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Design, Computational Evaluation and Route of Synthesis Validation of New JAK2 inhibitors to Treat Inflammatory Diseases
(2025-01-01)
Pornsupawat, Jarukorn
;
Paul Gleeson, M.
In this research we report the design of new JAK2 inhibitors using structure-based and ligand-based design approaches. Novel JAK2 inhibitors were designed containing biostatic modifications developed from related scaffolds. The JAK2 binding characteristics were studied using molecular docking and an assessment of their overall drug likeness was made though the prediction of key physical properties. Validation of routes of synthesis have been undertaken to assess the feasibility of preparing the compounds. Our results suggest that the new molecules have desirable physical properties and are highly likely to be inhibitors of JAK2 kinase. In addition, we have validated the synthetic conditions and intermediates needed for their preparation by preparing 4 key exemplars.
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Assessment of the Utility of Chitosan in Drug Delivery of Sulfamethoxazole
(2024-01-01)
Soontorntepwarakul, Nussara
;
Boonyarattanakalin, Kanokthip
;
Srirussamee, Kasama
;
Paul Gleeson, M.
The objective of this research was to develop chitosan (CS) nanoparticles (NP) and microfibres (MF) for oral delivery applications related to low solubility drugs. The ionic gelation method in conjunction with freeze-drying was used to produce crosslinked chitosan material. Dynamic light scattering (DLS) was used to characterize particle size and polydispersity index (PDI). Surface morphology was analyzed using scanning electron microscopy (SEM). The antibiotic drug sulfamethoxazole (SMO) was loaded onto the chitosan nano/micro material. The degree of loading, loading efficiency and the release kinetics were investigated using high-performance liquid chromatography (HPLC) and UV-visible spectrophotometry, respectively. We found that CS nanoparticles have the potential to improve the delivery properties of SMO due to their more rapid release compared to microfibres or traditional tablet formulations.
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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.
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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 N2,N4-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 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.
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An influenza A virus agglutination test using antibody-like polymers
(2017-10-13)
Sukjee, Wannisa
;
Thitithanyanont, Arunee
;
Wiboon-ut, Suwimon
;
Lieberzeit, Peter A.
;
Paul Gleeson, M.
Antibodies are commonly used in diagnostic routines to identify pathogens. The testing protocols are relatively simple, requiring a certain amount of a specific antibody to detect its corresponding pathogen. Antibody functionality can be mimicked by synthesizing molecularly imprinted polymers (MIPs), i.e. polymers that can selectively recognize a given template structure. Thus, MIPs are sometimes termed ‘plastic antibody (PA)’. In this study, we have synthesized new granular MIPs using influenza A virus templates by precipitation polymerization. The selective binding of influenza A to the MIP particles was assessed and subsequently contrasted with other viruses. The affinities of influenza A virus towards the MIP was estimated based on an agglutination test by measuring the amount of influenza subtypes absorbed onto the MIPs. The MIPs produced using the H1N1 template showed specific reactivity to H1N1 while those produced using H5N1 and H3N2 templates showed cross-reactivity.

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