Browsing by Author "Kittakoop P."
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Item Metadata only Activation of farnesoid X receptor inhibits TMEM16A-mediated chloride secretion in renal collecting duct cells and retards renal cyst progression(2026-04-01) Srimai N.; Tonum K.; Sureram S.; Tubsuwan A.; Kittakoop P.; Soodvilai S.; Srimai N.; Mahidol UniversityThe farnesoid X receptor (FXR) plays a role in the regulation of renal transporters and ion channels. Our previous study reported that activation of FXR inhibited cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl- secretion and retarded microcyst progression. The present study aims to investigate whether FXR regulates TMEM16A, a calcium-activated Cl- channel that plays a major role in renal cyst progression in polycystic kidney disease (PKD). In vitro experiments were conducted to investigate the roles of FXR in TMEM16A-mediated Cl- secretion and cyst progression using wild-type and Pkd1-deleted collecting duct cells (mIMCD3pkd1-/- cells). In vivo experiments were performed in cystic polycystic kidney (PCK) rats. Treating collecting duct cells with FXR agonists (GW4064 and altenusin) decreased TMEM16A-mediated Cl-secretion, an effect that required FXR activation. The inhibitory effect of FXR activation correlated with a reduction in TMEM16A protein levels. Decreased TMEM16A protein expression was associated with reduced Tmem16a mRNA expression and activation of lysosomal degradation pathways. GW4064 and altenusin retarded the enlargement of cysts derived from mIMCD3pkd1-/- cells, an effect attenuated by FXR inhibition. In cystic PCK rats, treatment with altenusin at doses of 7.5 and 15 mg/kg body wt significantly reduced the cystic index, kidney weight, blood urea nitrogen, and serum creatinine levels compared with vehicle-treated rats. These effects correlated with decreased TMEM16A expression in cystic kidneys. In addition, altenusin exhibited anti-inflammatory properties by attenuating the levels of inflammatory cytokines. This study highlights the role of FXR in regulating TMEM16A and in attenuating renal cyst progression, positioning FXR as a promising target for PKD treatment.Item Metadata only Albiflorenes A–L, polyoxygenated cyclohex(a/e)ne diterpene esters from Kaempferia albiflora(2024-12-01) Booranaseensuntorn P.; Boonsombat J.; Thongnest S.; Batsomboon P.; Reuk-Ngam N.; Khlaychan P.; Ruchisansakun S.; Kittakoop P.; Techasakul S.; Mahidol C.; Ruchirawat S.; Booranaseensuntorn P.; Mahidol UniversityTwelve polyoxygenated cyclohex(a/e)ne diterpene esters, named albiflorenes A–L (1–12), were isolated from the whole plants of Kaempferia albiflora, known as “Prao Mang Mum.” Their structures and relative stereochemistry were determined by extensive spectroscopic analysis. Furthermore, the comparison of experimental electronic circular dichroism (ECD) curves with the curves predicted by TDDFT was used to determine the absolute configurations. Albiflorenes contain polyoxygenated cyclohexane (or cyclohexene) derivatives, which are linked to either isopimarane or abietane diterpene acid units. The discovery marks the first occurrence of a conjugate between polyoxygenated cyclohexane (or cyclohexene) rings and diterpenoids. Among the isolates, albiflorene C specifically exhibited antibacterial activity against Bacillus cereus with MIC and MBC values of 3.13 and 6.25 μg/mL, respectively.Item Metadata only Altenusin inhibits epithelial to mesenchymal transition via suppression of TGF-β/MAPK signaling pathway in human renal proximal tubular cells and unilateral ureteral obstruction mice(2023-01-01) Thipboonchoo N.; Sureram S.; Sa-nguansak S.; Kesornpun C.; Kittakoop P.; Soodvilai S.; Thipboonchoo N.; Mahidol UniversityRenal fibrosis is recognized as a key pathological feature of chronic kidney disease (CKD), which progresses toward end stage renal disease (ESRD). Transforming growth factor (TGF)-β-induced epithelial to mesenchymal transition (EMT) of renal epithelial tubular cells is the key mechanism of renal fibrosis. The aim of this study is to investigate the pharmacological effect of altenusin, an active compound derived from fungi, on TGF-β/mitogen-activated protein kinase (MAPK) signaling pathway-induced fibrosis in renal proximal tubular cells and in mouse unilateral ureteral obstruction (UUO) model. As a result, TGF-β1 induced EMT of RPTECT/TERT1 cells (an immortalized human renal proximal tubular cells) by concentration- and time-dependent manners. Incubating cells with 10 ng/ml TGF-β1 for 48 hours significantly upregulated MAPK signaling pathway by increase phosphorylated (p)-Jun N-terminal kinase (JNK), p-p38, and p-Extracellular signal-regulated kinase (ERK) 1/2. Treating the cells with altenusin (50 -100 μM) significantly attenuated TGF-β1-induced EMT. The inhibitory effect of altenusin on EMT was mediated by inhibition of p38 and ERK1/2 but not JNK. UUO in mice for 14 days dramatically increased p-JNK, p-p38, and p-ERK1/2, activation of these proteins by UUO were attenuated by co-treatment with altenusin 3 mg/kg. These results demonstrate the inhibitory effect of altenusin on TGF-β/MAPK signaling pathway-induced EMT in human renal proximal tubular cells and in animal model of renal fibrosis.Item Metadata only Altenusin, a fungal metabolite, alleviates TGF-β1-induced EMT in renal proximal tubular cells and renal fibrosis in unilateral ureteral obstruction(2024-02-15) Thipboonchoo N.; Fongsupa S.; Sureram S.; Sa-nguansak S.; Kesornpun C.; Kittakoop P.; Soodvilai S.; Thipboonchoo N.; Mahidol UniversityRenal fibrosis is a pathological feature of chronic kidney disease (CKD), progressing toward end-stage kidney disease (ESKD). The aim of this study is to investigate the therapeutic potential of altenusin, a farnesoid X receptor (FXR) agonist derived from fungi, on renal fibrosis. The effect of altenusin was determined (i) in vitro using the transforming growth factor β1 (TGF-β1)-induced epithelial to mesenchymal transition (EMT) of human renal proximal tubular cells and (ii) in vivo using mouse unilateral ureteral obstruction (UUO). The findings revealed that incubation of 10 ng/ml TGF-β1 promotes morphological change in RPTEC/TERT1 cells, a human renal proximal tubular cell line, from epithelial to fibroblast-like cells. TGF-β1 markedly increased EMT markers namely α-smooth muscle actin (α-SMA), fibronectin, and matrix metalloproteinase 9 (MMP-9), while decreased the epithelial marker E-cadherin. Co-incubation TGF-β1 with altenusin preserved the epithelial characteristics of the renal epithelial cells by antagonizing TGF-β/Smad signaling pathway, specifically a decreased phosphorylation of Smad2/3 with an increased level of Smad7. Interestingly, the antagonizing effect of altenusin does not require FXR activation. Moreover, altenusin could reverse TGF-β1-induced fibroblast-like cells to epithelial-like cells. Treatment on UUO mice with 30 mg/kg altenusin significantly reduced the expression of α-SMA, fibronectin, and collagen type 1A1 (COL1A1). The reduction in the renal fibrosis markers is correlated with the decreased phosphorylation of Smad2/3 levels but does not improve E-cadherin protein expression. Collectively, altenusin reduces EMT in human renal proximal tubular cells and renal fibrosis by antagonizing the TGF-β/Smad signaling pathway.Item Metadata only An Anisole Derivative in the Essential oil of Wurfbainia schmidtii with Virucidal Activity Against SARS-CoV-2 and Anti-Inflammatory Properties(2025-03-01) Sagayap C.; Chuysinuan P.; Chutiwitoonchai N.; Pripdeevech P.; Kaewsri W.; Sureram S.; Chantratita N.; Lirdprapamongkol K.; Svasti J.; Techasakul S.; Mahidol C.; Ruchirawat S.; Kittakoop P.; Sagayap C.; Mahidol UniversityObjectives: Essential oils from many plants have been reported to have anti-inflammatory activity. However, essential oil of Wurfbainia schmidtii leaves has never been reported for anti-inflammatory activity. Moreover, previous works on the essential oil compositions of W. schmidtii (synonyms Amomum biflorum and Amomum schmidtii) reported varied compositions in its oils. This work aims at investigating the essential oil compositions of W. schmidtii and its anti-inflammatory activity, as well as virucidal activity against SARS-CoV-2 virus. Methods: The composition of W. schmidtii essential oil was analyzed by gas chromatography-mass spectrometry (GC-MS) technique. A crude hexane extract of W. schmidtii was separated by chromatographic method, giving a major phenylbutanoid, trans-p-(l-butenyl)-anisole (1), whose structure was elucidated by analysis of 1D and 2D 1H nuclear magnetic resonance (NMR) spectra. Anti-inflammatory activity of the essential oil and the major compound 1 was evaluated, and virucidal activity of against SARS-CoV-2 virus was assessed for compound 1. Results: A major component in W. schmidtii essential oil was found to be trans-p-(l-butenyl)-anisole (1), accounting for 88.69%, and it exhibited virucidal activity against SARS-CoV-2 with EC50 value of 119.60 μM. W. schmidtii essential oil and the major compound 1 exhibited anti-inflammatory activity with the IC50 values of 0.0282 mg/mL and 12.74 μM, respectively. Conclusion: trans-p-(l-Butenyl)-anisole (1) was the major compound in the essential oil of W. schmidtii, and it displayed anti-inflammatory and virucidal activities. The essential oil of W. schmidtii showed anti-inflammatory activity.Item Metadata only Anti-Xanthine Oxidase 5′-Hydroxyhericenes A-D from the Edible Mushroom Hericium erinaceus and Structure Revision of 3-[2,3-Dihydroxy-4-(hydroxymethyl)tetrahydrofuran-1-yl]-pyridine-4,5-diol(2023-01-01) Thongkongkaew T.; Jariyasopit N.; Khoomrung S.; Siritutsoontorn S.; Jitrapakdee S.; Kittakoop P.; Ruchirawat S.; Mahidol UniversityHericium erinaceus is an edible mushroom with diverse pharmaceutical applications. Although this mushroom is an attractive source of natural products for cancer treatment, little is known about the bioactive compounds from this mushroom, which may possess antibreast cancer activity. Here, we report the isolation and structure elucidation of new compounds, 5′-hydroxyhericenes A-D (1-4) as an inseparable mixture, together with known compounds (5-16) from the fruiting body of H. erinaceus. Based on NMR spectroscopic data and MS fragmentation analysis, the structure of a previously reported natural product, 3-[2,3-dihydroxy-4-(hydroxymethyl)tetrahydrofuran-1-yl]-pyridine-4,5-diol (5), should be revised to adenosine (6). Compounds 1-4 inhibit xanthine oxidase activity, while compounds 6, 9, and 10 scavenge reactive oxygen species generated by xanthine oxidase. Moreover, hericerin (13) exhibits strong growth inhibitory activity against T47D breast cancer cells and, to a lesser extent, against MDA-MB-231 breast cancer and MRC-5 normal embryonic cells. Exposure of T47D and MDA-MB-231 cells slightly increased PARP cleavage, suggesting that the growth inhibitory effect of hericerin may be mediated through nonapoptotic pathways. Our results suggest that the bioactive compounds of mushroom H. erinaceus hold promise as antibreast cancer agents.Item Metadata only Antiviral and virucidal activities against SARS-CoV-2 and antibacterial properties of bile acids and their salts with naturally occurring organic cations of l-carnitine, creatinine, and choline(2026-01-01) Varongkriengkrai C.; Chutiwitoonchai N.; Leerach N.; Sureram S.; Pooprasert T.; Aree T.; Khoomrung S.; Mahidol C.; Ruchirawat S.; Kittakoop P.; Varongkriengkrai C.; Mahidol UniversityBile acids have many roles in biological systems, and they have received great attention recently. Bile from a cow, known as gall, together with garlic, wine, and leeks, is used in the traditional medicine recipe of Bald's Leechbook, a thousand-year-old Anglo-Saxon formula for the treatment of infected eyelash follicles. Different aspects of previous works on bile acids have been reported, and this work adds antiviral, virucidal, and antibacterial properties of bile acids and their salts against SARS-CoV-2. Four bile acids, lithocholic acid (LCA, 1), deoxycholic acid (DCA, 5), ursodeoxycholic acid (UDCA, 9), and chenodeoxycholic acid (CDCA, 13), were used to form salts with l-carnitine [X], creatinine [Y], and choline [Z], which are naturally occurring compounds. Bile acids and their salts were evaluated for antiviral and virucidal activities against SARS-CoV-2 as well as for their antibacterial properties. Among the bile acids tested, LCA (1) was found to display virucidal activity against SARS-CoV-2 with an EC50of 9.69 µg mL−1and a selectivity index (SI) of >5.16. However, its salts, [LCA][X] (2), [LCA][Y] (3), and [LCA][Z] (4), were 1.31–3.27 times less active than the bile acid LCA (1), indicating that salt forms of this bile acid did not have improved virucidal activity. Bile acids DCA (5), UDCA (9), and CDCA (13) exhibited antibacterial activity against Gram-positive bacteria (Bacillus cereus, Staphylococcus aureus, Staphylococcus epidermidis, and Enterococcus faecalis) and against a Gram-negative bacterium (Escherichia coli). Cholinium salts of these bile acids exhibited enhanced antibacterial activity; for example, 41.4–41.5% antibacterial improvement was observed for the [DCA][Z] (8) salt when compared with its corresponding bile acid DCA (5). This work provides evidence that certain salts of bile acids have improved antibacterial activity, but they do not enhance antiviral properties.Item Metadata only Auroranes A–G: Polyoxygenated cyclohex(a/e)ne diterpenes from Kaempferia aurora and their anti-inflammatory activity via inhibition of nitric oxide production(2026-04-01) Booranaseensuntorn P.; Boonsombat J.; Thongnest S.; Sirirak J.; Kongwaen P.; Jongsomjainuk O.; Suriyo T.; Sitthimonchai N.; Ruchisansakun S.; Charoensutthivarakul S.; Kittakoop P.; Satayavivad J.; Mahidol C.; Ruchirawat S.; Booranaseensuntorn P.; Mahidol UniversityKaempferia species have long been used in traditional medicine; however, their diterpenoid constituents remain underexplored, particularly in relation to anti-inflammatory potential. In this work, the chemical constituents and anti-inflammatory properties of Kaempferia aurora were investigated. Seven polyoxygenated cyclohex(a/e)ne diterpene esters, auroranes A–G (3–9), together with their biosynthetic precursors, antiacanthoic acid (1), and antiacanthol (2), were isolated from the rhizomes of K. aurora. Their structures and relative configurations were determined by extensive spectroscopic analyses. The absolute configurations of compounds 6–8 were assigned using NMR-based DP4+ probability calculations in combination with TDDFT-calculated ECD spectra. These compounds represent a structurally rare subclass of diterpenoids within the Zingiberaceae, contributing to the phytochemical diversity of this plant group. All compounds, except for compounds 2 and 3, were evaluated for their inhibitory effects on nitric oxide (NO) production in LPS-stimulated RAW 264.7 macrophages. Compounds 1, 4–6, 8, and 9 exhibited notable NO inhibitory activity, with IC50 values ranging from 4.82 to 9.00 μM. To explore potential molecular interactions, molecular docking and molecular dynamics simulations were performed, suggesting favorable binding of the active compounds to inducible nitric oxide synthase (iNOS). A preliminary structure–activity relationship (SAR) analysis indicated that the presence of an epoxide ring or a double bond within the cyclohexane ring moiety may contribute to the observed activity. These findings provide a basis for further investigation into the bioactive constituents of K. aurora and may support its value as a potential source of anti-inflammatory agents.Item Metadata only Bioisosteric Design Identifies Inhibitors of Mycobacterium tuberculosis DNA Gyrase ATPase Activity(2023-05-08) Kamsri B.; Pakamwong B.; Thongdee P.; Phusi N.; Kamsri P.; Punkvang A.; Ketrat S.; Saparpakorn P.; Hannongbua S.; Sangswan J.; Suttisintong K.; Sureram S.; Kittakoop P.; Hongmanee P.; Santanirand P.; Leanpolchareanchai J.; Goudar K.E.; Spencer J.; Mulholland A.J.; Pungpo P.; Mahidol UniversityMutations in DNA gyrase confer resistance to fluoroquinolones, second-line antibiotics for Mycobacterium tuberculosis infections. Identification of new agents that inhibit M. tuberculosis DNA gyrase ATPase activity is one strategy to overcome this. Here, bioisosteric designs using known inhibitors as templates were employed to define novel inhibitors of M. tuberculosis DNA gyrase ATPase activity. This yielded the modified compound R3-13 with improved drug-likeness compared to the template inhibitor that acted as a promising ATPase inhibitor against M. tuberculosis DNA gyrase. Utilization of compound R3-13 as a virtual screening template, supported by subsequent biological assays, identified seven further M. tuberculosis DNA gyrase ATPase inhibitors with IC50 values in the range of 0.42-3.59 μM. The most active compound 1 showed an IC50 value of 0.42 μM, 3-fold better than the comparator ATPase inhibitor novobiocin (1.27 μM). Compound 1 showed noncytotoxicity to Caco-2 cells at concentrations up to 76-fold higher than its IC50 value. Molecular dynamics simulations followed by decomposition energy calculations identified that compound 1 occupies the binding pocket utilized by the adenosine group of the ATP analogue AMPPNP in the M. tuberculosis DNA gyrase GyrB subunit. The most prominent contribution to the binding of compound 1 to M. tuberculosis GyrB subunit is made by residue Asp79, which forms two hydrogen bonds with the OH group of this compound and also participates in the binding of AMPPNP. Compound 1 represents a potential new scaffold for further exploration and optimization as a M. tuberculosis DNA gyrase ATPase inhibitor and candidate anti-tuberculosis agent.Item Metadata only Design, synthesis, in silico and in vitro evaluation of pyrrole-indole hybrids as dual tubulin and aromatase inhibitors with potent anticancer activities(2025-06-27) Saruengkhanphasit R.; Chatwichien J.; Ngiwsara L.; Lirdprapamongkol K.; Niwetmarin W.; Eurtivong C.; Kittakoop P.; Svasti J.; Ruchirawat S.; Saruengkhanphasit R.; Mahidol UniversityTwenty-four new pyrrolyl-3-phenyl-1H-indole-2-carbohydrazide derivatives were designed, synthesized and evaluated for their anticancer activities and dual inhibition properties against tubulin and aromatase. Their anticancer activities were highly potent against the NCI60 human cancer cell line panel. Amongst them, single chloro-substituted derivative 3h was the strongest tubulin inhibitor, disrupting the microtubule structure by inhibiting the colchicine site, while potently inhibiting aromatase (IC50 = 1.8 µM) with strong activity against the estrogen receptor-positive T47D breast cancer cell line (IC50 = 2.4 µM). Ester derivative 3k showed the best aromatase inhibitory activity (IC50 = 18 nM) with moderate anti-T47D activity (IC50 = 10.6 µM). Molecular docking predicted the derivatives inhibited the colchicine site of tubulin by forming mainly hydrophobic interactions with the surrounding amino acid residues. Moreover, heme chelation with the pyrrole ring was predicted as a key interaction, and the formation of intermolecular bonds with adjacent amino acid residues was predicted as important for inhibitory activity.Item Metadata only Discovery of procyanidin condensed tannins of (−)-epicatechin from Kratom, Mitragyna speciosa, as virucidal agents against SARS-CoV-21(2024-07-01) Sureram S.; Chutiwitoonchai N.; Pooprasert T.; Sangsopha W.; Limjiasahapong S.; Jariyasopit N.; Sirivatanauksorn Y.; Khoomrung S.; Mahidol C.; Ruchirawat S.; Kittakoop P.; Sureram S.; Mahidol UniversityKratom, Mitragyna speciosa, is one of the most popular herbs in the West and Southeast Asia. A number of previous works have focused on bioactive alkaloids in this plant; however, non-alkaloids have never been investigated for their biological activities. Antiviral and virucidal assays of a methanol leaf extract of Kratom, M. speciosa, revealed that a crude extract displayed virucidal activity against the SARS-CoV-2. Activity-guided isolation of a methanol leaf extract of Kratom led to the identification of B-type procyanidin condensed tannins of (−)-epicatechin as virucidal compounds against SARS-CoV-2. The fraction containing condensed tannins exhibited virucidal activity with an EC50 value of 8.38 μg/mL and a selectivity index (SI) value >23.86. LC-MS/MS analysis and MALDI-TOF MS identified the structure of the virucidal compounds in Kratom as B-type procyanidin condensed tannins, while gel permeation chromatograph (GPC) revealed weight average molecular weight of 238,946 Da for high molecular-weight condensed tannins. In addition to alkaloids, (−)-epicatechin was found as a major component in the leaves of M. speciosa, but it did not have virucidal activity. Macromolecules of (−)-epicatechin, i.e., procyanidin condensed tannins, showed potent virucidal activity against SARS-CoV-2, suggesting that the high molecular weights of these polyphenols are important for virucidal activity.Item Metadata only 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 UniversityDirect 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.Item Metadata only Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis(2022-04-11) Pakamwong B.; Thongdee P.; Kamsri B.; Phusi N.; Kamsri P.; Punkvang A.; Ketrat S.; Saparpakorn P.; Hannongbua S.; Ariyachaokun K.; Suttisintong K.; Sureram S.; Kittakoop P.; Hongmanee P.; Santanirand P.; Spencer J.; Mulholland A.J.; Pungpo P.; Mahidol UniversityMycobacterium tuberculosis DNA gyrase manipulates the DNA topology using controlled breakage and religation of DNA driven by ATP hydrolysis. DNA gyrase has been validated as the enzyme target of fluoroquinolones (FQs), second-line antibiotics used for the treatment of multidrug-resistant tuberculosis. Mutations around the DNA gyrase DNA-binding site result in the emergence of FQ resistance in M. tuberculosis; inhibition of DNA gyrase ATPase activity is one strategy to overcome this. Here, virtual screening, subsequently validated by biological assays, was applied to select candidate inhibitors of the M. tuberculosis DNA gyrase ATPase activity from the Specs compound library (www.specs.net). Thirty compounds were identified and selected as hits for in vitro biological assays, of which two compounds, G24 and G26, inhibited the growth of M. tuberculosis H37Rv with a minimal inhibitory concentration of 12.5 μg/mL. The two compounds inhibited DNA gyrase ATPase activity with IC50values of 2.69 and 2.46 μM, respectively, suggesting this to be the likely basis of their antitubercular activity. Models of complexes of compounds G24 and G26 bound to the M. tuberculosis DNA gyrase ATP-binding site, generated by molecular dynamics simulations followed by pharmacophore mapping analysis, showed hydrophobic interactions of inhibitor hydrophobic headgroups and electrostatic and hydrogen bond interactions of the polar tails, which are likely to be important for their inhibition. Decreasing compound lipophilicity by increasing the polarity of these tails then presents a likely route to improving the solubility and activity. Thus, compounds G24 and G26 provide attractive starting templates for the optimization of antitubercular agents that act by targeting DNA gyrase.Item Metadata only In Vitro Development of Local Antiviral Formulations with Potent Virucidal Activity Against SARS-CoV-2 and Influenza Viruses(2025-03-01) Ponphaiboon J.; Krongrawa W.; Limmatvapirat S.; Tubtimsri S.; Jittmittraphap A.; Leaungwutiwong P.; Mahidol C.; Ruchirawat S.; Kittakoop P.; Limmatvapirat C.; Ponphaiboon J.; Mahidol UniversityBackground/Object: This study investigates the in vitro antiviral potential of D-limonene (DLM), monolaurin (ML), and cetylpyridinium chloride (CPC) in formulations targeting SARS-CoV-2 and influenza viruses. The aim was to develop oral and nasal formulations with optimized concentrations of these active ingredients to evaluate their efficacy, safety, and stability. Methods: Oral (formulation D) and nasal (formulation E) products were developed using specific concentrations of DLM (0.2–0.3% w/w), ML (0.1–0.2% w/w), and CPC (0.05–0.075% w/w). In vitro virucidal activity assays were conducted to assess the antiviral efficacy of the formulations against SARS-CoV-2 and influenza viruses. Stability testing was also performed under various storage conditions. Results: Formulation D (0.3% w/w DLM, 0.2% w/w ML, 0.05% w/w CPC, and 1.5% w/w Cremophor RH40) demonstrated a 3.875 ± 0.1021 log reduction and 99.99 ± 0.0032% efficacy against SARS-CoV-2 within 120 s. Formulation E (0.2% w/w DLM, 0.05% w/w CPC, and 0.75% w/w Cremophor RH40) showed a 2.9063 ± 0.1197 log reduction and 99.87 ± 0.0369% efficacy against SARS-CoV-2. Both formulations achieved >99.99% efficacy and log reductions exceeding 4.000 against various influenza strains. Stability testing confirmed optimal performance at 4 °C with no microbial contamination. Conclusions: The findings suggest that both formulations exhibit broad-spectrum antiviral activity against SARS-CoV-2 and influenza viruses in vitro. These results support their potential for further clinical evaluations and therapeutic applications, particularly in oral and nasal spray formulations.Item Metadata only 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 UniversityMycobacterium 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.Item Metadata only Regulation of adipocyte differentiation and lipid metabolism by novel synthetic chromenes exploring anti-obesity and broader therapeutic potential(2025-02-03) Inthanon K.; Wong-a-nan N.; Dheeranupattana S.; Guerra A.G.; Davies N.M.; Kesornpun C.; Sangher S.; Kittakoop P.; Inthanon K.; Mahidol UniversityObesity poses a significant global health challenge, necessitating the search for novel therapeutic agents to address this epidemic. Chromenes, known for their diverse bioactivities, hold promise as potential anti-obesity compounds, yet research in this area remains limited. This pioneering study represents the first exploration of synthetic chromenes as potential anti-obesity agents, unveiling the underlying molecular pathways governing adipogenesis and lipolysis. Twenty-nine chromenes were synthesized using green chemistry approaches, resulting in five novel compounds: 1, 2, 3, 4, and 5. Among them, 14 chromenes demonstrated a lack of toxicity to pre-adipocytes (PAs) and mature adipocytes (MAs) of 3T3-L1 cells. The anti-adipogenesis and lipolysis enhancement potential of these non-toxic 14 chromenes were comprehensively evaluated using Oil Red O staining technique, LDH activity measurement, and glycerol release assays. Notably, 4, 5, 21 and 25 exhibited remarkable efficacy in reducing intracellular lipid accumulation without inducing cellular stress or cell death. Molecular analysis revealed significant alterations in the expression of key transcription factors involved in adipogenesis and lipid metabolism, including PPARγ, C/EBPα, ADD-1, Pref-1, IRS-1, GLUT-4, adiponectin, FAS, aP2, ATGL, and HSL. This suggests their potential role in anti-adipogenesis. Additionally, the treatments with 4 and 25 showed potential for enhancing lipolysis, providing further evidence of their anti-obesity properties. This study presents several promising prospects for the development of synthetic chromenes as potential anti-obesity agents, opening new avenues for drug discovery and benefitting individuals worldwide in addressing obesity-related challenges to human health. In addition, predictive in silico modeling was performed on the identified candidate chromenes. This modeling provides prospective anti-HIV activity, pharmacokinetic, metabolism, and permeability data, setting the groundwork for further investigation into these potential new chemical entities.Item Metadata only Spatial Mapping of Stereoisomeric and Isobaric Alkaloids in Mitragyna speciosa Tissues by High-Resolution DESI-cIM-MS(2025-12-02) Wisanpitayakorn P.; Konsue A.; Sartyoungkul T.; In-on A.; Sirivatanauksorn Y.; Gang D.R.; Kittakoop P.; Khoomrung S.; Wisanpitayakorn P.; Mahidol UniversityConventional mass spectrometry imaging (MSI), even when combined with low-resolution ion mobility, lacks the resolving power to distinguish stereoisomers. To address this limitation, we developed a high-resolution desorption electrospray ionization cyclic ion mobility mass spectrometry (DESI-cIM-MS) method for in situ separation and spatial mapping of stereoisomeric compounds, using Mitragyna speciosa (kratom) as a model system. We characterized and validated the separation of four mitragynine-type stereoisomers─mitragynine (MG), speciogynine (SG), mitraciliatine (MC), and speciociliatine (SC)─using chemical standards. Notably, SC exhibited two gas-phase conformers, fast (SC-F) and slow (SC-S), supported by quantum chemical calculations. Using multipass separation and targeted ion slicing, we resolved and mapped SG, MC, and SC-S in surface-spotted standards. To address coelution between MG and SC-F, we developed a pixel-wise subtraction strategy based on the SC-F/SC-S intensity ratio to mitigate SC-F interference in the MG ion image. Direct analysis of kratom twig tissue revealed distinct spatial distributions for each stereoisomer. MG was found broadly throughout the twig except in the xylem. MC was concentrated in the pith, with some presence in the bark. SC and SG were predominantly localized in the bark, especially the epidermis. Furthermore, we resolved two additional important alkaloids, paynantheine and 7-OH-mitragynine, from their isobaric compounds; both were distributed throughout the twig except the xylem. These findings demonstrate the importance of high-resolution ion mobility in MSI for accurately resolving structurally similar compounds and improving spatial analysis in metabolomics and natural product research.Item Metadata only 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 UniversityProtein 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.Item Metadata only Synthesis, in silico, in vitro evaluation of furanyl- and thiophenyl-3-phenyl-1H-indole-2-carbohydrazide derivatives as tubulin inhibitors and anticancer agents(2024-01-01) Saruengkhanphasit R.; Ngiwsara L.; Lirdprapamongkol K.; Chatwichien J.; Niwetmarin W.; Eurtivong C.; Kittakoop P.; Svasti J.; Ruchirawat S.; Saruengkhanphasit R.; Mahidol UniversityTwenty-one new indole derivatives comprising of seven furanyl-3-phenyl-1H-indole-carbohydrazide derivatives and fourteen thiophenyl-3-phenyl-1H-indole-carbohydrazide derivatives were synthesised and biologically evaluated for their microtubule-destabilising effects, and antiproliferative activities against the National Cancer Institute 60 (NCI60) human cancer cell line panel. Among the derivatives, 6i showed the best cytotoxic activity exhibiting selectivity for COLO 205 colon cancer (LC50 = 71 nM), SK-MEL-5 melanoma cells (LC50 = 75 nM), and MDA-MB-435 (LC50 = 259 nM). Derivative 6j showed the strongest microtubule-destabilising effect. Both 6i and 6j were able to induce G2/M cell cycle arrest and apoptosis in MDA-MB-231 triple-negative breast cancer cells. Molecular docking simulation results suggested that these derivatives inhibit tubulin by binding at the colchicine site. The calculated molecular descriptors showed that the most potent derivatives have acceptable pharmacokinetic profiles and are favourable for oral drug administration.Item Metadata only Traveling Wave Ion Mobility-Derived Collision Cross Section Database for Plant Specialized Metabolites: An Application to Ventilago harmandiana Pierre(2022-10-07) Jariyasopit N.; Limjiasahapong S.; Kurilung A.; Sartyoungkul S.; Wisanpitayakorn P.; Nuntasaen N.; Kuhakarn C.; Reutrakul V.; Kittakoop P.; Sirivatanauksorn Y.; Khoomrung S.; Mahidol UniversityThe combination of ion mobility mass spectrometry (IM-MS) and chromatography is a valuable tool for identifying compounds in natural products. In this study, using an ultra-performance liquid chromatography system coupled to a high-resolution quadrupole/traveling wave ion mobility spectrometry/time-of-flight MS (UPLC-TWIMS-QTOF), we have established and validated a comprehensive TWCCSN2and MS database for 112 plant specialized metabolites. The database included 15 compounds that were isolated and purified in-house and are not commercially available. We obtained accurate m/z, retention times, fragment ions, and TWIMS-derived CCS (TWCCSN2) values for 207 adducts (ESI+and ESI-). The database included novel 158 TWCCSN2values from 79 specialized metabolites. In the presence of plant matrix, the CCS measurement was reproducible and robust. Finally, we demonstrated the application of the database to extend the metabolite coverage of Ventilago harmandiana Pierre. In addition to pyranonaphthoquinones, a group of known specialized metabolites in V. harmandiana, we identified flavonoids, xanthone, naphthofuran, and protocatechuic acid for the first time through targeted analysis. Interestingly, further investigation using IM-MS of unknown features suggested the presence of organonitrogen compounds and lipid and lipid-like molecules, which is also reported for the first time. Data are available on the MassIVE (https://massive.ucsd.edu, data set identifier MSV000090213).