Lee H, Park H, Kwak K
… +6 more, Lee CE, Yun J, Lee D, Lee JH, Lee SH, Kang LW
J Enzyme Inhib Med Chem
· 2025 Dec · PMID 39714271
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β-lactams have been the most successful antibiotics, but the rise of multi-drug resistant (MDR) bacteria threatens their effectiveness. Serine β-lactamases (SBLs), among the most common causes of resistance, are classifi...β-lactams have been the most successful antibiotics, but the rise of multi-drug resistant (MDR) bacteria threatens their effectiveness. Serine β-lactamases (SBLs), among the most common causes of resistance, are classified as A, C, and D, with numerous variants complicating structural and substrate spectrum comparisons. This study compares representative SBLs of these classes, focusing on the substrate-binding pocket (SBP). SBP is kidney bean-shaped on the indented surface, formed mainly by loops L1, L2, and L3, and an additional loop Lc in class C. β-lactams bind in a conserved orientation, with the β-lactam ring towards L2 and additional rings towards the space between L1 and L3. Structural comparison shows each class has distinct SBP structures, but subclasses share a conserved scaffold. The SBP structure, accommodating complimentary β-lactams, determines the substrate spectrum of SBLs. The systematic comparison of SBLs, including structural compatibility between β-lactams and SBPs, will help understand their substrate spectrum.
Fuchs K, Totaro MG, Toplak M
… +2 more, Bijelic A, Macheroux P
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39654448
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The efficient inhibition of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) by the broad-spectrum herbicide glyphosate validates the shikimate pathway as a promising target for developing antimicrobial, fungicidal an...The efficient inhibition of 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) by the broad-spectrum herbicide glyphosate validates the shikimate pathway as a promising target for developing antimicrobial, fungicidal and herbicidal agents. The last enzyme of this pathway, chorismate synthase (CS), catalyses an unusual reaction, making it an attractive target for novel inhibitors. Therefore, we tested a series of azo-dyes for their inhibitory potential against CS from the pathogenic fungus (CS) and identified the azo-dye PH011669 that exhibits a dissociation () and 50% inhibitory constant (IC) of 1.1 ± 0.1 and 10 ± 1 µM, respectively. Molecular docking and MD simulations provided insight into the mode of inhibition, showing that PH011669 binds to the enzyme's active site primarily through electrostatic interactions. Thus, our study is the first to integrate structural and computational methods to guide future efforts towards designing the next generation of CS inhibitors.
Bartolić M, Matošević A, Maraković N
… +6 more, Bušić V, Roca S, Vikić-Topić D, Sabljić A, Bosak A, Gašo-Sokač D
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39654394
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The growing prevalence of Alzheimer's disease calls for a drug that can simultaneously act towards several targets involved in the pathophysiology of the disease. In our study, we evaluated the potential of hydrazone and...The growing prevalence of Alzheimer's disease calls for a drug that can simultaneously act towards several targets involved in the pathophysiology of the disease. In our study, we evaluated the potential of hydrazone and -acylhydrazone derivatives of vitamin B6 and pyridine-4-carbaldehyde to be used as multi-target directed ligands targeting cholinergic system by inhibiting acetyl- and butyrylcholinesterase, lowering the accumulation of β-amyloid plaques by inhibiting both the β-secretase activity and amyloid self-aggregation, and maintaining the biometal balance by chelating certain biometals. Our results showed that all of the tested hydrazones were potent inhibitors of human cholinesterases with inhibition constants (i) in micromolar range able to lower the activity of β-secretase, inhibit amyloid aggregation, chelate biometals and act as antioxidants. Also, most of them were estimated to be able to cross the blood-brain barrier by passive transport and to be absorbed in human intestines as well as with moderate metabolic stability in liver microsomes.
Popczyk P, Ghinet A, Bortolus C
… +5 more, Kamus L, Lensink MF, de Ruyck J, Sendid B, Dubar F
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39589067
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Worldwide, invasive candidiasis are a burden for the health system due to difficulties to manage patients, to the increasing of the resistance of the current therapeutics and the emergence of naturally resistant species...Worldwide, invasive candidiasis are a burden for the health system due to difficulties to manage patients, to the increasing of the resistance of the current therapeutics and the emergence of naturally resistant species of . In this context, the development of innovative antifungal drugs is urgently needed. During invasive candidiasis, yeast is submitted to many stresses (oxidative, thermic, osmotic) in the human host. In order to resist in this context, yeast develops different strategy, especially the biosynthesis of trehalose. Starting from the 3D structural data of TPS2, an enzyme implicated in trehalose biosynthesis, we identified hydrazone as an interesting scaffold to design new antifungal drugs. Interestingly, our hydrazone derivatives which demonstrate antifungal and anti-biofilm effects on ., are non-toxic in and models ().
Li H, Jia MQ, Qin ZL
… +7 more, Lu C, Chu W, Zhang Z, Niu J, Song J, Zhang SY, Fu L
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39560175
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In this work, thirty 2,4-diarylaminopyrimidine-based hydrazones were designed, synthesised, and their anti-thyroid cancer activity were explored. The majority of compounds exhibit moderate to excellent cytotoxic activity...In this work, thirty 2,4-diarylaminopyrimidine-based hydrazones were designed, synthesised, and their anti-thyroid cancer activity were explored. The majority of compounds exhibit moderate to excellent cytotoxic activity against FAK overexpressing TPC-1 cells, with IC values ranging from 0.113 to 1.460 μM. Among them, compound displayed exceptional anti-proliferative effect against TPC-1 cells (IC = 0.113 μM) and potent FAK inhibitory potency (IC = 35 nM). In studies indicated that compound could well bind to FAK (Focal Adhesion Kinase) and have favourable pharmacokinetic profiles. In addition, compound could inhibit the phosphorylation of FAK at Tyr397, Tyr576/577 and Tyr925, and did not affect the expression level of FAK in TPC-1 cells. Compound was also effective in inhibiting the proliferation and migration of thyroid cancer cells TPC-1. Thus, these novel 4-arylaminopyrimidine hydrazone derivatives exhibited potent anti-thyroid cancer activities through the inhibition of FAK.
Morcos CA, Haiba NS, Bassily RW
… +5 more, Abu-Serie MM, El-Yazbi AF, Soliman OA, Khattab SN, Teleb M
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39513468
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A series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by M...A series of triazole-tethered triazines bearing pharmacophoric features of DNA-targeting agents and non-hydroxamate MMPs inhibitors were synthesized and screened against HCT-116, Caco-2 cells, and normal colonocytes by MTT assay. and surpassed doxorubicin against HCT-116 cells regarding potency (IC = 0.87 and 1.41 nM) and safety (SI = 181.93 and 54.41). was potent against liver cancer (HepG-2; IC = 65.08 nM), the main metastatic site of CRC with correlation to MMP-13 expression. Both derivatives induced DNA damage at 2.67 and 1.87 nM, disrupted HCT-116 cell cycle and triggered apoptosis by 33.17% compared to doxorubicin (DNA damage at 0.76 nM and 40.21% apoptosis induction). surpassed NNGH against MMP-10 (IC = 0.205 μM) and MMP-13 (IC = 0.275 μM) and downregulated HCT-116 VEGF related to CRC progression by 38%. Docking and MDs simulated ligands-receptors binding modes and highlighted SAR. Their ADMET profiles, drug-likeness and possible off-targets were computationally predicted.
Tu HJ, Chao MW, Lee CC
… +8 more, Peng CS, Wu YW, Lin TE, Chang YW, Yen SC, Hsu KC, Pan SL, HuangFu WC
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39494990
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Dual-specificity tyrosine-regulated kinase 1 A (DYRK1A) is crucial in neurogenesis, synaptogenesis, and neuronal functions. Its dysregulation is linked to neurodegenerative disorders like Down syndrome and Alzheimer's di...Dual-specificity tyrosine-regulated kinase 1 A (DYRK1A) is crucial in neurogenesis, synaptogenesis, and neuronal functions. Its dysregulation is linked to neurodegenerative disorders like Down syndrome and Alzheimer's disease. Although the development of DYRK1A inhibitors has significantly advanced in recent years, the selectivity of these drugs remains a critical challenge, potentially impeding further progress. In this study, we utilised structure-based virtual screening (SBVS) from NCI library to discover novel DYRK1A inhibitors. The top-ranked compounds were then validated through enzymatic assays to assess their efficacy towards DYRK1A. Among them, NSC361563 emerged as a potent and selective DYRK1A inhibitor. It was shown to decrease tau phosphorylation at multiple sites, thereby enhancing tubulin stability. Moreover, NSC361563 diminished the formation of amyloid β and offered neuroprotective benefits against amyloid β-induced toxicity. Our research highlights the critical role of selective DYRK1A inhibitors in treating neurodegenerative diseases and presents a promising starting point for the development of targeted therapies.
Choi YS, Kim YJ, Jeon Y
… +7 more, Kang JS, Lee J, Hong E, Park YH, Kim W, Cha B, Jeon R
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39494490
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Transcriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds...Transcriptional enhanced associate domain (TEAD) transcription factors undergo auto-palmitoylation, which is critical to mediate their function and maintain stability. Targeting the palmitate binding pocket of TEAD holds considerable promise for drug discovery, and it can be characterised into three components: a conserved cysteine, a hydrophobic main pocket, and a hydrophilic side pocket. Endogenous palmitate and several known TEAD inhibitors interact with the cysteine and hydrophobic residues in the deep hydrophobic pocket. We anticipate that precise targeting of the polar side pocket could facilitate the discovery of inhibitors with enhanced potencies and properties. Herein, we selected niflumic acid as the core scaffold suitable for targeting the three characteristic components of TEAD palmitate pocket. Reversible and irreversible compounds with substituents capable of directing each part of the palmitate pocket were designed. The newly synthesised compounds inhibited the palmitoylation and transcriptional activity of TEAD and elicited growth-inhibitory effects against several carcinomas, including mesothelioma.
González-González A, Sánchez-Sánchez O, Yépez-Mulia L
… +11 more, Delgado-Maldonado T, Vázquez-Jiménez LK, López-Velázquez G, de la Mora-de la Mora JI, Pacheco-Gutierrez S, Chino-Ríos L, Arias D, Moreno-Rodríguez A, Paz-González A, Ortíz-Pérez E, Rivera G
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39470324
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In this study, n-butyl and iso-butyl quinoxaline-7-carboxylate-1,4-di--oxide derivatives were evaluated against () (), and (). The potential mechanism of action determination was approached by analysis on and trios...In this study, n-butyl and iso-butyl quinoxaline-7-carboxylate-1,4-di--oxide derivatives were evaluated against () (), and (). The potential mechanism of action determination was approached by analysis on and triosephosphate isomerase (TIM and TIM, respectively), and on thioredoxin reductase (). Enzyme inactivation assays were performed on recombinant GTIM and TrxR. Compound T-167 showed the best giardicidal activity (IC = 25.53 nM) and the highest inactivation efficiency against GTIM without significantly perturbing its human homolog. Compounds T-142 and T-143 showed the best amoebicidal (IC = 9.20 nM) and trichomonacidal (IC = 45.20 nM) activity, respectively. Additionally, T-143 had a high activity as giardicial (IC = 29.13 nM) and amoebicidal (IC = 15.14 nM), proposing it as a broad-spectrum antiparasitic agent. Compounds T-145, and T-161 were the best TrxR inhibitors with IC of 16 µM, and 18 µM, respectively.
Chen M, Chen D, Xiao R
… +3 more, Zheng X, Liu B, Wang J
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39434248
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lipopeptides have been reported to display anti-obesity effects. In the present study, Lipopeptides from FJAT-45028 that consisted of iturin, fengycin and surfactin were reported. The lipopeptides exhibited a strong lip...lipopeptides have been reported to display anti-obesity effects. In the present study, Lipopeptides from FJAT-45028 that consisted of iturin, fengycin and surfactin were reported. The lipopeptides exhibited a strong lipase inhibition activity in a concentration-dependent manner with a half maximal inhibitory concentration of 0.012 mg/mL, and the inhibition mechanism and type were reversible and competitive, respectively. Results of CCK8 assay showed that 3T3-L1 preadipocyte cells were completely viable under treatment of 0.050-0.2 mg/mL lipopeptides for 24 or 48 h. It was found that the lipopeptides could increase lipid droplets in the differentiated 3T3-L1 adipocytes in tested concentration and suppress the expression of peroxisome proliferator-activated receptor gamma (PPARγ). These results indicated the potential anti-obesity mechanism of the tested lipopeptides might be to inhibit lipase activity but not to suppress lipid accumulation in the adipocytes. Moreover, the lipopeptides could elevate glucose utilisation by 14.43%-33.81% in the differentiated 3T3-L1 adipocytes.
Han X, Lan P, Chen Q
… +4 more, Liu H, Chen Z, Wang T, Wang Z
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39431736
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Inhibiting apoptosis signal regulated kinase 1 (ASK1) is an attractive strategy for treating diseases such as non-alcoholic steatohepatitis and multiple sclerosis. Here, we report the discovery of a dibromo substituted q...Inhibiting apoptosis signal regulated kinase 1 (ASK1) is an attractive strategy for treating diseases such as non-alcoholic steatohepatitis and multiple sclerosis. Here, we report the discovery of a dibromo substituted quinoxaline fragment containing as an effective small-molecule inhibitor of ASK1, with an IC value of 30.17 nM. In addition, the cell survival rate of at different concentrations was greater than 80%, especially at 0.4 μM. Its cell survival rate was significantly higher than , indicating its good safety in normal human liver LO2 cells. The Oil Red O staining experiment showed that decreased the lipid droplets in a dose-dependent manner. Further biochemical analyses revealed that could reduce the content of T-CHO, LDL, and TG in FFA-induced LO2 cells, and had the potential to treat non-alcoholic fatty disease. These findings provide a good choice for the future development of ASK1 inhibitors.
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39404032
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1'-Hydroxy-4',8,8'-trimethoxy-[2,2'-binaphthalene]-1,4-dione (compound ), a secondary metabolite recently discovered in marine fungi, demonstrates promising cytotoxic and anticancer potential. However, knowledge regardin...1'-Hydroxy-4',8,8'-trimethoxy-[2,2'-binaphthalene]-1,4-dione (compound ), a secondary metabolite recently discovered in marine fungi, demonstrates promising cytotoxic and anticancer potential. However, knowledge regarding the anticancer activities and biological mechanisms of its derivatives remains limited. Herein, a series of novel naphthoquinone-naphthol derivatives were designed, synthesised, and evaluated for their anticancer activity against cancer cells of different origins. Among these, Compound , featuring an oxopropyl group at the -position of quinone group, exhibited the most potent inhibitory effects on HCT116, PC9, and A549 cells, with IC values decreasing from 5.27 to 1.18 μM (4.5-fold increase), 6.98 to 0.57 μM (12-fold increase), and 5.88 to 2.25 μM (2.6-fold increase), respectively, compared to compound . Further mechanistic studies revealed that compound significantly induced cell apoptosis by increasing the expression levels of cleaved caspase-3 and reducing Bcl-2 proteins through downregulating the EGFR/PI3K/Akt signalling pathway, leading to the inhibition of proliferation in HCT116 and PC9 cells. The present findings suggest this novel naphthoquinone-naphthol derivative may hold potential as an anticancer therapeutic lead.
Wang ZZ, Weng J, Qi J
… +6 more, Fu XX, Xing BB, Hu Y, Huang CH, Chen CY, Wei Z
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39390714
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The zoonosis caused by is increasing seriously. But commonly used antibiotic drugs often lead to resistance. dUTPase (dUTPase) plays a key role in the proliferation of , and was regarded as a potent drug target. Howeve...The zoonosis caused by is increasing seriously. But commonly used antibiotic drugs often lead to resistance. dUTPase (dUTPase) plays a key role in the proliferation of , and was regarded as a potent drug target. However, there was little report about the dUTPase inhibitors. In this study, we discovered a series of novel dUTPase inhibitors to fight against . The first crystal structure of dUTPase was released, and a structure-based computational design was performed. Compounds and exhibited promising activities towards dUTPase (IC = 0.99 μM and 0.7 μM). In addition, they showed satisfied anti- activity (MIC value ranges from 0.5 to 2 mg/L) and low cytotoxicity, which were better than approved drugs oxytetracycline and florfenicol. Molecular modelling study indicated that hydrophobic interaction might be the main contribution for ligand binding. Our results suggested that dUTPase inhibitors might be a useful way to repress .
Xu Z, Ye C, Wang X
… +5 more, Kong R, Chen Z, Shi J, Chen X, Liu S
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39377432
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A series of triazolopyridine-based dual JAK/HDAC inhibitors were rationally designed and synthesised by merging different pharmacophores into one molecule. All triazolopyridine derivatives exhibited potent inhibitory act...A series of triazolopyridine-based dual JAK/HDAC inhibitors were rationally designed and synthesised by merging different pharmacophores into one molecule. All triazolopyridine derivatives exhibited potent inhibitory activities against both targets and the best compound 4-(((5-(benzo[][1, ]dioxol-5-yl)-[1, 2, 4]triazolo[1, 5-]pyridin-2-yl)amino)methyl)--hydroxybenzamide (19) was dug out. 19 was proved to be a pan-HDAC and JAK1/2 dual inhibitor and displayed high cytotoxicity against two cancer cell lines MDA-MB-231 and RPMI-8226 with IC values in submicromolar range. Docking simulation revealed that 19 fitted well into the active sites of HDAC and JAK proteins. Moreover, 19 exhibited better metabolic stability in vitro than SAHA. Our study demonstrated that compound 19 was a promising candidate for further preclinical studies.
Singh M, Batt SM, Canales CSC
… +8 more, Pavan FR, Kumar SA, Akshatha HS, Bhagyalalitha M, Pujar KG, Bidye D, Pujar GV, Besra GS
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39329328
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Decaprenylphosphoryl-β-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2'-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the path...Decaprenylphosphoryl-β-D-ribose-oxidase (DprE1), a subunit of the essential decaprenylphosphoribose-2'-epimerase, plays a crucial role in the synthesis of cell wall arabinan components in mycobacteria, including the pathogen responsible for tuberculosis, . In this study, we designed, synthesised, and evaluated 15 (BOK-1-BOK-10 and BOP-1-BOP-5) potential inhibitors of DprE1 from a series of 1,2,3-triazole ligands using a validated DprE1 inhibition assay. Two compounds, BOK-2 and BOK-3, demonstrated significant inhibition with IC values of 2.2 ± 0.1 and 3.0 ± 0.6 μM, respectively, whereas the standard drug (TCA-1) showed inhibition at 3.0 ± 0.2 μM. Through molecular modelling and dynamic simulations, we explored the structural relationships between selected 1,2,3-triazole compounds and DprE1, revealing key features for effective drug-target interactions. This study introduces a novel approach for designing ligands against DprE1, offering a potential therapeutic strategy for tuberculosis treatment.
Liu Y, Ding F, Deng L
… +3 more, Zhang S, Wu L, Tong H
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39316789
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Acyl-CoA: cholesterol acyltransferase (ACAT), a pivotal enzyme in the absorption and metabolism of cholesterol, is primarily responsible for intracellular esterification. ACAT inhibition is expected to diminish plasma li...Acyl-CoA: cholesterol acyltransferase (ACAT), a pivotal enzyme in the absorption and metabolism of cholesterol, is primarily responsible for intracellular esterification. ACAT inhibition is expected to diminish plasma lipid levels by impeding intestinal cholesterol absorption, thereby preventing the progression of atherosclerotic lesions. A previous study shows that selective inhibition of ACAT2 significantly mitigated hypercholesterolaemia and atherosclerosis in mouse models. Therefore, the need for ACAT2 selective inhibitors becomes particularly urgent. In this study, we established a multilayer virtual screening workflow and subjected biologically evaluated representative compounds to enzyme inhibitory assays. The experimental results indicated that the two compounds, STL565001 (inhibition rate at 25 μM: 75.7 ± 27.8%, selectivity = 6) and STL528213 (inhibition rate at 25 μM: 87.8 ± 12.4%, selectivity = 13), demonstrated robust activity against ACAT2, displaying greater selectivity for ACAT2 than for ACAT1. The molecular mechanisms governing the inhibitory activities of the selected compounds were systematically elucidated using computational approaches. In addition, hotspot residues in ACAT2 that are crucial for ligand binding were successfully identified. In summary, we devised a multilayer screening scheme to expeditiously and efficiently identify compounds with enzyme inhibitory activity, offering novel scaffolds for subsequent drug design centred on ACAT2 targets.
Hsu KC, Huang YY, Chu JC
… +6 more, Huang YW, Hu JL, Lin TE, Yen SC, Weng JR, Huang WJ
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39316378
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Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited c...Class IIa histone deacetylases (HDACs) have been linked to tumorigenesis in various cancers. Previously, we designed phenylhydroxamic acid as a potent class IIa HDAC inhibitor. However, it also unselectively inhibited class I and class IIb HDACs. To enhance the compound's selectivity towards class IIa HDACs, the -phenyl group from the selective HDAC7 inhibitor is incorporated into position of the phenylhydroxamic acid in . Compared to , most resulting compounds displayed substantially improved selectivity towards the class IIa HDACs. Notably, compound exhibited the strongest HDAC9 inhibition with an IC value of 40 nM. Molecular modelling further identified the key interactions of compound bound to HDAC9. Compound significantly inhibited several human cancer cells, induced apoptosis, modulated caspase-related proteins as well as p38, and caused DNA damage. These findings suggest the potential of class IIa HDAC inhibitors as lead compounds for the development of cancer therapeutics.
Alasmary FAS, Abdullah DA, Masand VH
… +4 more, Ben Bacha A, Omar Ebeid AM, El-Araby ME, Alafeefy AM
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39311475
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Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applica...Quinoxalines are benzopyrazine derivatives with significant therapeutic impact in the pharmaceutical industry. They proved to be useful against inflammation, bacterial, fungal, viral infection, diabetes and other applications. Very recently, in January 2024, the FDA approved new quinoxaline containing drug, erdafitinib for treatment of certain carcinomas. Despite the diverse biological activities exhibited by quinoxaline derivatives and the role of secretory phospholipase A2 (sPLA2) in diabetes-related complications, the potential of sPLA2-targeting quinoxaline-based inhibitors to effectively address these complications remains unexplored. Therefore, we designed novel sPLA2- and α-glucosidase-targeting quinoxaline-based heterocyclic inhibitors to regulate elevated post-prandial blood glucose linked to patients with diabetes-related cardiovascular complications. Compounds and were synthesised by condensing quinoxaline hydrazides with various aryl sulphonyl chlorides. Biological screening revealed compound as a potent sPLA2 inhibitor (IC = 0.0475 µM), whereas compound most effectively inhibited α-glucosidase (IC = 0.0953 µM), outperforming the positive control acarbose. Moreover, compound was the best inhibitor for both enzymes. Molecular docking revealed pharmacophoric features, highlighting the importance of a sulfonohydrazide moiety in the structural design of these compounds, leading to the development of potent sPLA2 and α-glucosidase inhibitors. Collectively, our findings helped identify promising candidates for developing novel therapeutic agents for treating diabetes mellitus.
Abdel-Halim M, El-Gamil DS, Hammam MA
… +8 more, El-Shazly M, Wang YH, Kung PH, Chen YC, Korinek M, Abadi AH, Engel M, Hwang TL
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39297697
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Targeting neutrophil function has gained attention as a propitious therapeutic strategy for diverse inflammatory diseases. Accordingly, a series of enone-based derivatives were developed to inhibit neutrophil-mediated in...Targeting neutrophil function has gained attention as a propitious therapeutic strategy for diverse inflammatory diseases. Accordingly, a series of enone-based derivatives were developed to inhibit neutrophil-mediated inflammation, showing promise for treating inflammatory diseases. These compounds fall into two clusters with distinct effects: one inhibits neutrophilic superoxide (SO) anion production and elastase release triggered by N-formyl-Met-Leu-Phe (fMLF), with compound being most effective (IC values of 1.23 and 1.37 μM, respectively), affecting c-Jun N-terminal kinase (JNK) and Akt phosphorylation. The second cluster suppresses formation of SO anion without affecting elastase levels, surpassed by compound (IC of 1.56 μM), which attenuates various mitogen-activated protein kinases (MAPKs) with minimal Akt impact. Notably, none of the tested compounds showed cytotoxicity in human neutrophils, underscoring their potential as therapeutic agents against inflammatory diseases.
Samaha D, Mahmoud S, Mohamed MS
… +4 more, Abdullah RS, A Abou Taleb N, Nagamatsu T, Ali HI
J Enzyme Inhib Med Chem
· 2024 Dec · PMID 39287132
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This study describes the development of novel alloxazine analogues as potent antitumor agents with enhanced selectivity for tumour cells. Twenty-nine out of 45 newly compounds were investigated for their growth inhibito...This study describes the development of novel alloxazine analogues as potent antitumor agents with enhanced selectivity for tumour cells. Twenty-nine out of 45 newly compounds were investigated for their growth inhibitory activities, against two human tumour cell lines, namely, the human T-cell acute lymphoblastoid leukaemia cell line (CCRF-HSB-2) and human oral epidermoid carcinoma cell line (KB), and the antitumor agent "Ara-C" was used as a positive reference in this investigation. Compounds and were the highest among their analogues, against both tumour cell lines (CCRF-HSB-2 and KB). Correlation analyses demonstrated a strong relationship between the IC values and AutoDock binding free energy or calculated inhibition (). The study delves into structure-activity relationships (SARs) through advanced modelling tools integrated with structure-based drug design (SBDD) using GOLD 5.2.2, AutoDock 4.2, and Accelrys Discovery Studio 3.5. Physicochemical properties, pharmacokinetics, drug-likeness, and toxicity predictions of the most potent alloxazine derivatives were conducted using ProTox-II and Swiss ADME for effective antitumor agents with improved selectivity.