Pub Date : 2024-09-25DOI: 10.1016/j.ejmcr.2024.100219
Aqsa Arif , Muhammad Sharif Khar , Nariman Shahid , Waqar Aman , Joham Javed , Amina Rubab , Mashal Nayab , khadija mastoor , Rabia Arshad , Abbas Rahdar , Sonia Fathi-karkan , Zelal Kharaba , Sadanand Pandey
Pathogenic bacteria consistently pose significant challenges within the oral mucosal environment by altering bioflora, biofilm development, and enamel demineralization, thus leading to extensive clinical resources for treatment. This review aims to gather suitable and novel information in terms of providing advanced bio-inspired therapeutic facilities to alleviate the burden of treatment on both the patient and medical infrastructure. Botanical nanoparticle-based mouthwashes have been synthesized using mostly green synthesis technology. Botanical nanoformulations-based mouthwashes are efficient for maintaining microbial flora and mimicking natural extracellular matrix (ECM) components. Furthermore, dental caries can also be treated by these nanoparticles through the promotion of enamel remineralization and bacterial growth suppression. These nature-inspired oral rinses/mouthwashes confer significant advantages relative to their synthetic counterparts, particularly in terms of safety, efficacy, and formulation simplicity. The potential applications of these bioinspired nanomaterials extend beyond wound healing and dental infection management, heralding a promising frontier in oral health restoration. The diversified range of these nanomaterials, from Propolis, Miswak, and Chitosan nanoparticles (NPs) to pomegranate extract and Matricaria chamomilla L. extract-based mouthwashes, introduces an exciting new dimension to oral care.
{"title":"Progression in nano-botanical oral hygiene solutions: The Dawn of biomimetic nanomaterials","authors":"Aqsa Arif , Muhammad Sharif Khar , Nariman Shahid , Waqar Aman , Joham Javed , Amina Rubab , Mashal Nayab , khadija mastoor , Rabia Arshad , Abbas Rahdar , Sonia Fathi-karkan , Zelal Kharaba , Sadanand Pandey","doi":"10.1016/j.ejmcr.2024.100219","DOIUrl":"10.1016/j.ejmcr.2024.100219","url":null,"abstract":"<div><div>Pathogenic bacteria consistently pose significant challenges within the oral mucosal environment by altering bioflora, biofilm development, and enamel demineralization, thus leading to extensive clinical resources for treatment. This review aims to gather suitable and novel information in terms of providing advanced bio-inspired therapeutic facilities to alleviate the burden of treatment on both the patient and medical infrastructure. Botanical nanoparticle-based mouthwashes have been synthesized using mostly green synthesis technology. Botanical nanoformulations-based mouthwashes are efficient for maintaining microbial flora and mimicking natural extracellular matrix (ECM) components. Furthermore, dental caries can also be treated by these nanoparticles through the promotion of enamel remineralization and bacterial growth suppression. These nature-inspired oral rinses/mouthwashes confer significant advantages relative to their synthetic counterparts, particularly in terms of safety, efficacy, and formulation simplicity. The potential applications of these bioinspired nanomaterials extend beyond wound healing and dental infection management, heralding a promising frontier in oral health restoration. The diversified range of these nanomaterials, from Propolis, Miswak, and Chitosan nanoparticles (NPs) to pomegranate extract and <em>Matricaria chamomilla L.</em> extract-based mouthwashes, introduces an exciting new dimension to oral care.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100219"},"PeriodicalIF":0.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142418210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-25DOI: 10.1016/j.ejmcr.2024.100218
Bharat Goel , Shreyans K. Jain
Natural products (NPs) have played a central role in drug discovery particularly in therapeutic areas like oncology, and infectious diseases. Despite their pharmacological potential, natural products present some significant challenges for therapeutic applications, such as toxicity, pharmacokinetic characteristics, supply problems, and drug resistance. Some of these issues have been solved by semisynthetic derivatives of natural products, and many semisynthetic drugs have been developed and approved for clinical use. Repeatedly, it has been observed that outcomes of semisynthetic modifications of natural products retain the medicinal activity of the parent compound while altering other characteristics such as toxicity and oral bioavailability, escalating their momentum of reaching the market. This review describes NP-derived semisynthetic anticancer drugs approved from 1981 to 2023. The review also confers the advantages of semisynthetic modifications of natural products, including supply fulfillment, improved pharmacokinetics (increased bioavailability, plasma half-life, etc.), improved solubility and lipophilicity, reduced toxicity, enhanced selectivity, and reduced resistance.
{"title":"Semisynthesis: Bridging natural products and novel anticancer therapies","authors":"Bharat Goel , Shreyans K. Jain","doi":"10.1016/j.ejmcr.2024.100218","DOIUrl":"10.1016/j.ejmcr.2024.100218","url":null,"abstract":"<div><div>Natural products (NPs) have played a central role in drug discovery particularly in therapeutic areas like oncology, and infectious diseases. Despite their pharmacological potential, natural products present some significant challenges for therapeutic applications, such as toxicity, pharmacokinetic characteristics, supply problems, and drug resistance. Some of these issues have been solved by semisynthetic derivatives of natural products, and many semisynthetic drugs have been developed and approved for clinical use. Repeatedly, it has been observed that outcomes of semisynthetic modifications of natural products retain the medicinal activity of the parent compound while altering other characteristics such as toxicity and oral bioavailability, escalating their momentum of reaching the market. This review describes NP-derived semisynthetic anticancer drugs approved from 1981 to 2023. The review also confers the advantages of semisynthetic modifications of natural products, including supply fulfillment, improved pharmacokinetics (increased bioavailability, plasma half-life, etc.), improved solubility and lipophilicity, reduced toxicity, enhanced selectivity, and reduced resistance.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100218"},"PeriodicalIF":0.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142358670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1016/j.ejmcr.2024.100216
Vahid Barati , Anna Hruzíková , Eliška Procházková , Martin Zavřel , Jaroslav Kozák , Jana Trylčová , Dominik Rejman , Jan Weber , Kateřina Bogdanová , Milan Kolář , Ondřej Baszczyňski
Heterocyclic drugs display diverse pharmacological activities and metabolic stability. However, their poor solubility and pharmacokinetic properties often compromise bioavailability and clinical outcomes. Nevertheless, the prodrug approach provides a viable strategy to overcome unwanted attributes of drug candidates. In this proof-of-concept study, we report the synthesis and biological evaluation of glycol methylene-bridged phosphate (GMBP) prodrugs developed for heterocyclic drug delivery. Through methylene bridging, the heterocyclic nitrogen was directly attached to the phosphate, whereas the glycol moiety enabled drug release via cyclization, as confirmed by 31P NMR spectroscopy. Additional prodrugs of carboxylic acids, phenols, and thiols confirmed the broad application scope of our GMPB approach. Heterocyclic GMBP prodrugs were stable in aqueous buffers and activated by phospholipase CAL-B in vitro. Select prodrugs, including zidovudine prodrug 33, were even more potent (3 nM on HIV-1) than the parent compound. These findings demonstrate that our GMBP approach is not only feasible but also highly versatile.
{"title":"Delivery of N-heterocyclic drugs, acids, phenols, and thiols via Tailor−made Self−immolative linkers","authors":"Vahid Barati , Anna Hruzíková , Eliška Procházková , Martin Zavřel , Jaroslav Kozák , Jana Trylčová , Dominik Rejman , Jan Weber , Kateřina Bogdanová , Milan Kolář , Ondřej Baszczyňski","doi":"10.1016/j.ejmcr.2024.100216","DOIUrl":"10.1016/j.ejmcr.2024.100216","url":null,"abstract":"<div><div>Heterocyclic drugs display diverse pharmacological activities and metabolic stability. However, their poor solubility and pharmacokinetic properties often compromise bioavailability and clinical outcomes. Nevertheless, the prodrug approach provides a viable strategy to overcome unwanted attributes of drug candidates. In this proof-of-concept study, we report the synthesis and biological evaluation of glycol methylene-bridged phosphate (GMBP) prodrugs developed for heterocyclic drug delivery. Through methylene bridging, the heterocyclic nitrogen was directly attached to the phosphate, whereas the glycol moiety enabled drug release via cyclization, as confirmed by <sup>31</sup>P NMR spectroscopy. Additional prodrugs of carboxylic acids, phenols, and thiols confirmed the broad application scope of our GMPB approach. Heterocyclic GMBP prodrugs were stable in aqueous buffers and activated by phospholipase CAL-B <em>in vitro</em>. Select prodrugs, including zidovudine prodrug <strong>33</strong>, were even more potent (3 nM on HIV-1) than the parent compound. These findings demonstrate that our GMBP approach is not only feasible but also highly versatile.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100216"},"PeriodicalIF":0.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142418790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-23DOI: 10.1016/j.ejmcr.2024.100217
Muhammad Salman Hameed , Hongxuan Cao , Li Guo , Lei Zeng , Yanliang Ren
Recent progress in the realm of covalent inhibitors and covalent drugs, placing a distinct emphasis on precisely defining the scope and outlining key objectives. The scope of this review encompasses a broad examination of various classes of covalent inhibitors and drugs, with a focus on their mechanisms, applications, and limitations. Specifically, we discuss the chemical principles underlying covalent interactions in drug design and delve into the structural features that render these compounds effective in their respective targets. Our objectives include summarizing recent research progress in the development and application of covalent inhibitors and drugs, identifying key challenges faced by researchers and clinicians, and proposing future directions for advancing the field. By synthesizing current knowledge and addressing emerging trends, this review aims to contribute to a deeper understanding of covalent inhibitors and drugs and to inspire further research efforts towards their development and optimization.
{"title":"Advancements, challenges, and future frontiers in covalent inhibitors and covalent drugs: A review","authors":"Muhammad Salman Hameed , Hongxuan Cao , Li Guo , Lei Zeng , Yanliang Ren","doi":"10.1016/j.ejmcr.2024.100217","DOIUrl":"10.1016/j.ejmcr.2024.100217","url":null,"abstract":"<div><div>Recent progress in the realm of covalent inhibitors and covalent drugs, placing a distinct emphasis on precisely defining the scope and outlining key objectives. The scope of this review encompasses a broad examination of various classes of covalent inhibitors and drugs, with a focus on their mechanisms, applications, and limitations. Specifically, we discuss the chemical principles underlying covalent interactions in drug design and delve into the structural features that render these compounds effective in their respective targets. Our objectives include summarizing recent research progress in the development and application of covalent inhibitors and drugs, identifying key challenges faced by researchers and clinicians, and proposing future directions for advancing the field. By synthesizing current knowledge and addressing emerging trends, this review aims to contribute to a deeper understanding of covalent inhibitors and drugs and to inspire further research efforts towards their development and optimization.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100217"},"PeriodicalIF":0.0,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142318700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-19DOI: 10.1016/j.ejmcr.2024.100215
Julia Beveridge , Marcus Söderström , Rubén Prieto-Díaz , Hugo Gutierrez-de-Teran , Luke R. Odell , Mathias Hallberg , Mats Larhed , Johan Gising
With the objective of finding new classes of cognitive enhancers with potential for the treatment of neurodegenerative disorders, such as Alzheimer's disease, small molecule inhibitors of insulin-regulated aminopeptidase (IRAP) were designed and synthesized. IRAP is a member of the M1 family of zinc aminopeptidases and is abundantly expressed in areas of the brain associated with cognition, such as the amygdala, hippocampus and cerebral cortex. IRAP inhibitors were previously shown to enhance memory and learning in animal models. A comprehensive high throughput screening of 400,000 small molecules from the European Lead Factory library provided a series of 50 promising compounds in a qualified hit list (QHL). More than 30 IRAP inhibitors with an IC50 below 3.5 μM were identified. Herein, selected compounds from this QHL were assayed for solubility and permeability. Most of the selected compounds displayed good solubility, but further permeability studies on the best compounds revealed low blood brain barrier (BBB) permeability and high efflux in cells overexpressing P-gp pumps, rendering them less promising as starting points in drug discovery processes. Two compounds from the QHL were prioritized for further structural optimization; the pyridyl-substituted isoxazole 1a (QHL27) and the benzylhydroxamic acid derivative 1b (QHL1), both demonstrating fair BBB permeability and no indication of efflux. While our attempts to improve the isoxazole derivative 1a were not fruitful, a structural modification of 1b to provide the chloro-substituted benzylhydroxamic acid 14b resulted in a ten-fold improvement of the IRAP inhibition with an IC50 value of 60 nM. The binding modes of 1b and 14b were determined by free energy perturbation (FEP) analysis performed on candidate docking poses, determining a binding mode that accurately explained the experimental SAR. Further FEP studies of compound 14b suggested that it exhibits selectivity towards IRAP over Aminopeptidase N (APN), indicating its potential for targeted therapeutic applications.
{"title":"Benzylhydroxamic acids as inhibitors of insulin regulated aminopeptidase (IRAP)","authors":"Julia Beveridge , Marcus Söderström , Rubén Prieto-Díaz , Hugo Gutierrez-de-Teran , Luke R. Odell , Mathias Hallberg , Mats Larhed , Johan Gising","doi":"10.1016/j.ejmcr.2024.100215","DOIUrl":"10.1016/j.ejmcr.2024.100215","url":null,"abstract":"<div><div>With the objective of finding new classes of cognitive enhancers with potential for the treatment of neurodegenerative disorders, such as Alzheimer's disease, small molecule inhibitors of insulin-regulated aminopeptidase (IRAP) were designed and synthesized. IRAP is a member of the M1 family of zinc aminopeptidases and is abundantly expressed in areas of the brain associated with cognition, such as the amygdala, hippocampus and cerebral cortex. IRAP inhibitors were previously shown to enhance memory and learning in animal models. A comprehensive high throughput screening of 400,000 small molecules from the European Lead Factory library provided a series of 50 promising compounds in a qualified hit list (QHL). More than 30 IRAP inhibitors with an IC<sub>50</sub> below 3.5 μM were identified. Herein, selected compounds from this QHL were assayed for solubility and permeability. Most of the selected compounds displayed good solubility, but further permeability studies on the best compounds revealed low blood brain barrier (BBB) permeability and high efflux in cells overexpressing P-gp pumps, rendering them less promising as starting points in drug discovery processes. Two compounds from the QHL were prioritized for further structural optimization; the pyridyl-substituted isoxazole <strong>1a</strong> (<strong>QHL27</strong>) and the benzylhydroxamic acid derivative <strong>1b</strong> (<strong>QHL1</strong>), both demonstrating fair BBB permeability and no indication of efflux. While our attempts to improve the isoxazole derivative <strong>1a</strong> were not fruitful, a structural modification of <strong>1b</strong> to provide the chloro-substituted benzylhydroxamic acid <strong>14b</strong> resulted in a ten-fold improvement of the IRAP inhibition with an IC<sub>50</sub> value of 60 nM. The binding modes of <strong>1b</strong> and <strong>14b</strong> were determined by free energy perturbation (FEP) analysis performed on candidate docking poses, determining a binding mode that accurately explained the experimental SAR. Further FEP studies of compound <strong>14b</strong> suggested that it exhibits selectivity towards IRAP over Aminopeptidase N (APN), indicating its potential for targeted therapeutic applications.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100215"},"PeriodicalIF":0.0,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142318705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-07DOI: 10.1016/j.ejmcr.2024.100214
Amgad M. Rabie , Imane Yamari , Samir Chtita
Isoquinoline compounds holding some nucleosidic structural hallmarks are considered possible attractive options for effectively combating the different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their associated disease, the coronavirus disease 2019 (COVID-19). The CYNOVID molecule ((S)-6-chloro-2-{[(1-cyanocyclopropyl)methyl]sulfonyl}-N-(isoquinolin-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide) is a recently-discovered isoquinoline compound with potent anticoronaviral activities against several SARS-CoV-2 variants according to different antiviral cellular assays. CYNOVID nonspecifically binds to the main protease (Mpro) enzyme of several coronaviruses. As an extensive continued effort to develop this potential anti-SARS-CoV-2 agent and examine its nonspecific broad potential to be an effective broad-spectrum anti-COVID-19 therapy, a new comprehensive in-silico research study was proposed and designed to explore the inhibitory abilities of this isoquinoline derivative against the two major highly-conserved SARS-CoV-2 replication enzymes (i.e., the SARS-CoV-2 replication proteins other than Mpro), which are the RNA-dependent RNA polymerase (RdRp) and 3′-to-5′ exoribonuclease (ExoN) enzymes. The various computational results of the present study significantly supported the previous biochemical/biological findings as well as the newly-suggested multiple-targeting hypothesis, disclosing the possible nonspecific anticoronaviral activities of this promising experimental agent, CYNOVID, against nearly any coronaviral-2 variants and, probably, any future coronaviral species, e.g., SARS-CoV-3.
{"title":"The isoquinoline derivative \"CYNOVID\" as a prospective anti-SARS-CoV-2 agent: An expanded investigative computational study","authors":"Amgad M. Rabie , Imane Yamari , Samir Chtita","doi":"10.1016/j.ejmcr.2024.100214","DOIUrl":"10.1016/j.ejmcr.2024.100214","url":null,"abstract":"<div><div>Isoquinoline compounds holding some nucleosidic structural hallmarks are considered possible attractive options for effectively combating the different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and their associated disease, the coronavirus disease 2019 (COVID-19). The CYNOVID molecule ((<em>S</em>)-6-chloro-2-{[(1-cyanocyclopropyl)methyl]sulfonyl}-<em>N</em>-(isoquinolin-4-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide) is a recently-discovered isoquinoline compound with potent anticoronaviral activities against several SARS-CoV-2 variants according to different antiviral cellular assays. CYNOVID nonspecifically binds to the main protease (M<sup>pro</sup>) enzyme of several coronaviruses. As an extensive continued effort to develop this potential anti-SARS-CoV-2 agent and examine its nonspecific broad potential to be an effective broad-spectrum anti-COVID-19 therapy, a new comprehensive <em>in-silico</em> research study was proposed and designed to explore the inhibitory abilities of this isoquinoline derivative against the two major highly-conserved SARS-CoV-2 replication enzymes (i.e., the SARS-CoV-2 replication proteins other than M<sup>pro</sup>), which are the RNA-dependent RNA polymerase (RdRp) and 3′-to-5′ exoribonuclease (ExoN) enzymes. The various computational results of the present study significantly supported the previous biochemical/biological findings as well as the newly-suggested multiple-targeting hypothesis, disclosing the possible nonspecific anticoronaviral activities of this promising experimental agent, CYNOVID, against nearly any coronaviral-2 variants and, probably, any future coronaviral species, e.g., SARS-CoV-3.</div></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100214"},"PeriodicalIF":0.0,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142699513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mycobacterium tuberculosis (MTB) is the agent that causes tuberculosis (TB), the most lethal infectious illness that affects around one-third of the global population and has resulted in 1.5 million fatalities in recent years. As of right now, sensitive MTB strain-caused tuberculosis can be successfully treated with short-term tuberculosis therapy regimens. However, an increasing issue in many nations is tuberculosis brought on by multidrug-resistant (MDR) and extensively drug-resistant (XDR) MTB strains.
In recent years, TB has remained major global public health issue. The screening of novel bioactive compounds with new targets and alternative mechanisms of action is urgently needed. The WHO is working to eliminate tuberculosis globally and has set the goal of reducing TB case by 90 % and incidence 80 % by 2035 as part of the sustainable development Goals. Quinoline-based heterocyclic compounds have become quite important in medical chemistry. Due to the exceptional outcomes of their derivatives, quinoline hydrazone scaffold is crucial in the creation of anti-tubercular drugs. The synthetic flexibility of quinoline, which enables the creation of a vast variety of structurally diverse hydrazone derivatives and their metal complexes, has further aided this wide range of biological and biochemical activities.
{"title":"“Quinoline analogues and nanocarrier systems: A dual approach to anti-tubercular therapy\"","authors":"Satendra Kumar , Niranjan Kaushik , Jagdish Kumar Sahu , Surendra Jatav","doi":"10.1016/j.ejmcr.2024.100212","DOIUrl":"10.1016/j.ejmcr.2024.100212","url":null,"abstract":"<div><p>Mycobacterium tuberculosis (MTB) is the agent that causes tuberculosis (TB), the most lethal infectious illness that affects around one-third of the global population and has resulted in 1.5 million fatalities in recent years. As of right now, sensitive MTB strain-caused tuberculosis can be successfully treated with short-term tuberculosis therapy regimens. However, an increasing issue in many nations is tuberculosis brought on by multidrug-resistant (MDR) and extensively drug-resistant (XDR) MTB strains.</p><p>In recent years, TB has remained major global public health issue. The screening of novel bioactive compounds with new targets and alternative mechanisms of action is urgently needed. The WHO is working to eliminate tuberculosis globally and has set the goal of reducing TB case by 90 % and incidence 80 % by 2035 as part of the sustainable development Goals. Quinoline-based heterocyclic compounds have become quite important in medical chemistry. Due to the exceptional outcomes of their derivatives, quinoline hydrazone scaffold is crucial in the creation of anti-tubercular drugs. The synthetic flexibility of quinoline, which enables the creation of a vast variety of structurally diverse hydrazone derivatives and their metal complexes, has further aided this wide range of biological and biochemical activities.</p></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100212"},"PeriodicalIF":0.0,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772417424000840/pdfft?md5=44c66b3cb7d41866b98dd1dd90f691fb&pid=1-s2.0-S2772417424000840-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142241348","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1016/j.ejmcr.2024.100211
Afeez I. Kareem, Sarel F. Malan, Erika Kapp, Sean Shamido, Jacques Joubert
This study presents a series of coumarin nitric oxide donor hybrids that were synthesized, and characterized using FT-IR, H NMR, C NMR, and HR-MS techniques. Initial screening for anti-tubercular activity was conducted against Mycolicibacterium smegmatis MC2155 (M.smeg) under both nutrient-rich and nutrient-poor conditions. Under nutrient-rich conditions, little inhibition was observed. However, four compounds (1e, 2o, 3f, and 5e) demonstrated notable antiproliferative activity under nutrient-poor conditions, with inhibition rates exceeding 95 % at a 50 μM concentration. Subsequent testing of these compounds on Mycobacterium tuberculosis (M.tb) under nutrient-rich conditions showed inhibition rates ranging from 11 % to 37 % at 50 μM. These results indicate that the coumarin nitric oxide donor hybrids are potentially effective in nutrient-limited environments, similar to the intracellular conditions faced by M.tb. In silico cytotoxicity predictions, compared with rifampicin, indicated potentially low toxicity for these compounds. Further optimization and studies are needed to enhance their efficacy under normal conditions, which could lead to the development of new therapeutic strategies against tuberculosis.
{"title":"Synthesis, characterization, and biological evaluation of coumarin-nitric oxide donor hybrids as anti-tubercular agents","authors":"Afeez I. Kareem, Sarel F. Malan, Erika Kapp, Sean Shamido, Jacques Joubert","doi":"10.1016/j.ejmcr.2024.100211","DOIUrl":"10.1016/j.ejmcr.2024.100211","url":null,"abstract":"<div><p>This study presents a series of coumarin nitric oxide donor hybrids that were synthesized, and characterized using FT-IR, H NMR, C NMR, and HR-MS techniques. Initial screening for anti-tubercular activity was conducted against <em>Mycolicibacterium smegmatis MC</em><sup><em>2</em></sup><em>155</em> (<em>M.smeg</em>) under both nutrient-rich and nutrient-poor conditions. Under nutrient-rich conditions, little inhibition was observed. However, four compounds (<strong>1e</strong>, <strong>2o</strong>, <strong>3f</strong>, and <strong>5e</strong>) demonstrated notable antiproliferative activity under nutrient-poor conditions, with inhibition rates exceeding 95 % at a 50 μM concentration. Subsequent testing of these compounds on <em>Mycobacterium tuberculosis</em> (<em>M.tb)</em> under nutrient-rich conditions showed inhibition rates ranging from 11 % to 37 % at 50 μM. These results indicate that the coumarin nitric oxide donor hybrids are potentially effective in nutrient-limited environments, similar to the intracellular conditions faced by <em>M.tb</em>. <em>In silico</em> cytotoxicity predictions, compared with rifampicin, indicated potentially low toxicity for these compounds. Further optimization and studies are needed to enhance their efficacy under normal conditions, which could lead to the development of new therapeutic strategies against tuberculosis.</p></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100211"},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772417424000839/pdfft?md5=787f13a81d1a5e770c8ee2ce13838dee&pid=1-s2.0-S2772417424000839-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142151804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-05DOI: 10.1016/j.ejmcr.2024.100210
Duryodhan Sahu , P.S. Rama Sreekanth , Prasanta Kumar Behera , Manoj Kumar Pradhan , Amit Patnaik , Sachin Salunkhe , Robert Cep
Pyridine derivatives have emerged as promising candidates in the field of biomedical research, showcasing a wide array of applications in drug development and therapeutic interventions. The recent advances in the design and utilization of pyridine derivatives, focusing on their diverse roles in biomedical applications is the key understanding in this study. The versatility of pyridine-based compounds has been leveraged to address various challenges in the realms of pharmaceuticals and medicinal chemistry, offering innovative solutions for improved healthcare outcomes. This review encompasses the synthesis methodologies of pyridine derivatives, elucidating key synthetic strategies that enable the tailoring of these compounds for specific biomedical purposes and medicinal properties. This underscores the recent advancements in understanding the pharmacokinetics and pharmacodynamics of pyridine derivatives, emphasizing their potential impact on the future landscape of biomedical research. The synthesis and application of these compounds represent a dynamic frontier in drug development, offering innovative solutions to address unmet medical needs and propel the field toward more effective and personalized therapies. Pyridine derivatives play an important role in bio-imaging applications for the diagnosis of various diseases. Pyridine-based macromolecules have great potential for the efficient and specific delivery of drugs.
{"title":"Advances in synthesis, medicinal properties and biomedical applications of pyridine derivatives: A comprehensive review","authors":"Duryodhan Sahu , P.S. Rama Sreekanth , Prasanta Kumar Behera , Manoj Kumar Pradhan , Amit Patnaik , Sachin Salunkhe , Robert Cep","doi":"10.1016/j.ejmcr.2024.100210","DOIUrl":"10.1016/j.ejmcr.2024.100210","url":null,"abstract":"<div><p>Pyridine derivatives have emerged as promising candidates in the field of biomedical research, showcasing a wide array of applications in drug development and therapeutic interventions. The recent advances in the design and utilization of pyridine derivatives, focusing on their diverse roles in biomedical applications is the key understanding in this study. The versatility of pyridine-based compounds has been leveraged to address various challenges in the realms of pharmaceuticals and medicinal chemistry, offering innovative solutions for improved healthcare outcomes. This review encompasses the synthesis methodologies of pyridine derivatives, elucidating key synthetic strategies that enable the tailoring of these compounds for specific biomedical purposes and medicinal properties. This underscores the recent advancements in understanding the pharmacokinetics and pharmacodynamics of pyridine derivatives, emphasizing their potential impact on the future landscape of biomedical research. The synthesis and application of these compounds represent a dynamic frontier in drug development, offering innovative solutions to address unmet medical needs and propel the field toward more effective and personalized therapies. Pyridine derivatives play an important role in bio-imaging applications for the diagnosis of various diseases. Pyridine-based macromolecules have great potential for the efficient and specific delivery of drugs.</p></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100210"},"PeriodicalIF":0.0,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772417424000827/pdfft?md5=810fec813bfb8c4e372565f0d1c88f7e&pid=1-s2.0-S2772417424000827-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142158134","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.1016/j.ejmcr.2024.100213
Shankar Gharge, Shankar G. Alegaon, Swaroop Jadhav, Shriram D. Ranade, Rohini S. Kavalapure
In search of new antidiabetic agents, heterocyclic compounds containing 3,5-Substituted thiazolidinedione moieties were synthesized through a concise three-step reaction process. The synthesis involved Knoevenagel condensation at the 5th position of the 3,5-Substituted thiazolidinedione ring-system (6a-6c). Comprehensive physicochemical and spectral analyses, including FTIR, HR-MS, 1H NMR and 13C NMR, were performed to characterize the synthesized compounds. The synthesized derivatives were subjected to evaluation for their In vivo anti-diabetic activity against diabetes induced wistar rats and In vitro activity against α-amylase, α-glucosidase and glucose uptake by yeast cells. On the basis of the combined results of network pharmacology, In vitro and animal study experiments revealed that the compounds 6c predicted to have the greatest effect out of the compounds (6a-6c), showing interactions with targets exhibited potential binding patterns against the active site of target α-amylase, α-glucosidase with modulating AMY2A, GAA, PPARG, PIK3CA, PRKCB, INSR, and PRKCB signalling pathways and this is evidenced by molecular docking, dynamics simulation (MD) studies. Further, compound 6c showed In vitro α-amylase, α-glucosidase inhibitory activity with IC50 value of 86.06 ± 1.1 μM and 74.97 ± 1.23 μM as opposed to standard acarbose (IC50 value of 26.89 ± 3.12 and 29.25 ± 0.15 μM) and 58.23 ± 0.13 % of glucose uptake and also exhibited significant reduction (p < 0.001) in blood glucose levels (114 ± 1.17 mg/dL) comparable to the effect of pioglitazone (102.2 ± 0.79 mg/dL). The present study suggests that modified thiazolidinediones act as potential lead compounds to carter the need of antidiabetic agents.
{"title":"Design, synthesis, characterization and antidiabetic evaluation of 3,5-substituted thiazolidinediones: Evidenced by network pharmacology, Molecular docking, dynamic simulation, in vitro and in vivo assessment","authors":"Shankar Gharge, Shankar G. Alegaon, Swaroop Jadhav, Shriram D. Ranade, Rohini S. Kavalapure","doi":"10.1016/j.ejmcr.2024.100213","DOIUrl":"10.1016/j.ejmcr.2024.100213","url":null,"abstract":"<div><p>In search of new antidiabetic agents, heterocyclic compounds containing 3,5-Substituted thiazolidinedione moieties were synthesized through a concise three-step reaction process. The synthesis involved Knoevenagel condensation at the 5th position of the 3,5-Substituted thiazolidinedione ring-system (6a-6c). Comprehensive physicochemical and spectral analyses, including FTIR, HR-MS, <sup>1</sup>H NMR and <sup>13</sup>C NMR, were performed to characterize the synthesized compounds. The synthesized derivatives were subjected to evaluation for their <em>In vivo</em> anti-diabetic activity against diabetes induced wistar rats and <em>In vitro</em> activity against <em>α-amylase, α-glucosidase</em> and glucose uptake by yeast cells. On the basis of the combined results of network pharmacology<em>, In vitro</em> and animal study experiments revealed that the compounds 6c predicted to have the greatest effect out of the compounds (6a-6c), showing interactions with targets exhibited potential binding patterns against the active site of target <em>α-amylase, α-glucosidase</em> with modulating <em>AMY2A, GAA, PPARG, PIK3CA, PRKCB, INSR,</em> and <em>PRKCB</em> signalling pathways and this is evidenced by molecular docking, dynamics simulation (MD) studies. Further, compound 6c showed <em>In vitro α-amylase, α-glucosidase</em> inhibitory activity with IC<sub>50</sub> value of 86.06 ± 1.1 μM and 74.97 ± 1.23 μM as opposed to standard acarbose (IC<sub>50</sub> value of 26.89 ± 3.12 and 29.25 ± 0.15 μM) and 58.23 ± 0.13 % of glucose uptake and also exhibited significant reduction (p < 0.001) in blood glucose levels (114 ± 1.17 mg/dL) comparable to the effect of pioglitazone (102.2 ± 0.79 mg/dL). The present study suggests that modified thiazolidinediones act as potential lead compounds to carter the need of antidiabetic agents.</p></div>","PeriodicalId":12015,"journal":{"name":"European Journal of Medicinal Chemistry Reports","volume":"12 ","pages":"Article 100213"},"PeriodicalIF":0.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772417424000852/pdfft?md5=6937eab5d75386afd4b218c9aad7de7a&pid=1-s2.0-S2772417424000852-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142167391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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