Medicinal Chemistry Research最新文献

{"title":"Pancreatic lipase inhibitors as anti-obesity agents: a review of recent chemical scaffolds and their pancreatic lipase inhibitory potential","authors":"Noor ul Amin Mohsin,&nbsp;Matloob Ahmad,&nbsp;Maryam Farrukh,&nbsp;Sidra Rafique","doi":"10.1007/s00044-025-03371-y","DOIUrl":"10.1007/s00044-025-03371-y","url":null,"abstract":"<div><p>Obesity is an excessive accumulation of fat in the body. The disease of obesity is increasing all over the world. At present, only a few drugs are available for the treatment of obesity. Various strategies have been explored for the management of obesity. The inhibition of fat metabolizing enzyme, pancreatic lipase (PL) is one of the best strategies for its treatment. In recent years, many organic compounds, heterocyclic and phytochemicals have been evaluated as PL inhibitors. The nitrogen-containing heterocyclic compounds have acquired great consideration due to their significant biological activities. Most of the compounds have been evaluated by in vitro and in silico experiments. The review highlights the PL inhibitory effects of different chemical scaffolds.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"497 - 516"},"PeriodicalIF":2.6,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, in vitro evaluation, and molecular dynamics simulation studies of novel coumarin-acetohydrazide Schiff base derivatives as urease enzyme inhibitors","authors":"Mohammad Azimi,&nbsp;Hassan Sepehrmansourie,&nbsp;Ahmad Ebadi,&nbsp;Gholamabbas Chehardoli,&nbsp;Mohammad Ali Zolfigol,&nbsp;Massoud Amanlou,&nbsp;Mohammad Nazari Montazer,&nbsp;Mohammad Mahdavi,&nbsp;Zahra Najafi","doi":"10.1007/s00044-024-03369-y","DOIUrl":"10.1007/s00044-024-03369-y","url":null,"abstract":"<div><p>Urease inhibition, a nickel-containing metalloenzyme, is a promising approach for treating Helicobacter pylori (H. pylori) infections as a critical virulence factor that allows the bacteria to colonize the gastric mucosa and survive the acidic environment of the stomach. In this context, we report the design, synthesis, in vitro evaluation, and molecular dynamics simulation (MD) studies of novel ((4,7-dimethyl-2-oxo-2<i>H</i>-chromen-5-yl)oxy)acetohydrazide derivatives as urease enzyme inhibitors. Notably, all compounds exhibited potent inhibitory activities, with IC₅₀ values ranging from 2.438 µM to 4.427 µM. Further kinetic studies revealed that compound <b>11g</b> as the most potent compound with IC₅₀ value of 2.438 ± 0.31 μM acts as a non-competitive inhibitor toward urease with an inhibition constant (Ki) of 2.33 μM. In silico studies elucidated the binding interactions of compound <b>11g</b>, revealing crucial hydrogen bonds with key amino acid residues as well as chelation with Ni ions within the active site of urease. Molecular dynamics (MD) simulations confirmed the stable ligand-urease complex maintains interactions with both the active site residues and the flap moiety of urease, acting as noncompetitive inhibitors. These findings demonstrate the potential of coumarin-acetohydrazide Schiff base derivatives as a new frontier in developing urease inhibitors.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"675 - 689"},"PeriodicalIF":2.6,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vitro and in silico studies on α-glucosidase inhibitory properties of bioactive components from the rhizomes of Alpinia officinarum Hance","authors":"Zakhele Mphatsi Dlamini,&nbsp;Bongani Sicelo Dlamini,&nbsp;Shih-Han Fu,&nbsp;Ya-Lin Chang,&nbsp;Chi-Chien Lin,&nbsp;Yu-Kuo Chen,&nbsp;Kok-Tong Tan,&nbsp;Chi-I Chang","doi":"10.1007/s00044-024-03366-1","DOIUrl":"10.1007/s00044-024-03366-1","url":null,"abstract":"<div><p>Key digestive enzymes, <i>α</i>-glucosidase and <i>α</i>-amylase, are associated with the occurrence of type 2 diabetes mellitus (T2DM). Inhibition of these important enzymes is one of the important strategies for the treatment of T2DM. In the search for alternative <i>α</i>-glucosidase inhibitors, five compounds (<b>1–5</b>) were obtained from the rhizomes of <i>Alpinia officinarum</i> Hance by chromatographic methods. In vitro enzyme inhibition assays, kinetic analysis, and molecular docking studies were conducted to investigate the inhibition mechanism of the isolated compounds against <i>α</i>-glucosidase. Compounds <b>1</b>, <b>3</b>, <b>4</b>, and <b>5</b> showed comparable <i>α</i>-glucosidase inhibitory activities to quercetin (IC₅₀ value of 19.77 µM) with IC₅₀ values ranging from 37.48 to 89.08 µM. According to the findings of the kinetic analysis, compounds <b>1</b>, <b>2</b>, and <b>4</b> were uncompetitive inhibitors, while compound <b>3</b> was a competitive inhibitor and compound <b>5</b> was a mixed-type inhibitor of <i>α</i>-glucosidase. In the computational investigation, hydrogen bonds served as the primary bond between the compounds and the amino acid residues. The results showed that <i>A. officinarum</i> might be a viable source of <i>α</i>-glucosidase inhibitors and antidiabetic agents.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"664 - 674"},"PeriodicalIF":2.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of novel triconjugates fusing melatonin/isatin/N-acylhydrazone targeting colorectal cancer: design, synthesis, biological, and in silico ADME/Tox profiling","authors":"Sara M. Gutiérrez,&nbsp;Wilson Cardona-Galeano,&nbsp;Angie Herrera-Ramírez,&nbsp;Andres F. Yepes","doi":"10.1007/s00044-024-03358-1","DOIUrl":"10.1007/s00044-024-03358-1","url":null,"abstract":"<div><p>Herein, a new library of triconjugates linked melatonin with the biological active cores of isatin and <i>N</i>-acylhydrazone were designed, synthetized, and their biological activity was evaluated in human colorectal cancer cells. All compounds were screened to determine the potential at a single dose of 100 µM against human colon adenocarcinoma SW480 cells, finding one compound <b>3e</b> which caused 100% inhibition and a certain grade of lethality at the conditions evaluated. In addition, the most active and soluble hybrids were further assessed using a five-dose scheme in the same colon cancer cells, and non-malignant human colon epithelial cells (NCM460) to establish the selective potential, finding that hybridized molecules <b>3e</b>, <b>3g</b>, and <b>3l</b> were more cytotoxic than parental compounds and 4-fold more selective than the reference drug (5-fluorouracil, 5-FU) which shows that molecular hybridization remains as a valuable tool to produce novel chemical entities that may result in advances in medicine. Lastly, according to a theoretical analysis on drug-like properties, pharmacokinetics, and toxicology, for the most promising hybrid <b>3e</b> would show a strong possibility of moving on to further preclinical research. Our results clearly demonstrated the effectiveness of melatonin/isatin/<i>N</i>-acylhydrazone triconjugates, with the 2-hydroxyphenylsubstituted compound in particular serving as a prototype drug for future investigations into innovative therapeutic treatments for colorectal cancer.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"648 - 663"},"PeriodicalIF":2.6,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis and anti-inflammatory activity of chromone-sulfonamide derivatives as COXs/iNOS dual-target inhibitors","authors":"Meng Qin,&nbsp;Tao Xing,&nbsp;Mengdi Zhang,&nbsp;Jiatong Han,&nbsp;Shuyan Yu,&nbsp;Jianping Chen,&nbsp;Yuheng Ma","doi":"10.1007/s00044-024-03368-z","DOIUrl":"10.1007/s00044-024-03368-z","url":null,"abstract":"<div><p>Cyclooxygenase and inducible nitric oxide synthase are key proteins in two different pathways that produce inflammation. In this study, we based on the principle of pharmacophore combination to obtain small molecules that can block the dual targets of COXs and iNOS. We screened two pharmacophores with anti-inflammatory activity, chromone ring and sulfonamide from clinical drugs, natural products and other compounds with outstanding biological activity, and synthesized 9 novel chromone-sulfonamide derivatives, among which compounds 4a, 4b, 4c, 4d and 4i exhibited different degrees of COXs and iNOS inhibition. In particular, compound 4i exhibited the most significant dual inhibitory effect, with an IC₅₀ of 28.83 ± 0.06 μM for PGE₂ and an IC₅₀ of 36.95 ± 3.9 μM for NO content, which was superior to the positive drugs ibuprofen (IBU, IC₅₀ = 246.5 ± 3.8 μM) and L-canavanine (L-Can., IC₅₀ = 440.0 ± 7.9 μM). In addition, the research group used Discovery Studio to dock the target compounds with COX-1, COX-2 and iNOS, respectively, and the results showed that compound 4i had the best docking method (its -CDOCK INTERACTION ENERGY scores were 48.2967, 45.3519 and 43.4412, respectively, which were better than those of other compounds), which was consistent with the results of activity experiments, and the chromone ring and sulfonamide group could form hydrogen bonds between the two target proteins, conjugation and van der Waals interactions, indicating that the chromone ring and sulfonamide group are key pharmacophores. In addition, a preliminary study of the structure-activity relationship of the compound was carried out to identify the key factors affecting the anti-inflammatory activity, and 4i matched the structure-activity relationship, which indicated that 4i was a lead compound for the development of dual COXs/iNOS inhibition for the treatment of inflammatory diseases.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"638 - 647"},"PeriodicalIF":2.6,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143480975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and neuroprotective activity of salidroside-based dual inhibitors of selective monoamine oxidase B and amyloid-β aggregation","authors":"Juan Zhang,&nbsp;Kong-Kai Zhu,&nbsp;Kai-Ming Wang,&nbsp;Cheng-Shi Jiang","doi":"10.1007/s00044-024-03367-0","DOIUrl":"10.1007/s00044-024-03367-0","url":null,"abstract":"<div><p>This study focuses on the design, synthesis, and evaluation of a series of salidroside derivatives (pOBZ-1~pOBZ-11) for their potential as inhibitors of monoamine oxidase B (MAO-B) and amyloid beta (Aβ₄₂) aggregation, and neuroprotective agents. Among the synthesized derivatives, pOBZ-1 and pOBZ-2 exhibited superior MAO-B inhibitory activity compared to salidroside, with notable selectivity over MAO-A. These compounds demonstrated linear competitive inhibition. Additionally, the derivatives effectively inhibited Aβ₄₂ aggregation and protected SH-SY5Y cells from Aβ₄₂ and hydrogen peroxide (H₂O₂)-induced neurotoxicity. The findings suggest that pOBZ-2, in particular, holds promise as a therapeutic candidate for Alzheimer’s disease.</p><h3>Graphical abstract</h3><div><figure><div><div><picture><source><img></source></picture></div><div><p>Novel dual inhibitors of selective MAO-B/amyloid-β aggregation</p></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"625 - 637"},"PeriodicalIF":2.6,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, synthesis, and evaluation of benzylpiperidine-derived hydrazones as dual inhibitors of monoamine oxidases and acetylcholinesterase","authors":"Nikita Negi,&nbsp;Senthil R. Ayyannan,&nbsp;Rati K. P. Tripathi","doi":"10.1007/s00044-024-03365-2","DOIUrl":"10.1007/s00044-024-03365-2","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder characterized by cognitive decline and memory loss, with currently available treatments offering limited effectiveness, underscoring the need for multifunctional therapies. This study investigates benzylpiperidine derivatives as dual inhibitors of monoamine oxidases (MAOs) and acetylcholinesterase (AChE), enzymes implicated in AD pathology. Benzylpiperidine-derived hydrazones (4–13) were designed, synthesized and evaluated for inhibition against AChE and MAO-A/B isoforms. Among all, compounds <b>8</b> and <b>5</b> demonstrated a balanced multifunctional profile, effectively inhibiting MAO-A, MAO-B, and AChE. Compound <b>8</b> exhibited high potency against AChE (IC₅₀ = 0.064 ± 0.001 μM), comparable to donepezil (IC₅₀ = 0.084 ± 0.002 μM), with moderate inhibition of MAO-A (IC₅₀ = 2.55 ± 0.02 μM) and MAO-B (IC₅₀ = 1.47 ± 0.06 μM). Conversely, compound <b>5</b> displayed strongest inhibition against MAO-A (IC₅₀ = 0.26 ± 0.01 μM) and MAO-B (IC₅₀ = 0.116 ± 0.005 μM) within the series, along with moderate AChE inhibition (IC₅₀ = 3.70 ± 0.14 μM). Both compounds showed antioxidant activity, though mild neurotoxicity. Molecular docking studies highlighted crucial intermolecular interactions, including π-π stacking and H-bonding, essential for ligand-protein stabilization. Computational ADMET predictions suggested favorable drug-like properties, while conformational alignment studies further elucidated their binding efficiency compared to reference drugs. These findings showcase benzylpiperidine derivatives as potential multifunctional agents for further development in AD treatment, with compounds <b>8</b> and <b>5</b> emerging as primary leads for additional refinement.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"583 - 601"},"PeriodicalIF":2.6,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481108","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel alkoxy- and prenyl-xanthones derivatives as potential antidiabetic agents: Synthesis, in vitro evaluation and in silico studies","authors":"Gabriel Vázquez-Lira,&nbsp;Brandon Hernández-Gutierrez,&nbsp;María C. Cruz-López,&nbsp;Patricia Ibarra-Torres,&nbsp;Omar Gomez-García,&nbsp;Joaquín Tamariz,&nbsp;Aarón Mendieta-Moctezuma","doi":"10.1007/s00044-024-03364-3","DOIUrl":"10.1007/s00044-024-03364-3","url":null,"abstract":"<div><p>Novel alkoxy-xanthones <b>5</b>, <b>7</b>, <b>9</b>, <b>10</b>, and <b>10-14</b> were synthesized and evaluated in vitro for their ability to inhibit α-glucosidase, α-amylase, and pancreatic lipase. Compounds <b>5c</b>, <b>9</b> <b>d</b>, <b>11</b> <b>d</b>, and <b>14b</b> exhibited potent α-glucosidase inhibition (IC₅₀ 20.3, 32.4, 35.2, and 18.0 µM, respectively) while showing lower activity against α-amylase compared to acarbose (IC₅₀ 308.0 µM for α-glucosidase and 25.0 µM for α-amylase). In contrast, <b>9b</b> and <b>10c</b> demonstrated moderate inhibition and selectivity for α-amylase. Additionally, <b>10a</b> and <b>10c</b> displayed mild inhibitory effects across these digestive enzymes. These results suggest that the (4-chlorophenyl)-2-oxoethoxy moiety linked to the 3-hydroxy group of xanthone core is a potent inhibitor against of α-glucosidase and has mild activity against α-amylase, whereas the allyloxy moiety shows a modest inhibitory effect. Kinetic studies indicated that compounds <b>9b</b> and <b>11b</b> are mixed inhibitors of α-glucosidase and non-competitive inhibitors of α-amylase. For pancreatic lipase, <b>10c</b> acted as an uncompetitive inhibitor. Docking studies further supported the critical role of these hydrophobic groups in interacting with the catalytic pocket of these enzymes. ADMET studies identified derivatives <b>5c</b>, <b>10a</b>, <b>10c</b>, and <b>11b</b> as promising candidates for the developing antidiabetic agents.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"602 - 624"},"PeriodicalIF":2.6,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multivalent MMP-12 inhibitors as a valuable approach to counteract the intestinal epithelial barrier impairment and inflammation in an in vitro model mimicking intestinal high-fat exposure","authors":"Doretta Cuffaro,&nbsp;Vanessa D’Antongiovanni,&nbsp;Camilla Mangini,&nbsp;Clelia Di Salvo,&nbsp;Laura Benvenuti,&nbsp;Jennifer Vandooren,&nbsp;Marco Macchia,&nbsp;Luca Antonioli,&nbsp;Armando Rossello,&nbsp;Matteo Fornai,&nbsp;Elisa Nuti","doi":"10.1007/s00044-024-03361-6","DOIUrl":"10.1007/s00044-024-03361-6","url":null,"abstract":"<div><p>Intestinal epithelial barrier (IEB) impairment represents a prodromal event underlying obesity and related systemic inflammation. In this context, metalloproteinase-12 (MMP-12) has been reported to increase the IEB permeability through the reduction of tight junction proteins expression. Herein we report our effort to develop a small series of MMP-12 inhibitors as potential agents able to counteract the IEB alterations and intestinal inflammation associated with obesity. Three multivalent and gut-restricted carboxylate-based selective inhibitors of MMP-12 were synthesized and tested first on human recombinant MMP-12 isolated enzyme and then on human intestinal epithelial Caco-2 cells treated with palmitate (PA) and lipopolysaccharide (LPS), to mimic the in vivo exposure to hypercaloric diet. Trimeric derivative <b>2</b> in particular showed a nanomolar activity against MMP-12 and was able to increase both ZO-1 and claudin-1 tight junction expression in a concentration-dependent manner, already at a concentration of 50 nM. This compound was also the most effective in reducing interleukin-1β release from Caco-2 cells treated with PA and LPS. This preliminary work indicates that a pharmacological modulation of MMP-12 represents a promising strategy to counteract the impairment of IEB integrity and intestinal inflammation associated with obesity.</p></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 3","pages":"571 - 582"},"PeriodicalIF":2.6,"publicationDate":"2024-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143481107","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis, bacteria activity and molecular simulation of D-galactose-conjugated thiosemicarbazones of 3-aryl-4-formylsydnones","authors":"Nguyen Dinh Thanh,&nbsp;Vu Ngoc Toan,&nbsp;Duong Ngoc Toan,&nbsp;Vu Minh Trang","doi":"10.1007/s00044-024-03363-4","DOIUrl":"10.1007/s00044-024-03363-4","url":null,"abstract":"<div><p>A series of D-galactose-conjugated substituted 4-formylsydnone thiosemicarbazones <b>4a-j</b> were designed and synthesized from appropriate substituted 3-aryl-4-formylsydnones <b>2a-j</b> and tetra-<i>O</i>-acetyl-β-<span>d</span>-galactopyranose <b>3</b>. These synthesized thioureas exhibited the remarkable inhibitory activity against both selected Gram-(+)- and Gram-(–)-bacteria. Amongst them, thiosemicarbazones <b>4a</b>,<b>b</b>,<b>c</b>,<b>f</b>,<b>j</b> were the most potent inhibitors against Gram-(+) bacterial strains with MIC values of 0.78–1.56 μg/mL, while compounds <b>4b</b>,<b>c</b>,<b>g</b>,<b>j</b> had the most inhibitions against Gram-(–) bacterial ones with MIC values of 0.78–1.56 μg/mL. The thiosemicarbazones <b>4b</b>, <b>4c</b>, <b>4</b> <b>f</b> and that contain simultaneously two methyl or methyl/nitro substituents on benzene ring exhibited the strong inhibition against both Gram-(+), including MRSA bacterium, and Gram-(–) bacterial strains with MIC values of 0.78–1.56 μg/mL. In addition, compound <b>4j</b> had strongest potent inhibitory activity against <i>S. aureus</i> DNA Gyrase and compound <b>4b</b> was the strongest inhibitor against <i>S. aureus</i> Topoisomerase IV. Almost all of the most potential compounds had low toxicity to WI-38 normal cell line. The in silico studies, including predictive ADMET and induced fit docking simulations, for the most potential compounds were performed. Molecular dynamics simulations applied for two most potential complexes <b>4b</b>/URN and <b>4j</b>/4URO to understand their mechanism of active interaction for these respective enzymes.</p><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":699,"journal":{"name":"Medicinal Chemistry Research","volume":"34 2","pages":"476 - 495"},"PeriodicalIF":2.6,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142925773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}