Medicinal Chemistry最新文献

{"title":"Triple Action of Lignosulfonic Acid Sodium: Anti-protease, Antioxidant, and Anti-inflammatory Effects of a Polymeric Heparin Mimetic.","authors":"Rami A Al-Horani, Kholoud F Aliter","doi":"10.2174/0115734064275120231222111145","DOIUrl":"10.2174/0115734064275120231222111145","url":null,"abstract":"<p><strong>Background: </strong>Heparins are sulfated glycosaminoglycans that are used as anticoagulants to treat thrombosis. Heparins exhibit other potential therapeutic effects, such as anti-inflammatory, anti-viral, and anti-malarial effects. However, the strong anticoagulant activity of heparins poses a risk of life-threatening bleeding, limiting their therapeutic use for other diseases beyond thrombosis. To exploit the other effects of heparins and eliminate the bleeding risk, we explored an alternative polymer called lignosulfonic acid sodium (LSAS), which acts as a sulfonated heparin mimetic. LSAS targets factor XIa to exert an anticoagulant effect, and thus, unlike heparins, it is unlikely to cause bleeding.</p><p><strong>Methods: </strong>This study investigated the multiple effects of LSAS to identify potential leads for complex pathologies treatment. A series of chromogenic substrate hydrolysis assays were used to evaluate the inhibition of three inflammation-related proteases by LSAS. Its chemical antioxidant activity against the system of ABTS/hydrogen peroxide/metmyoglobin was also determined. Lastly, the effect of LSAS on TNFα-induced activation of the NF-κB pathway in HEK-293 cells was also tested to determine its cellular anti-inflammatory activity.</p><p><strong>Results: </strong>The results showed that LSAS effectively inhibited human neutrophil elastase, cathepsin G, and plasmin, with IC₅₀ values ranging from 0.73 to 212.5 μg/mL. Additionally, LSAS demonstrated a significant chemical antioxidant effect, with an IC50 value of 44.1 μg/mL. Furthermore, at a concentration of approximately 530 μg/mL, LSAS inhibited the TNFα-induced activation of the NF-κB pathway in HEK-293 cells, indicating a substantial anti-inflammatory effect. An essential advantage of LSAS is its high water solubility and virtual non-toxicity, making it a safe and readily available polymer.</p><p><strong>Conclusion: </strong>Based on these findings, LSAS is put forward as a polymeric heparin mimetic with multiple functions, serving as a potential platform for developing novel therapeutics to treat complex pathologies.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"414-421"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11228124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting the Efficacy of Novel Synthetic Compounds in the Treatment of Osteosarcoma <i>via</i> Anti-Receptor Activator of Nuclear Factor-κB Ligand (RANKL)/Receptor Activator of Nuclear Factor-κB (RANK) Targets.","authors":"Wenhua Zhang, Siping Xu, Peng Liu, Xusheng Li, Xinyuan Yu, Bing Kang","doi":"10.2174/0115734064287922240222115200","DOIUrl":"10.2174/0115734064287922240222115200","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma (OS) currently demonstrates a rising incidence, ranking as the predominant primary malignant tumor in the adolescent demographic. Notwithstanding this trend, the pharmaceutical landscape lacks therapeutic agents that deliver satisfactory efficacy against OS.</p><p><strong>Objective: </strong>This study aimed to authenticate the outcomes of prior research employing the HM and GEP algorithms, endeavoring to expedite the formulation of efficacious therapeutics for osteosarcoma.</p><p><strong>Methods: </strong>A robust quantitative constitutive relationship model was engineered to prognosticate the IC₅₀ values of innovative synthetic compounds, harnessing the power of gene expression programming. A total of 39 natural products underwent optimization <i>via</i> heuristic methodologies within the CODESSA software, resulting in the establishment of a linear model. Subsequent to this phase, a mere quintet of descriptors was curated for the generation of non-linear models through gene expression programming.</p><p><strong>Results: </strong>The squared correlation coefficients and <i>s</i>2 values derived from the heuristics stood at 0.5516 and 0.0195, respectively. Gene expression programming yielded squared correlation coefficients and mean square errors for the training set at 0.78 and 0.0085, respectively. For the test set, these values were determined to be 0.71 and 0.0121, respectively. The s2 of the heuristics for the training set was discerned to be 0.0085.</p><p><strong>Conclusion: </strong>The analytic scrutiny of both algorithms underscores their commendable reliability in forecasting the efficacy of nascent compounds. A juxtaposition based on correlation coefficients elucidates that the GEP algorithm exhibits superior predictive prowess relative to the HM algorithm for novel synthetic compounds.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"733-740"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11348461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design, Synthesis and Evaluation of Antifungal Activity of Pyrazoleacetamide Derivatives.","authors":"Onkar G Kachi, Hari R Pawar, Anuruddha R Chabukswar, Swati Jagdale, Vishwanath Swamy, Kadam Vinayak, Dattatray Hingane, Mahadev Shinde, Nagesh Pawar","doi":"10.2174/0115734064300961240417063246","DOIUrl":"10.2174/0115734064300961240417063246","url":null,"abstract":"<p><strong>Background: </strong>Fungal infections have posed a big challenge in the management of their treatment. Due to the resistance and toxicity of existing drug molecules in the light of pandemic infections, like COVID-19, there is an urgent need to find newer derivatives of active molecules, which can be effective in fungal infections.</p><p><strong>Objective: </strong>In the present study, we aimed to design pyrazole derivatives using molecular modeling studies against target 1EA1 and synthesize 10 molecules of pyrazole derivatives using a multi-step synthesis approach.</p><p><strong>Methods: </strong>Designed pyrazole derivatives were synthesized by conventional organic methods. The newly synthesized pyrazole molecules were characterized by using FT-IR, ¹HNMR, ¹³CNMR, and LC-MS techniques. Molecular docking studies were also performed. The antifungal activity of newly synthesized compounds was assessed <i>in vitro</i> against <i>Candida albicans and Aspergillus niger</i> using the well plate method.</p><p><strong>Results: </strong>Two of the compounds, OK-7 and OK-8, have been found to show significant docking interaction with target protein 1EA1. These two compounds have also been found to show significant anti-fungal activity against <i>Candida albicans</i> and <i>Aspergillus nigra</i> when compared to the standard fluconazole. The Minimum Inhibitory Concentration (MIC) value of these two compounds has been found to be 50 μg/ml.</p><p><strong>Conclusion: </strong>Pyrazole derivatives with -CH₃, CH₃O-, and -CN groups have been found to be active against tested fungi and can be further explored for their potential as promising anti-fungal agents for applications in the field of medicinal chemistry.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"957-968"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141311058","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":"The Catalysts-Based Synthetic Approaches to Quinolines: A Review.","authors":"Shrishti Tripathi, Rajnish Kumar, Avijit Mazumder, Salahuddin, Neelima Kukreti, Arvind Kumar, Saurabh Singh","doi":"10.2174/0115734064315729240610045009","DOIUrl":"10.2174/0115734064315729240610045009","url":null,"abstract":"<p><p>The most common heterocyclic aromatic molecule with potential uses in industry and medicine is quinoline. Its chemical formula is C9H7N, and it has a distinctive double-ring structure with a pyridine moiety fused with a benzene ring. Various synthetic approaches synthesize quinoline derivatives. These approaches include solvent-free synthetic approach, mechanochemistry, ultrasonic, photolytic synthetic approach, and microwave and catalytic synthetic approaches. One of the important synthetic approaches is a catalyst-based synthetic approach in which different catalysts are used such as silver-based catalysts, titanium-based nanoparticle catalysts, new iridium catalysts, barium-based catalysts, iron-based catalysts, gold-based catalysts, nickel-based catalyst, some metal-based photocatalyst, α-amylase biocatalyst, by using multifunctional metal-organic framework-metal nanoparticle tandem catalyst etc. In the present study, we summarized different catalyst-promoted reactions that have been reported for the synthesis of quinoline. Hopefully, the study will be helpful for the researchers.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"921-937"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450841","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 Anticonvulsant Activity of Cinnamoyl Derivatives of 3,4,6,7,8,9-hexahydrodibenzo[<i>b,d</i>]furan-1-(2H)-one Oxime.","authors":"Grigory V Mokrov, Valentina E Biryukova, Tatiana Y Vorobieva, Andry S Pantileev, Oksana S Grigorkevich, Ludmila A Zhmurenko, Alexey G Rebeko, Felix S Bayburtskiy, Svetlana A Litvinova, Tatiana A Voronina, Tatiana A Gudasheva, Sergei B Seredenin","doi":"10.2174/1573406419666230908121759","DOIUrl":"10.2174/1573406419666230908121759","url":null,"abstract":"<p><strong>Background: </strong>Epilepsy continues to be a significant global health problem and the search for new drugs for its treatment remains an urgent task. 5-HT2 and GABAA-receptors are among promising biotargets for the search for new anticonvulsants.</p><p><strong>Methods: </strong>New potential 5-HT2 and GABAA ligands in the series of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime were designed using pharmacophore model and molecular docking analysis. The synthesis of new compounds was carried out from 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1(2H)-one oxime and substituted cinnamoyl chlorides. The anticonvulsant activity of new substances has been established using the maximal electroshock seizure test.</p><p><strong>Results: </strong>Several synthesized substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo [b,d]furan-1-(2H)-one oxime significantly reduced the severity of convulsive manifestations and completely prevented the death of animals after MES. The structure-activity relationship was investigated. The most effective compound was found to be GIZH-348 (1g) (3,4,6,7,8,9-hexahydrodibenzo[ b,d]furan-1(2Н)-one О-(4-chlorophenyl)acryloyl)oxime) at the doses of 10-20 mg/kg.</p><p><strong>Conclusion: </strong>Molecular and pharmacophore modelling methods allowed us to create a new group of substituted cinnamoyl derivatives of 3,4,6,7,8,9-hexahydrodibenzo[b,d]furan-1-(2H)-one oxime with anticonvulsant activity.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"92-107"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10554806","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 and Synthesis of New <i>bis</i>-oxindole and Spiro(triazole-oxindole) as CDK4 Inhibitors with Potent Anti-breast Cancer Activity.","authors":"Thoraya A Farghaly, Rami A Pashameah, Abrar Bayazeed, Amerah M Al-Soliemy, Amani M R Alsaedi, Marwa F Harras","doi":"10.2174/1573406419666230810124855","DOIUrl":"10.2174/1573406419666230810124855","url":null,"abstract":"<p><strong>Background: </strong>Since CDKs have been demonstrated to be overexpressed in a wide spectrum of human malignancies, their inhibition has been cited as an effective technique for anticancer drug development.</p><p><strong>Methods: </strong>In this context, new bis-oxindole/spiro-triazole-oxindole anti-breast cancer drugs with potential CDK4 inhibitory effects were produced in this work. The novel series of bis-oxindole/spirotriazole- oxindole were synthesized from the reaction of bis-oxindole with the aniline derivatives then followed by 1,3-dipolar cycloaddition of hydrazonoyl chloride.</p><p><strong>Results: </strong>The structure of these bis-oxindole/spiro-triazole-oxindole series was proven based on their spectral analyses. Most bis-oxindole and bis-spiro-triazole-oxindole compounds effectively inhibited the growth of MCF-7 (IC₅₀ = 2.81-17.61 μM) and MDA-MB-231 (IC₅₀ = 3.23-7.98 μM) breast cancer cell lines with low inhibitory activity against normal WI-38 cells. While the reference doxorubicin showed IC50 values of 7.43 μM against MCF-7 and 5.71 μM against the MDA-MB-231 cell line. Additionally, compounds 3b, 3c, 6b, and 6d revealed significant anti-CDK4 activity (IC₅₀ = 0.157- 0.618 μM) compared to palbociclib (IC₅₀ = 0.071 μM). Subsequent mechanistic investigations demonstrated that 3c was able to trigger tumor cell death through the induction of apoptosis. Moreover, it stimulated cancer cell cycle arrest in the G1 phase. Furthermore, western blotting disclosed that the 3c-induced cell cycle arrest may be mediated through p21 upregulation.</p><p><strong>Conclusion: </strong>According to all of the findings, bis-oxindole 3c shows promise as a cancer treatment targeting CDK4.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"63-77"},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10657899","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, Antimicrobial Evaluation, and Interaction of Emodin Alkyl Azoles with DNA and HSA.","authors":"Yu-Hang Zhou, Ying Wang, Hui-Zhen Zhang","doi":"10.2174/0115734064283049240124115544","DOIUrl":"10.2174/0115734064283049240124115544","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to overcome the growing antibiotic resistance. Moreover, the new series of emodin alkyl azoles were synthesized.</p><p><strong>Method: </strong>The novel emodin alkyl azoles were synthesized using commercial emodin and azoles by alkylation. The NMR and HRMS spectra were employed to confirm the structures of novel prepared compounds. The <i>in vitro</i> antibacterial and antifungal activities of the prepared emodin compounds were studied by the 96-well plate method. The binding behavior between emodin 4-nitro imidazole compound 3c and <i>S. aureus</i> DNA was researched using an ultraviolet-visible spectrophotometer. Furthermore, fluorescence spectrometry was used to explore the interaction with human serum albumin (HSA).</p><p><strong>Results: </strong>The <i>in vitro</i> antimicrobial results displayed that compound 3c gave relatively strong activities with MIC values of 4-16 μg/mL. Notably, this compound exhibited 2-fold more potent activity against <i>S. aureus</i> (MIC = 4 μg/mL) and <i>E. coli</i> (MIC = 8 μg/mL) strains than clinical drug Chloromycin (MIC = 8 and 16 μg/mL). The UV-vis absorption spectroscopy showed that 4-nitro imidazole emodin 3c could form the 3c-DNA complex by intercalating into <i>S. aureus</i> DNA, inhibiting antimicrobial activities. The simulation results displayed that the emodin 3c and DNA complex were formed by hydrogen bonds. The spectral experiment demonstrated that compound 3c could be transported by human serum albumin (HSA) <i>via</i> hydrogen bonds. The molecular simulation found that the hydroxyl group and the nitroimidazole ring of the emodin compound showed an important role in transportation behavior.</p><p><strong>Conclusion: </strong>This work may supply useful directions for the exploration of novel antimicrobial agents.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"422-433"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139729982","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":"A Review of Antidiabetic Medicinal Plants as a Novel Source of Phosphodiesterase Inhibitors: Future Perspective of New Challenges Against Diabetes Mellitus.","authors":"Hayat Ouassou, Nour Elhouda Daoudi, Saliha Bouknana, Rhizlan Abdnim, Mohamed Bnouham","doi":"10.2174/0115734064255060231116192839","DOIUrl":"10.2174/0115734064255060231116192839","url":null,"abstract":"<p><p>Intracellular glucose concentration plays a crucial role in initiating the molecular secretory process of pancreatic β-cells through multiple messengers and signaling pathways. Cyclic nucleotides are key physiological regulators that modulate pathway interactions in β -cells. An increase of cyclic nucleotides is controled by hydrolysed phosphodiesterases (PDEs), which degrades cyclic nucleotides into inactive metabolites. Despite the undeniable therapeutic potential of PDE inhibitors, they are associated with several side effects. The treatment strategy for diabetes based on PDE inhibitors has been proposed for a long time. Hence, the world of natural antidiabetic medicinal plants represents an ideal source of phosphodiesterase inhibitors as a new strategy for developing novel agents to treat diabetes mellitus. This review highlights medicinal plants traditionally used in the treatment of diabetes mellitus that have been proven to have inhibitory effects on PDE activity. The contents of this review were sourced from electronic databases, including Science Direct, PubMed, Springer Link, Web of Science, Scopus, Wiley Online, Scifinder and Google Scholar. These databases were consulted to collect information without any limitation date. After comprehensive literature screening, this paper identified 27 medicinal plants that have been reported to exhibit anti-phosphodiesterase activities. The selection of these plants was based on their traditional uses in the treatment of diabetes mellitus. The review emphasizes the antiphosphodiesterase properties of 31 bioactive components derived from these plant extracts. Many phenolic compounds have been identified as PDE inhibitors: Brazilin, mesozygin, artonin I, chalcomaracin, norartocarpetin, moracin L, moracin M, moracin C, curcumin, gallic acid, caffeic acid, rutin, quercitrin, quercetin, catechin, kaempferol, chlorogenic acid, and ellagic acid. Moreover, smome lignans have reported as PDE inhibitors: (+)-Medioresinol di-O-β-d-glucopyranoside, (+)- Pinoresinol di-O-β-d-glucopyranoside, (+)-Pinoresinol-4-O-β-d-glucopyranosyl (1→6)-β-dglucopyranoside, Liriodendrin, (+)-Pinoresinol 4'-O-β-d-glucopyranoside, and forsythin. This review provides a promising starting point of medicinal plants, which could be further studied for the development of natural phosphodiesterase inhibitors to treat diabetes mellitus. Therefore, it is important to consider clinical studies for the identification of new targets for the treatment of diabetes.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"467-486"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139542424","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":"Biochemical and <i>In Silico</i> Studies on Triazole Derivatives as Tyrosinase Inhibitors: Potential Treatment of Hyperpigmentation Related Skin Disorders.","authors":"Yusra Choudhary, Atia-Tul-Wahab, Humaira Zafar, Salman Siddiqui, Majid Khan, Khalid M Khan, Amer H Asseri, M Iqbal Choudhary, Atta-Ur-Rahman","doi":"10.2174/0115734064271581231219111952","DOIUrl":"10.2174/0115734064271581231219111952","url":null,"abstract":"<p><strong>Introduction: </strong>Tyrosinase is a versatile, glycosylated copper-containing oxidase enzyme that mainly catalyzes the biosynthesis of melanin in mammals. Its overexpression leads to the formation of excess melanin, resulting in hyperpigmentary skin disorders, such as dark spots, melasma, freckles, etc. Therefore, inhibition of tyrosinase is a therapeutic approach for the treatment of hyperpigmentation.</p><p><strong>Methods: </strong>The current study focused on evaluating tyrosinase inhibitory activities of triazole derivatives 1-20, bearing different substituents on the phenyl ring. 17 derivatives have shown a potent tyrosinase inhibition with IC₅₀ values between 1.6 to 13 μM, as compared to the standard drug, i.e., kojic acid (IC₅₀ = 24.1 ± 0.5 μM). Particularly, compounds 11 and 15 displayed 12 times more potent inhibitory effects than the kojic acid.</p><p><strong>Results: </strong>The structure-activity relationship revealed that substituting halogens at the C-4 position of the benzene ring renders remarkable anti-tyrosinase activities. Compounds 1-3 and 8 showed a competitive type of inhibition, while compounds 5, 11, and 15 showed a non-competitive mode of inhibition. Next, we performed molecular docking analyses to study the binding modes and interactions between the ligands (inhibitors) and the active site of the tyrosinase enzyme (receptor). Besides this, we have assessed the toxicity profile of inhibitors on the BJ human fibroblast cell line.</p><p><strong>Conclusion: </strong>The majority of the newly identified tyrosinase inhibitors were found to be noncytotoxic. The results presented herein form the basis of further studies on triazole derivatives as potential drug leads against tyrosinase-related diseases.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"397-413"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139996699","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 and Synthesis of 6-amido-3-carboxypyridazine Derivatives as Potent T3SS Inhibitors of <i>Salmonella enterica</i> Serovar Typhimurium.","authors":"Zhenyu Li, Zhiyong Liu, Yuemao Shen, Chengwu Shen","doi":"10.2174/0115734064252833231129062005","DOIUrl":"10.2174/0115734064252833231129062005","url":null,"abstract":"<p><strong>Background: </strong><i>Salmonella enterica (S. enterica)</i> serovar Typhimurium, an anaerobic enteric pathogene, could cause human and animal diseases ranging from mild gastroenteritis to whole body serious infections.</p><p><strong>Objective: </strong>The goal of this paper was to synthesize new 6-amido-3-carboxypyridazine derivatives with different lengths of side chains with the aim of getting potent antibacterial agents.</p><p><strong>Methods: </strong>Synthesized compounds were analyzed by analytical techniques, such as ¹H NMR, ¹³C NMR spectra, and mass spectrometry. We designed a series of novel 6-amido-3-carboxypyridazines using FA as the lead compound with the scaffold hopping strategy and their inhibitory activity against the effectors of type III secretion system (T3SS) using SDS-PAGE and western blot analysis for two rounds. Also, the preliminary mechanism of action of this series of compounds on T3SS was performed using real-time qPCR.</p><p><strong>Results: </strong>Nine 6-amido-3-carboxypyridazines was synthesized. The inhibitory activities evaluated showed that compound 2i was the most potent T3SS inhibitor, which demonstrated potent inhibitory activities on the secretion of the T3SS SPI-1 effectors in a dose-dependent manner. The transcription of SPI-1 may be affected by compound 2i through the <i>SicA/InvF</i> regulatory pathway.</p><p><strong>Conclusion: </strong>The novel synthetic 6-amido-3-carboxypyridazines could act as potent leads for the development of novel antibacterial agents.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":" ","pages":"689-693"},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403588","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}