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Author: search.filters.author.Hannongbua, SupaSubject: search.filters.subject.A549

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    Synthesis, plasmodium falciparum inhibitory activity, cytotoxicity and solubility of n2,n4-disubstituted quinazoline-2,4-diamines
    (2019-01-01)
    Pobsuk, Nattakarn
    ;
    Suphakun, Praphasri
    ;
    Hannongbua, Supa
    ;
    Nantasenamat, Chanin
    ;
    Choowongkomon, Kiattawee
    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 anti-parasitic 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 N<sup>2</sup>,N<sup>4</sup>-disubstituted quina-zoline-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. Method: The synthesis of N<sup>2</sup>,N<sup>4</sup>-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 N<sup>2</sup>,N<sup>4</sup>-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.
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    Synthesis and evaluation of the NSCLC anti-cancer activity and physical properties of 4-aryl-N-phenylpyrimidin-2-amines
    (2017-01-01)
    Toviwek, Borvornwat
    ;
    Suphakun, Praphasri
    ;
    Choowongkomon, Kiattawee
    ;
    Hannongbua, Supa
    ;
    Gleeson, M. Paul
    Reported herein are efforts to profile 4-aryl-N-phenylpyrimidin-2-amines in terms of their anti-cancer activity towards non small-cell lung carcinoma (NSCLC) cells. We have synthesized new 4-aryl-N-phenylpyrimidin-2-amines and assessed them in terms of their cytotoxicity (A549, NCI-H187, MCF7, Vero & KB) and physicochemical properties (logD<inf>7.4</inf> and solubility). 13f and 13c demonstrated potent anti-cancer activity in A549 cells (0.2 µM), compared to 0.4 μM for the NSCLC drug Doxorubicin. 13f also displayed low experimental logD<inf>7.4</inf> (2.9) and the best solubility (∼40 μM). Compounds 13b and 13d showed the best balance of A549 anti-cancer activity and selectivity. 13g showed good activity and selectivity comparable with the anti-cancer drug Doxorubicin.