chem. Biol., 2013, 9(4), 206-209.
[12]
Swinney, D.C. Phenotypic versus target-based drug discovery for first-in-class medicines. Clin. Pharmacol. Ther., 2013, 93, 299-301.
[13]
Guiguemde, W.; Shelat, A.; Garcia-Bustos, J.; Diagana, T.; Gamo, F.; Guy, R. Global phenotypic screening for antimalarials. Chem. Biol., 2012, 19, 116-129.
[14]
Lee, J.A.; Uhlik, M.T.; Moxham, C.M.; Tomandl, D.; Sall, D.J. Modern phenotypic drug discovery is a viable, neoclassic pharma strategy. J. Med. Chem., 2012, 55, 4527-4538.
[15]
Angelo, M.M.; Ortwine, D.; Worth, D.F.; Werbel, L.M. N2-1H-benzimidazol-2-yl-N4-phenyl-2,4-pyrimidinediamines and N2-1H-benzimidazol-2-yl-5,6,7,8-tetrahydro-N4-phenyl-2,4 quinazolinediamines as potential antifilarial agents. J. Med. Chem., 1983, 26(9), 1311-1316.
[16]
Martyn, D.C.; Nijjar, A.; Celatka, C.A.; Mazitschek, R.; Cortese, J.F.; Tyndall, E.; Liu, H.; Fitzgerald, M.M.; O’Shea, T.J.; Danthi, S.; Clardy, J. Synthesis and antiplasmodial activity of novel 2,4-diaminopyrimidines. Bioorg. Med. Chem. Lett., 2010, 20(1), 228-231.
[17]
Van Horn, K.S.; Zhu, X.; Pandharkar, T.; Yang, S.; Vesely, B.; Vanaerschot, M.; Dujardin, J-C.; Rijal, S.; Kyle, D.E.; Wang, M.Z.; Werbovetz, K.A.; Manetsch, R. Antileishmanial activity of a series of N2, N4-disubstituted quinazoline-2,4-diamines. J. Med. Chem., 2014, 57(12), 5141-5156.
[18]
Plouffe, D.; Brinker, A.; McNamara, C.; Henson, K.; Kato, N.; Kuhen, K.; Nagle, A.; Adrián, F.; Matzen, J.T.; Anderson, P.; Nam, T-G.; Gray, N.S.; Chatterjee, A.; Janes, J.; Yan, S.F.; Trager, R.; Caldwell, J.S.; Schultz, P.G.; Zhou, Y.; Winzeler, E.A. In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen. Proc. Natl. Acad. Sci. USA, 2008, 105(26), 9059-9064.
[19]
Van Voorhis, W.C.; Adams, J.H.; Adelfio, R.; Ahyong, V.; Akabas, M.H.; Alano, P.; Alday, A.; Alemán Resto, Y.; Alsibaee, A.; Alzualde, A. Open source drug discovery with the malaria box compound collection for neglected diseases and beyond. PLoS Pathog., 2016, 12(7)e1005763
[20]
Plouffe, D.; Brinker, A.; McNamara, C.; Henson, K.; Kato, N.; Kuhen, K.; Nagle, A.; Adrián, F.; Matzen, J.T.; Anderson, P.; Nam, T-G.; Gray, N.S.; Chatterjee, A.; Janes, J.; Yan, S.F.; Trager, R.; Caldwell, J.S.; Schultz, P.G.; Zhou, Y.; Winzeler, E.A. In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen. Proc. Natl. Acad. Sci. USA, 2008, 105(26), 9059-9064.
[21]
Rueeger, H.; Rigollier, P.; Yamaguchi, Y.; Schmidlin, T.; Schilling, W.; Criscione, L.; Whitebread, S.; Chiesi, M.; Walker, M.W.; Dhanoa, D.; Islam, I.; Zhang, J.; Gluchowski, C. Design, synthesis and SAR of a series of 2-substituted 4-amino-quinazoline neuropeptide Y Y5 receptor antagonists. Bioorg. Med. Chem. Lett., 2000, 10(11), 1175-1179.
[22]
Zhu, L.; Jin, J.; Liu, C.; Zhang, C.; Sun, Y.; Guo, Y.; Fu, D.; Chen, X.; Xu, B. Synthesis and biological evaluation of novel quinazoline-derived human Pin1 inhibitors. Bioorg. Med. Chem., 2011, 19(9), 2797-2807.
[23]
Pobsuk, N.; Urooj, P.T.; Chaichamnong, N.; Salaloya, N.; Suphakun, P.; Hannongbua, S.; Choowongkomon, K.; Pekthong, P.; Chootip, C.; Ingkaninan, K.; Gleeson, M.P. Design, synthesis and evaluation of N2, N4-diaminoquinazoline-based inhibitors of phosphodiesterase type 5. Bioorg. Med. Chem. Lett., 2019, 29(2), 267-270.
[24]
Gleeson, M.P.; Hersey, A.; Montanari, D.; Overington, J. Probing the links between in vitro potency, ADMET and physicochemical parameters. Nat. Rev. Drug Discov., 2011, 10, 197-208.
[25]
Gleeson, M.P. Generation of a set of simple, interpretable ADMET rules of thumb. J. Med. Chem., 2008, 51(4), 817-834.
[26]
Van Horn, K.S.; Burda, W.N.; Fleeman, R.; Shaw, L.N.; Manetsch, R. Antibacterial activity of a series of N2, N4-disubstituted quinazoline-2,4-diamines. J. Med. Chem., 2014, 57(7), 3075-3093.
[27]
Watanabe, N.; Adachi, H.; Takase, Y.; Ozaki, H.; Matsukura, M.; Miyazaki, K.; Ishibashi, K.; Ishihara, H.; Kodama, K.; Nishino, M.; Kakiki, M.; Kabasawa, Y. 4-(3-Chloro-4-methoxybenzyl) amino-phthalazines: Synthesis and inhibitory activity toward phosphodiesterase 5. J. Med. Chem., 2000, 43(13), 2523-2529.
[28]
Trager, W.; Jensen, J. Human malaria parasites in continuous culture. Science, 1976, 193(4254), 673-675.
[29]
Daengrot, C.; Rukachaisirikul, V.; Tansakul, C.; Thongpanchang, T.; Phongpaichit, S.; Bowornwiriyapan, K.; Sakayaroj, J. Eremophilane sesquiterpenes and diphenyl thioethers from the soil fungus Penicillium copticola PSU-RSPG138. J. Nat. Prod., 2015, 78(4), 615-622.
[30]
ChemAxon. J. Chem:. www.chemaxon.com
[31]
Avery, V.M.; Bashyam, S.; Burrows, J.N.; Duffy, S.; Papadatos, G.; Puthukkuti, S.; Sambandan, Y.; Singh, S.; Spangenberg, T.; Waterson, D.; Willis, P. Screening and hit evaluation of a chemical library against blood-stage Plasmodium falciparum. Malar. J., 2014, 13(1), 190.
[32]
Davis, A.M.; Keeling, D.J.; Steele, J.; Tomkinson, N.P.; Tinker, A.C. Components of successful lead generation. Curr. Top. Med. Chem., 2005, 5(4), 421-439.
[33]
Bollini, M.; Frey, K.M.; Cisneros, J.A.; Spasov, K.A.; Das, K.; Bauman, J.D.; Arnold, E.; Anderson, K.S.; Jorgensen, W.L. Extension into the entrance channel of HIV-1 reverse transcriptase-crystallography and enhanced solubility. Bioorg. Med. Chem. Lett., 2013, 23(18), 5209-5212.
[34]
Phuangsawai, O.; Beswick, P.; Ratanabunyong, S.; Tabtimmai, L.; Suphakun, P.; Obounchoey, P.; Srisook, P.; Horata, N.; Chuckowree, I.; Hannongbua, S.; Ward, S.E.; Choowongkomon, K.; Gleeson, M.P. Evaluation of the anti-malarial activity and cytotoxicity of 2,4-diamino-pyrimidine-based kinase inhibitors. Eur. J. Med. Chem., 2016, 124, 896-905.
[35]
Toviwek, B.; Suphakun, P.; Choowongkomon, K.; Hannongbua, S.; Gleeson, M.P. Synthesis and evaluation of the NSCLC anti-cancer activity and physical properties of 4-aryl-N-phenylpyrimidin-2-amines. Bioorg. Med. Chem. Lett., 2017, 27(20), 4749-4754.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 6
Year: 2019
Page: [693 - 704]
Pages: 12
DOI: 10.2174/1573406415666181219100307
Price: $58

Article Metrics

PDF: 23
HTML: 1