Gleeson, Duangkamol

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Gleeson, Duangkamol
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duangkamol.gl@kmitl.ac.th

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    Item type:Publication,
    Computational design, synthesis and biological evaluation of PDE5 inhibitors based on N2,N4-diaminoquinazoline and N2,N6-diaminopurine scaffolds
    (2022-12-15)
    Somnarin, Thanachon
    ;
    Pobsuk, Nattakarn
    ;
    Chantakul, Ruttanaporn
    ;
    Panklai, Teerapap
    ;
    Temkitthawon, Prapapan
    We report the synthesis, and characterization of twenty-nine new inhibitors of PDE5. Structure-based design was employed to modify to our previously reported 2,4-diaminoquinazoline series. Modification include scaffold hopping to 2,6-diaminopurine core as well as incorporation of ionizable groups to improve both activity and solubility. The prospective binding mode of the compounds was determined using 3D ligand-based similarity methods to inhibitors of known binding mode, combined with a PDE5 docking and molecular dynamics based-protocol, each of which pointed to the same binding mode. Chemical modifications were then designed to both increase potency and solubility as well as validate the binding mode prediction. Compounds containing a quinazoline core displayed IC<inf>50</inf>s ranging from 0.10 to 9.39 µM while those consisting of a purine scaffold ranging from 0.29 to 43.16 µM. We identified 25 with a PDE5 IC<inf>50</inf> of 0.15 µM, and much improved solubility (1.77 mg/mL) over the starting lead. Furthermore, it was found that the predicted binding mode was consistent with the observed SAR validating our computationally driven approach.