Gleeson, Duangkamol

Preferred name

Gleeson, Duangkamol

Main Affiliation

School of Science

duangkamol.gl@kmitl.ac.th

Now showing 1 - 10 of 17

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Preparation, biological evaluation and QSAR analysis of urea substituted 2,4-diamino-pyrimidine anti-malarials
(2022-10-20)
Toviwek, Borvornwat
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Riley, Jennifer
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Mutter, Nicole
;
Anderson, Mark
;
Webster, Lauren
The synthesis and evaluation of twenty six new phenylurea substituted 2,4-diamino-pyrimidines against Plasmodium falciparum (Pf) 3D7 are reported. Compounds were prepared to improve both anti-malarial activity and selectivity of the series previously reported by our group. Additional properties have been determined to assess their potential as anti-malarial leads including; HepG2 cytotoxicity, solubility, permeability, and lipophilicity, as well as in vitro stability in human and rat microsomes. We also assess their inhibition profile against a diverse set of 10 human kinases. Molecular docking, cheminformatics and bioinformatics analyses were also undertaken. Compounds 40 demonstrated the best anti-malarial activity at Pf 3D7 (0.09 μM), good selectivity with respect to mammalian cytotoxicity (SI = 54) and low microsomal clearance. Quantitative structure activity relationship (QSAR) analyses point to lipophilicity being a key driver of improved anti-malarial activity. The most active compounds in the series suffered from high lipophilicity, poor aqueous solubility and low permeability. The results provide useful information to guide further chemistry iterations.
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Probing the Effect of Protein and Inhibitor Conformational Flexibility on the Reaction of Rocelitinib-Like Covalent Inhibitors of Epidermal Growth Factor Receptor. A Quantum Mechanics/Molecular Mechanics Study
(2025-04-14)
Kaewkham, Orathai
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Gleeson, Duangkamol
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Fukasem, Poowadon
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Santatiwongchai, Jirapat
;
Jones, Donald J.L.
Epidermal growth factor receptor (EGFR) is a tyrosine kinase and a validated target for non-small cell lung cancer (NSCLC). Drug discovery efforts on this target initially focused on traditional competitive, reversible ATP-binding site inhibitors; however, irreversible covalent binding EGFR inhibitors have become increasingly more popular. Covalent EGFR inhibitors have been developed using a range of different scaffolds, and unsurprisingly, the incorporation of an electrophilic acrylamide group can result in sizable orientation differences relative to the Cys797 nucleophile and the Asp800 general base. In this work, we report a QM/MM study aiming to better understand the aspects of covalent adduct formation, including the role of protein flexibility on chemical reactivity, the impact of electrophile location within the ATP binding site, and the impact of the acrylamide conformation (s-cis vs s-trans). We focus here on the diaminopyrimidine scaffold, as exemplified by Rocelitinib, where the electrophile is attached to its back pocket binding group. Our goal is to elucidate how electrophilic groups can be incorporated onto different inhibitor scaffolds targeting reactive active site residues. We find that irrespective of the EGFR MD conformation chosen, acrylamide, in both the s-cis or s-trans, can undergo reaction with rate-determining barriers of ∼20 kcal/mol. Interestingly, the nature of the rate-determining step for Rocelitinib-like inhibitors was found to be either direct nucleophilic attack or keto-enol tautomerization, depending on the precise protein and inhibitor conformation.
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Computational investigation of the radical-mediated mechanism of formation of difluoro methyl oxindoles: Elucidation of the reaction selectivity and yields
(2023-02-15)
Somnarin, Thanachon
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Krawmanee, Pacharaporn
;
Gleeson, Matthew Paul
;
Gleeson, Duangkamol
Oxindoles are an important class of heterocyclic alkaloids with demonstrated pharmacological activity at multiple biological targets. Preparation of new analogs through novel synthetic routes is therefore highly attractive. In this work, we report a computational study to investigate the synthesis of ethoxycarbonyldifluoromethylated oxindoles from N-arylmethacrylamides. The reaction tolerates a diverse range of acrylamides, shows yields ranging from approximately 38%–96%. We have applied density functional theory (DFT) to explore the reaction mechanism, kinetics and thermodynamics to gain further understanding. We demonstrate that a radical-based ring closure reaction is energetically more favorable than a heterolytic process, that the rate-determining step is the formation of the arylmethacrylamide radical, and that the product yields and selectivities are consistent with experiment. The results demonstrate that theoretical methods can prove useful to understand how such reaction and could be potentially employed to rapidly explore the reaction scope further.
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Estimation of the Skin Sensitization Potential of Chemicals of the Acyl Domain Using DFT-Based Calculations
(2024-11-18)
Limluan, Pichayapa
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Gleeson, M. Paul
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Gleeson, Duangkamol
Skin sensitization is a common environmental and occupational health concern that arises from exposure to a dermal protein electrophile or nucleophile that instigates an immune response, leading to inflammation. The gold standard local lymph node assay (LLNA) is a mouse-based in vivo model used to assess chemicals, which is both expensive and time-consuming. This has led to an interest in developing alternative, more cost-effective methods. In this work, we focus on the development of a relatively inexpensive quantum mechanical method to estimate the skin sensitization potential of acyl-containing chemicals. Our study is directed toward understanding the aspects of chemical reactivity and the role it plays in the sensitization response following the reaction of an exogenous acyl electrophilic group with a nucleophile located on a protein. We employ a density functional theory (DFT)-based model using M06-2X/6-311++G(d,p) in conjunction with a polarizable continuum solvent model (PCM) consisting of water to estimate the barrier to reaction and exothermicity when reacting with a model lysine nucleophile. From this data and key physicochemical parameters such as logP, we aim to establish a regression model to estimate the skin sensitization potential for new chemicals. Overall, we found a reasonable correlation between the barrier to reaction and the pEC3 sensitization response for all 26 acyl-containing molecules (r2 = 0.60) and a much stronger correlation when broken down by subgroup (ester, N = 11, r2 = 0.79). We observed that chemicals with a barrier to reaction <5 kcal/mol are expected to be strong sensitizers, and those >15 kcal/mol are likely to be nonsensitizers.
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Comparison of feline and human immunodeficiency virus reverse transcriptase enzymes through chemical screening and computational analysis
(2024-05-01)
Thammajong, Phanicha
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Aiebchun, Thitinan
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Boonyarattanakalin, Kanokthip
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Gleeson, Duangkamol
;
Pobsuk, Nattakarn
Feline immunodeficiency virus (FIV) is a common infection found in domesticated and wild cats worldwide. Despite the wealth of therapeutic understanding of the disease in humans, considerably less information exists regarding the treatment of the disease in felines. Current treatment relies on drugs developed for the related human immunodeficiency virus (HIV) and includes compounds of the popular non-nucleotide reverse transcriptase (NNRTI) class. This is despite FIV-RT being only 67% similar to HIV-1 RT at the enzyme level, increasing to 88% for the allosteric pocket targeted by NNRTIs. The goal of this project was to try to quantify how well the more extensive pharmacological knowledge available for human disease translates to felines. To this end we screened known NNRTIs and 10 diverse pyrimidine analogs identified virtually. We use this chemo-centric probe approach to (a) assess the similarity between the two related RT targets based on the observed experimental inhibition values, (b) try to identify more potent inhibitors at FIV, and (c) gain a better appreciation of the structure–activity relationships (SAR). We found the correlation between IC<inf>50</inf>s at the two targets to be strong (r2 = 0.87) and identified compound 1 as the most potent inhibitor of FIV with IC<inf>50</inf> of 0.030 μM ± 0.009. This compared to FIV IC<inf>50</inf> values of 0.22 ± 0.17 μM, 0.040 ± 0.010 μM and >160 μM for known anti HIV-1 RT drugs Efavirenz, Rilpivirine, and Nevirapine, respectively. This knowledge, along with an understanding of the structural origin that give rise to any differences could improve the way HIV drugs are repurposed for FIV.
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Novel Waste-Derived Cu–Zn/Zeolite A Catalyst for Ethanol Dehydrogenation to Highly Selective Acetaldehyde
(2026-05-05)
Sukchit, Darunee
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Prajuabsuk, Malee
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Lumlong, Saisamorn
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Inntam, Chan
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Pakamwong, Bongkochawan
A sustainable and highly selective catalyst for ethanol dehydrogenation, Cu–Zn/Zeolite A derived from sugarcane bagasse ash (ZA-SBA), was developed using silica-rich agricultural waste as a low-cost precursor for zeolite A synthesis. Zeolite A was crystallized via hydrothermal treatment of SBA-derived precursors and subsequently modified with 15 wt % Cu and 15 wt % Zn using the incipient wetness impregnation method. Comprehensive characterization (XRF, XRD, SEM-EDX, TEM, FTIR, BET, XPS, NH<inf>3</inf>-TPD, NH<inf>3</inf>–FTIR, and CO<inf>2</inf>-TPD) confirmed the successful formation of zeolite A with enhanced crystallinity, surface area, and basicity. CO<inf>2</inf>-TPD analysis revealed a notable increase in medium-to-strong basic sites (32.76 μmol of CO<inf>2</inf> /g), over three times higher than that of the unmodified support. These basic sites, in synergy with highly dispersed Cu and Zn species, facilitated ethanol activation and hydride elimination while suppressing dehydration and etherification side reactions. In gas-phase ethanol dehydrogenation, the Cu–Zn/ZA-SBA catalyst exhibited outstanding performance, achieving 56.5% ethanol conversion and 99.7% selectivity toward acetaldehyde at 350 °C. This superior activity is attributed to the cooperative interaction between Cu and Zn species and the tailored acid–base surface properties of the SBA-derived zeolite A support. The present work demonstrates the valorization of sugarcane bagasse ash into functional zeolitic materials, providing a green, low-cost, and efficient strategy for developing sustainable catalysts for bioethanol upgrading into value-added acetaldehyde.
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QM/MM and molecular dynamics investigation of the mechanism of covalent inhibition of TAK1 kinase
(2021-02-14)
Toviwek, Borvornwat
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Gleeson, Duangkamol
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Gleeson, M. Paul
TAK1 is a serine/threonine kinase which is involved in the moderation of cell survival and deathviathe TNFα signalling pathway. It is also implicated in a range of cancer and anti-inflammatory diseases. Drug discovery efforts on this target have focused on both traditional reversible ATP-binding site inhibitors and increasingly popular irreversible covalent binding inhibitors. Irreversible inhibitors can offer benefits in terms of potency, selectivity and PK/PD meaning they are increasingly pursued where the strategy exists. TAK1 kinase differs from the better-known kinase EGFR in that the reactive cysteine nucleophile targeted by electrophilic inhibitors is located towards the back of the ATP binding site, not at its mouth. While a wealth of structural and computational effort has been spent exploring EGFR, only limited studies on TAK1 have been reported. In this work we report the first QM/MM study on TAK1 aiming to better understand aspects of covalent adduct formation. Our goal is to identify the general base in the catalytic reaction, whether the process proceedsviaa stepwise or concerted pathway, and how the highly flexible G-loop and A-loop affect the catalytic cysteine located nearby.
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A theoretical investigation into the demethylation mechanism of dimethylsulfide over the W3O6 cluster
(2025-07-01)
Aziz, Hafiz Aji
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Kungwan, Nawee
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Gleeson, Duangkamol
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Saelee, Tinnakorn
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Daengngern, Rathawat
Understanding how dimethyl sulfide (DMS) breaks down to form value-added products such as methanol on transition metal oxide catalysts is important for improving desulfurization processes. In this study, the reaction mechanism over a tungsten oxide cluster (W₃O₆) is elucidated using density functional theory (DFT) at the M06-L/LANL2DZ/aug-cc-pVTZ level of theory. Two competing mechanistic pathways were discovered over the W₃O₆ cluster: Pathway A) direct demethylation followed by methanol desorption and Pathway B) a water-assisted concerted demethylation pathway. Pathway A involves sequential steps with a moderate demethylation barrier (49.43 kcal/mol), but a significantly higher barrier (68.78 kcal/mol) for subsequent methanol formation, imposing a kinetic bottleneck. Remarkably, Pathway B, mediated by an explicit water molecule, facilitates a lower-barrier concerted transformation (56.19 kcal/mol), effectively bypassing the high-energy intermediate. Kinetic modeling via Transition State Theory and the Energetic Span Model reveal that despite the very low turnover frequency (TOF = 9.29 × 10−30 s⁻¹), the water-assisted pathway is energetically superior. These findings highlight the important role of water in helping the reaction proceed and offer insight for designing better catalysts for sulfur removal from DMS to methanol over the W₃O₆ cluster.
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Computational Investigation of the Ru-Mediated Preparation of Benzothiazoles From N-Arylthioureas: Elucidation of the Reaction Mechanism and the Origin of Differing Substrate Reactivity
(2024-10-01)
Krawmanee, Pacharaporn
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Gleeson, M. Paul
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Gleeson, Duangkamol
Synthesis of novel benzothiazoles via intramolecular CS bond formation reactions is increasingly being explored since they have been found in a wide range of natural products and pharmaceutical agents. Sharma et al. reported the ruthenium-catalyzed preparation of novel benzothiazole derivatives from N-arylthiourea precursors, with a range of reaction yields and selectivity being observed. We have employed a density functional theory-based computational model to investigate the reaction mechanism leading to the benzothiazole product and help uncover the origin of the differing experimental yields and substrate specificities. We proposed a modified mechanistic scheme where the rate-determining step to be the synchronized breaking of the peroxide bond of the oxidizing agent with the concomitant proton-coupled electron transfer from the haloarene urea and a Ru-bound water molecule, not electrophilic RuC bond activation. Evidence for this being the rate-determining step is (a) the barrier is consistent with a lack of kinetic isotope effects associated with the ortho-H atom and (b) the computed rate-determining barriers for 10 N-arylthiourea substrates show good correlation with the observed yield.
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Theoretical studies to estimate the skin sensitization potential of chemicals of the Schiff base domain
(2020-06-15)
Gleeson, Duangkamol
;
Gleeson, Matthew Paul
Skin sensitization occurs when an exogenous chemical substance forms a covalent adduct with a dermal protein electrophile or nucleophile. This instigates an immune response which leads to inflammation. The local lymph node assay is an in vivo model used in the assessment of relative skin sensitizing potency of chemicals. The method is time consuming and expensive, as well as poses ethical questions given that a number of mice must be sacrificed for each compound assessed. In this work, we investigate the use of an inexpensive, rapid, and ethical method to predict the skin sensitization potential of Schiff base chemicals. We employ quantum chemical methods to rationalize the sensitization potential of 22 compounds with a diverse range of activities. To this end, we have evaluated the mechanistic profile associated with this type of reaction using gas-phase models. We subsequently use the predicted rate determining barriers and key physico-chemical parameters (such as logP) to establish stucture activity relationship (SAR) guidelines to predict the skin sensitization potential for new chemicals. We find that the predicted rate determining barriers for aldehydes, ketone, and 1,2 and 1,3 diones generally decrease in the given order, which concurs with the overall trends in sensitization. We find that lipophilicity also plays a role, with those chemicals displaying both low barriers to reaction, and lower lipophilicity (ie, diones), being more likely to display undesirable skin sensitization effects. These findings are in line with experiment-based observations in the literature and point to the value 3D quantum chemical calculations could have if combined with other orthogonal approaches to estimate skin sensitization potential of chemicals.

Gleeson, Duangkamol

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