Pub Date : 2024-01-01DOI: 10.2174/1573406419666230908121759
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
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
{"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":null,"pages":null},"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}
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.
{"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":null,"pages":null},"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}
Pub Date : 2024-01-01DOI: 10.2174/0115734064283049240124115544
Yu-Hang Zhou, Ying Wang, Hui-Zhen Zhang
Objective: This study aimed to overcome the growing antibiotic resistance. Moreover, the new series of emodin alkyl azoles were synthesized.
Method: 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 in vitro 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 S. aureus DNA was researched using an ultraviolet-visible spectrophotometer. Furthermore, fluorescence spectrometry was used to explore the interaction with human serum albumin (HSA).
Results: The in vitro 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 S. aureus (MIC = 4 μg/mL) and E. coli (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 S. aureus 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) via 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.
Conclusion: This work may supply useful directions for the exploration of novel antimicrobial agents.
{"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":null,"pages":null},"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}
Pub Date : 2024-01-01DOI: 10.2174/0115734064271581231219111952
Yusra Choudhary, Atia-Tul-Wahab, Humaira Zafar, Salman Siddiqui, Majid Khan, Khalid M Khan, Amer H Asseri, M Iqbal Choudhary, Atta-Ur-Rahman
Introduction: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
{"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 IC<sub>50</sub> values between 1.6 to 13 μM, as compared to the standard drug, i.e., kojic acid (IC<sub>50</sub> = 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":null,"pages":null},"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}
Background: 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.
Objective: 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.
Methods: 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 via 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.
Results: The squared correlation coefficients and s2 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.
Conclusion: 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.
{"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 IC<sub>50</sub> 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":null,"pages":null},"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}
Introduction: Within the scope of the project, this study aimed to find novel inhibitors by combining computational methods. In order to design inhibitors, it was aimed to produce molecules similar to the RdRp inhibitor drug Favipiravir by using the deep learning method.
Methods: For this purpose, a Trained Neural Network (TNN) was used to produce 75 molecules similar to Favipiravir by using Simplified Molecular Input Line Entry System (SMILES) representations. The binding properties of molecules to Viral RNA-dependent RNA polymerase (RdRp) were studied by using molecular docking studies. To confirm the accuracy of this method, compounds were also tested against 3CL protease (3CLpro), which is another important enzyme for the progression of SARS-CoV-2. Compounds having better binding energies and RMSD values than favipiravir were searched with similarity analysis on the ChEMBL drug database in order to find similar structures with RdRp and 3CLpro inhibitory activities.
Results: A similarity search found new 200 potential RdRp and 3CLpro inhibitors structurally similar to produced molecules, and these compounds were again evaluated for their receptor interactions with molecular docking studies. Compounds showed better interaction with RdRp protease than 3CLpro. This result presented that artificial intelligence correctly produced structures similar to favipiravir that act more specifically as RdRp inhibitors. In addition, Lipinski's rules were applied to the molecules that showed the best interaction with RdRp, and 7 compounds were determined to be potential drug candidates. Among these compounds, a Molecular Dynamic simulation study was applied for ChEMBL ID:1193133 to better understand the existence and duration of the compound in the receptor site.
Conclusion: The results confirmed that the ChEMBL ID:1193133 compound showed good Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), hydrogen bonding, and remaining time in the active site; therefore, it was considered that it could be active against the virus. This compound was also tested for antiviral activity, and it was determined that it did not delay viral infection, although it was cytotoxic between 5mg/mL-1.25mg/mL concentrations. However, if other compounds could be tested, it might provide a chance to obtain activity, and compounds should also be tested against the enzymes as well as the other types of viruses.
{"title":"Determination of Novel SARS-CoV-2 Inhibitors by Combination of Machine Learning and Molecular Modeling Methods.","authors":"Ersin Güner, Özgür Özkan, Gözde Yalcin-Ozkat, Süreyya Ölgen","doi":"10.2174/0115734064265609231026063624","DOIUrl":"10.2174/0115734064265609231026063624","url":null,"abstract":"<p><strong>Introduction: </strong>Within the scope of the project, this study aimed to find novel inhibitors by combining computational methods. In order to design inhibitors, it was aimed to produce molecules similar to the RdRp inhibitor drug Favipiravir by using the deep learning method.</p><p><strong>Methods: </strong>For this purpose, a Trained Neural Network (TNN) was used to produce 75 molecules similar to Favipiravir by using Simplified Molecular Input Line Entry System (SMILES) representations. The binding properties of molecules to Viral RNA-dependent RNA polymerase (RdRp) were studied by using molecular docking studies. To confirm the accuracy of this method, compounds were also tested against 3CL protease (3CLpro), which is another important enzyme for the progression of SARS-CoV-2. Compounds having better binding energies and RMSD values than favipiravir were searched with similarity analysis on the ChEMBL drug database in order to find similar structures with RdRp and 3CLpro inhibitory activities.</p><p><strong>Results: </strong>A similarity search found new 200 potential RdRp and 3CLpro inhibitors structurally similar to produced molecules, and these compounds were again evaluated for their receptor interactions with molecular docking studies. Compounds showed better interaction with RdRp protease than 3CLpro. This result presented that artificial intelligence correctly produced structures similar to favipiravir that act more specifically as RdRp inhibitors. In addition, Lipinski's rules were applied to the molecules that showed the best interaction with RdRp, and 7 compounds were determined to be potential drug candidates. Among these compounds, a Molecular Dynamic simulation study was applied for ChEMBL ID:1193133 to better understand the existence and duration of the compound in the receptor site.</p><p><strong>Conclusion: </strong>The results confirmed that the ChEMBL ID:1193133 compound showed good Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), hydrogen bonding, and remaining time in the active site; therefore, it was considered that it could be active against the virus. This compound was also tested for antiviral activity, and it was determined that it did not delay viral infection, although it was cytotoxic between 5mg/mL-1.25mg/mL concentrations. However, if other compounds could be tested, it might provide a chance to obtain activity, and compounds should also be tested against the enzymes as well as the other types of viruses.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"92155166","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}
Pub Date : 2024-01-01DOI: 10.2174/0115734064252833231129062005
Zhenyu Li, Zhiyong Liu, Yuemao Shen, Chengwu Shen
Background: Salmonella enterica (S. enterica) serovar Typhimurium, an anaerobic enteric pathogene, could cause human and animal diseases ranging from mild gastroenteritis to whole body serious infections.
Objective: 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.
Methods: 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.
Results: 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 SicA/InvF regulatory pathway.
Conclusion: The novel synthetic 6-amido-3-carboxypyridazines could act as potent leads for the development of novel antibacterial agents.
{"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 <sup>1</sup>H NMR, <sup>13</sup>C 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":null,"pages":null},"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}
Pub Date : 2024-01-01DOI: 10.2174/1573406419666230823104300
Mohamed Abdella, Chandrajit Lahiri, Iskandar Abdullah, Ayaz Anwar
Background: Infectious diseases are the second leading cause of deaths worldwide. Pathogenic bacteria have been developing tremendous resistance against antibiotics which has placed an additional burden on healthcare systems. Gallic acid belongs to a naturally occurring phenolic class of compounds and is known to possess a wide spectrum of antimicrobial activities.
Aims & objectives: In this study, we synthesized thirteen derivatives of gallic acid and evaluated their antibacterial potential against seven multi-drug resistant bacteria, as well as cytotoxic effects against human embryonic kidney cell line in vitro. Methods: 13 compounds were successfully synthesized with moderate to good yield and evaluated. Synthesized derivatives were characterized by using nuclear magnetic resonance spectroscopy, mass spectrometry, and Fourier transformation infrared spectroscopy. Antibacterial activity was determined using microdilution while cytotoxicyt was assessed using MTT assay.
Results: The results of antibacterial assay showed that seven out of thirteen compounds exhibited antibacterial effects with compound 6 and 13 being most potent against Staphylococcus aureus (MIC 56 μg/mL) and Salmonella enterica (MIC 475 μg/mL) respectively. On the other hand, most of these compounds showed lower cytotoxicity against human embryonic kidney cells (HEK 293), with IC50 values ranging from over 700 μg/mL.
Conclusion: Notably, compound 13 was found to be non-toxic at concentrations as high as 5000 μg/mL. These findings suggest that the present synthetic derivatives of gallic acid hold potential for further studies in the development of potent antibacterial agents.
{"title":"Antibacterial Evaluation of Gallic Acid and its Derivatives against a Panel of Multi-drug Resistant Bacteria.","authors":"Mohamed Abdella, Chandrajit Lahiri, Iskandar Abdullah, Ayaz Anwar","doi":"10.2174/1573406419666230823104300","DOIUrl":"10.2174/1573406419666230823104300","url":null,"abstract":"<p><strong>Background: </strong>Infectious diseases are the second leading cause of deaths worldwide. Pathogenic bacteria have been developing tremendous resistance against antibiotics which has placed an additional burden on healthcare systems. Gallic acid belongs to a naturally occurring phenolic class of compounds and is known to possess a wide spectrum of antimicrobial activities.</p><p><strong>Aims & objectives: </strong>In this study, we synthesized thirteen derivatives of gallic acid and evaluated their antibacterial potential against seven multi-drug resistant bacteria, as well as cytotoxic effects against human embryonic kidney cell line <i>in vitro.</i> Methods: 13 compounds were successfully synthesized with moderate to good yield and evaluated. Synthesized derivatives were characterized by using nuclear magnetic resonance spectroscopy, mass spectrometry, and Fourier transformation infrared spectroscopy. Antibacterial activity was determined using microdilution while cytotoxicyt was assessed using MTT assay.</p><p><strong>Results: </strong>The results of antibacterial assay showed that seven out of thirteen compounds exhibited antibacterial effects with compound 6 and 13 being most potent against <i>Staphylococcus aureus</i> (MIC 56 μg/mL) and <i>Salmonella enterica</i> (MIC 475 μg/mL) respectively. On the other hand, most of these compounds showed lower cytotoxicity against human embryonic kidney cells (HEK 293), with IC<sub>50</sub> values ranging from over 700 μg/mL.</p><p><strong>Conclusion: </strong>Notably, compound 13 was found to be non-toxic at concentrations as high as 5000 μg/mL. These findings suggest that the present synthetic derivatives of gallic acid hold potential for further studies in the development of potent antibacterial agents.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10059044","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}
Pub Date : 2024-01-01DOI: 10.2174/0115734064268726231203164405
Birnur Akkaya, Recep Akkaya
Background: Hydroxyapatite and its derivatives have been used for a lot of applications. One of them is drug release studies. Due to its low adhesion strength and lack of the strength and durability required for load-carrying applications, there is a need to improve the properties of hydroxyapatite. For this aim, the most important factors are increasing pH sensitivity and preventing coagulation. Mixing it with multifunctional polymers is the best solution.
Objectives: The main objectives are: 1- preparing poly(acrylamide-co-acrylic acid/maleic acid)- hydroxyapatite (PAm-co-PAA/PMA-HApt), 2- assessment of (PAm-co-PAA/PMA-HApt) and dox-loaded poly(acrylamide-co-acrylic acid/maleic acid) (Dox-(PAm-co-PAA/PMA-HApt)) composite hydrogels, and 3- elucidating the difference in behavior of drug release studies between hydroxyapatite (HApt) and poly(acrylamide-co-acrylic acid/maleic acid) composite hydrogels.
Methods: A composite of PAm-co-PAA/PMA-HApt was prepared by direct polymerization of acrylamide-co-acrylic acid/maleic acid in a suspension of HApt. The drug loading and release features of PAm-co-PAA/PMA-HApt and HApt were then investigated for doxorubicin (dox) release. Using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and thermogravimetric analysis (TG/DTA), this unique composite hydrogel has been physicochemically investigated. Also, a colorimetric assay was used to assess the in vitro biocompatible support and anticancer activity of HApt and the newly developed composite hydrogel XTT (2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-2H-Tetrazolium-5-Carboxanilide) assay.
Results: According to the results of drug release studies of this new material, it is pH sensitive, and PAm-co-PAA/PMA-HApt demonstrated a faster release than HApt at 37°C in the acidic solution of pH 4.5 than in the neutral solution of pH 7.4. The XTT assay outcomes also demonstrated the biocompatibility of PAm-co-PAA/PMA-HApt and HApt and the cytotoxic effect of dox-loaded PAm-co-PAA/PMA-HApt.
Conclusion: It should be inferred that the drug release profile was improved at pH 4.5 by the newly produced pH-sensitive composite hydrogel.
{"title":"Synthesis, Characterization, and Investigation of Doxorubicin Drug Release Properties of Poly(acrylamide-co-acrylic Acid/Maleic Acid)-Hydroxyapatite Composite Hydrogel.","authors":"Birnur Akkaya, Recep Akkaya","doi":"10.2174/0115734064268726231203164405","DOIUrl":"10.2174/0115734064268726231203164405","url":null,"abstract":"<p><strong>Background: </strong>Hydroxyapatite and its derivatives have been used for a lot of applications. One of them is drug release studies. Due to its low adhesion strength and lack of the strength and durability required for load-carrying applications, there is a need to improve the properties of hydroxyapatite. For this aim, the most important factors are increasing pH sensitivity and preventing coagulation. Mixing it with multifunctional polymers is the best solution.</p><p><strong>Objectives: </strong>The main objectives are: 1- preparing poly(acrylamide-co-acrylic acid/maleic acid)- hydroxyapatite (PAm-co-PAA/PMA-HApt), 2- assessment of (PAm-co-PAA/PMA-HApt) and dox-loaded poly(acrylamide-co-acrylic acid/maleic acid) (Dox-(PAm-co-PAA/PMA-HApt)) composite hydrogels, and 3- elucidating the difference in behavior of drug release studies between hydroxyapatite (HApt) and poly(acrylamide-co-acrylic acid/maleic acid) composite hydrogels.</p><p><strong>Methods: </strong>A composite of PAm-co-PAA/PMA-HApt was prepared by direct polymerization of acrylamide-co-acrylic acid/maleic acid in a suspension of HApt. The drug loading and release features of PAm-co-PAA/PMA-HApt and HApt were then investigated for doxorubicin (dox) release. Using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), and thermogravimetric analysis (TG/DTA), this unique composite hydrogel has been physicochemically investigated. Also, a colorimetric assay was used to assess the <i>in vitro</i> biocompatible support and anticancer activity of HApt and the newly developed composite hydrogel XTT (2,3-Bis-(2-Methoxy-4-Nitro-5-Sulfophenyl)-<i>2</i>H-Tetrazolium-5-Carboxanilide) assay.</p><p><strong>Results: </strong>According to the results of drug release studies of this new material, it is pH sensitive, and PAm-co-PAA/PMA-HApt demonstrated a faster release than HApt at 37°C in the acidic solution of pH 4.5 than in the neutral solution of pH 7.4. The XTT assay outcomes also demonstrated the biocompatibility of PAm-co-PAA/PMA-HApt and HApt and the cytotoxic effect of dox-loaded PAm-co-PAA/PMA-HApt.</p><p><strong>Conclusion: </strong>It should be inferred that the drug release profile was improved at pH 4.5 by the newly produced pH-sensitive composite hydrogel.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139567236","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}
Pub Date : 2024-01-01DOI: 10.2174/0115734064290905231228110023
Shaista Qayyum, Almas Jabeen, Sajda Ashraf, Faiza Seraj, Khalid Mohammad Khan, Rafat Ali Siddiqui, Zaheer Ul-Haq
Background: Non-Hodgkin lymphoma of B cell origin is the common type of lymphoma- related malignancy with poor response rate with conventional front-line therapies.
Aim: The aim of the present study was to investigate the potential of new anti-inflammatory oxadiazole derivatives of Diclofenac as an anti-lymphoma agent through in vitro and in silico approaches.
Methods: Anti-lymphoma potential was evaluated by alamar blue technique. MTT assay employed for cytotoxicity. Gene and protein expression studies was performed by qRT-PCR and ELISA respectively. Docking studies was performed by using MOE program.
Results: Among five diclofenac derivatives, (II) showed promising anti-lymphoma effects, where it inhibited the expression of BCL-2, p-38 MAPK and TGF-β in both follicular and Burkitt's lymphoma cells and was non-toxic against normal human fibroblast cells. The in silico studies against BCL-2 revealed that the unsubstituted Sulphur group in (II) is involved in the crucial interactions with the binding site residue.
Conclusion: The compound (II) can be a potential therapeutic candidate for B-cell non-Hodgkin lymphoma and deserves further development as a novel anti-lymphoma agent.
{"title":"Oxadiazole Derivatives of Diclofenac as an Anti-proliferative Agent for B-cell Non-Hodgkin Lymphoma: An <i>In vitro</i> and <i>In Silico</i> Studies.","authors":"Shaista Qayyum, Almas Jabeen, Sajda Ashraf, Faiza Seraj, Khalid Mohammad Khan, Rafat Ali Siddiqui, Zaheer Ul-Haq","doi":"10.2174/0115734064290905231228110023","DOIUrl":"10.2174/0115734064290905231228110023","url":null,"abstract":"<p><strong>Background: </strong>Non-Hodgkin lymphoma of B cell origin is the common type of lymphoma- related malignancy with poor response rate with conventional front-line therapies.</p><p><strong>Aim: </strong>The aim of the present study was to investigate the potential of new anti-inflammatory oxadiazole derivatives of Diclofenac as an anti-lymphoma agent through <i>in vitro</i> and <i>in silico</i> approaches.</p><p><strong>Methods: </strong>Anti-lymphoma potential was evaluated by alamar blue technique. MTT assay employed for cytotoxicity. Gene and protein expression studies was performed by qRT-PCR and ELISA respectively. Docking studies was performed by using MOE program.</p><p><strong>Results: </strong>Among five diclofenac derivatives, (II) showed promising anti-lymphoma effects, where it inhibited the expression of BCL-2, p-38 MAPK and TGF-β in both follicular and Burkitt's lymphoma cells and was non-toxic against normal human fibroblast cells. The <i>in silico</i> studies against BCL-2 revealed that the unsubstituted Sulphur group in (II) is involved in the crucial interactions with the binding site residue.</p><p><strong>Conclusion: </strong>The compound (II) can be a potential therapeutic candidate for B-cell non-Hodgkin lymphoma and deserves further development as a novel anti-lymphoma agent.</p>","PeriodicalId":18382,"journal":{"name":"Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":1.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139567215","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}