Browsing by Author "Chayajarus K."

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    Hybrid virtual screening identifies dipyrazole carboxamide derivatives as novel direct InhA inhibitors with antitubercular activity
    (2025-07-01) Punkvang A.; Pakamwong B.; Phusi N.; Thongdee P.; Chayajarus K.; Sangswan J.; Pangjit K.; Suttisintong K.; Leanpolchareanchai J.; Hongmanee P.; Santanirand P.; Spencer J.; Mulholland A.J.; Sureram S.; Kittakoop P.; Pungpo P.; Punkvang A.; Mahidol University
    Direct inhibitors of M. tuberculosis enoyl-acyl carrier protein reductase (M. tuberculosis InhA) remain effective against variants with mutations associated with isoniazid resistance. In our previous study, structure-based virtual screening was employed to discover such inhibitors. However, most identified hits exhibited limited antimycobacterial activity, with minimum inhibitory concentration (MIC) values of >100 μg/mL. To address this challenge, we refined our virtual screening strategy by integrating ligand- and structure-based virtual screening approaches. The efficacy of this hybrid virtual screening approach was validated through biological assays measuring MIC and half-maximal inhibitory concentration (IC50) for the inhibition of M. tuberculosis growth and InhA activity, respectively. Among 14 identified hits, compounds 3 and 10, classified as dipyrazole carboxamide derivatives, were validated as promising lead candidates, with MIC values of 25 and 50 μg/mL and IC50 values of 10.60 ± 0.56 and 5.08 ± 0.30 μM, respectively. The relatively low hit-to‑lead conversion rate (14 %) is ascribed to our observation that nine of the identified hits, including compounds 3 and 10, showed some level of precipitation in the MIC assay medium. Molecular dynamics simulations show that the dipyrazole carboxamide moiety in compounds 3 and 10 forms essential hydrogen bonds with nicotinamide adenine dinucleotide (oxidized form) (NAD+) in the InhA binding pocket. Notably, both compounds 3 and 10 exhibit favorable safety profiles, with no toxicity observed in Caco-2 cells at concentrations up to 100 μg/mL. Consequently, we believe that these compounds present promising starting points for further lead optimization and development of novel antitubercular agents.
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    Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against Mycobacterium tuberculosis and Hit Validation by Biological Assays
    (2024-01-01) Pakamwong B.; Thongdee P.; Kamsri B.; Phusi N.; Taveepanich S.; Chayajarus K.; Kamsri P.; Punkvang A.; Hannongbua S.; Sangswan J.; Suttisintong K.; Sureram S.; Kittakoop P.; Hongmanee P.; Santanirand P.; Leanpolchareanchai J.; Spencer J.; Mulholland A.J.; Pungpo P.; Pakamwong B.; Mahidol University
    Mycobacterium tuberculosis is the single most important global infectious disease killer and a World Health Organization critical priority pathogen for development of new antimicrobials. M. tuberculosis DNA gyrase is a validated target for anti-TB agents, but those in current use target DNA breakage-reunion, rather than the ATPase activity of the GyrB subunit. Here, virtual screening, subsequently validated by whole-cell and enzyme inhibition assays, was applied to identify candidate compounds that inhibit M. tuberculosis GyrB ATPase activity from the Specs compound library. This approach yielded six compounds: four carbazole derivatives (1, 2, 3, and 8), the benzoindole derivative 11, and the indole derivative 14. Carbazole derivatives can be considered a new scaffold for M. tuberculosis DNA gyrase ATPase inhibitors. IC50 values of compounds 8, 11, and 14 (0.26, 0.56, and 0.08 μM, respectively) for inhibition of M. tuberculosis DNA gyrase ATPase activity are 5-fold, 2-fold, and 16-fold better than the known DNA gyrase ATPase inhibitor novobiocin. MIC values of these compounds against growth of M. tuberculosis H37Ra are 25.0, 3.1, and 6.2 μg/mL, respectively, superior to novobiocin (MIC > 100.0 μg/mL). Molecular dynamics simulations of models of docked GyrB:inhibitor complexes suggest that hydrogen bond interactions with GyrB Asp79 are crucial for high-affinity binding of compounds 8, 11, and 14 to M. tuberculosis GyrB for inhibition of ATPase activity. These data demonstrate that virtual screening can identify known and new scaffolds that inhibit both M. tuberculosis DNA gyrase ATPase activity in vitro and growth of M. tuberculosis bacteria.
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    Structural Modification of Indole Derivatives as PknB Inhibitors for Enhanced Enzymatic Inhibition and Antimycobacterial Activity
    (2026-05-19) Punkvang A.; Thongdee P.; Chayajarus K.; Pakamwong B.; Pornprom T.; Sangswan J.; Leanpolchareanchai J.; Suttisintong K.; Sureram S.; Kittakoop P.; Hongmanee P.; Santanirand P.; Pungpo P.; Punkvang A.; Mahidol University
    Protein kinase B (PknB) of Mycobacterium tuberculosis has emerged as a promising target for antituberculosis drug development. In our previous study, virtual screening combined with biological validation identified indole derivatives as novel PknB inhibitors with inhibitory activity against the growth of M. tuberculosis H37Rv, supporting a role for PknB inhibition in their antitubercular activity. Accordingly, the present study employed a structure-based drug design strategy using the previously identified indole scaffold as a template for optimization of PknB inhibitory activity and antimycobacterial potency. Twenty-seven indole derivatives were rationally designed and subjected to molecular docking calculations, which identified four candidates for chemical synthesis and evaluation of their inhibitory activity against M. tuberculosis growth and PknB. Three synthesized compounds (4b, 4c, and 4d) exhibited enhanced inhibition of M. tuberculosis growth, with minimum inhibitory concentration (MIC) values of 3.1 μg/mL, whereas compound 4a showed activity comparable to that of the parent indole (MIC = 6.2 μg/mL). All derivatives inhibited PknB activity with IC50 values ranging from 0.06 to 0.42 μM, which are comparable to that of the parent indole (IC50 = 0.45 μM). Notably, compound 4b demonstrated the highest potency against both M. tuberculosis growth and PknB activity, with an MIC value of 3.1 μg/mL and an IC50 value of 0.06 μM. Cytotoxicity evaluation against Caco-2 cells indicated low toxicity and favorable safety profiles for all indole derivatives at effective concentrations. These results highlight the indole scaffold as a promising structural template for the further development of new PknB inhibitors with potential antitubercular activity.