ACS Medicinal Chemistry Letters最新文献_第2页

Morita-Baylis-Hillman Adduct Chemistry as a Tool for the Design of Lysine-Targeted Covalent Ligands.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-28 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.4c00479

Marco Paolino, Giusy Tassone, Paolo Governa, Mario Saletti, Matteo Lami, Riccardo Carletti, Filippo Sacchetta, Cecilia Pozzi, Maurizio Orlandini, Fabrizio Manetti, Massimo Olivucci, Andrea Cappelli

{"title":"Morita-Baylis-Hillman Adduct Chemistry as a Tool for the Design of Lysine-Targeted Covalent Ligands.","authors":"Marco Paolino, Giusy Tassone, Paolo Governa, Mario Saletti, Matteo Lami, Riccardo Carletti, Filippo Sacchetta, Cecilia Pozzi, Maurizio Orlandini, Fabrizio Manetti, Massimo Olivucci, Andrea Cappelli","doi":"10.1021/acsmedchemlett.4c00479","DOIUrl":"10.1021/acsmedchemlett.4c00479","url":null,"abstract":"The use of Targeted Covalent Inhibitors (TCIs) is an expanding strategy for the development of innovative drugs. It is driven by two fundamental steps: (1) recognition of the target site by the molecule and (2) establishment of the covalent interaction by its reactive group. The development of new TCIs depends on the development of new warheads. Here, we propose the use of Morita-Baylis-Hillman adducts (MBHAs) to covalently bind Lys strategically placed inside a lipophilic pocket. A human cellular retinoic acid binding protein II mutant (M2) was selected as a test bench for a library of 19 MBHAs. The noncovalent interaction step was investigated by molecular docking studies, while experimentally the entire library was incubated with M2 and crystallized to confirm covalent binding with the target lysine. The results, rationalized through covalent docking analysis, support our hypothesis of MBHAs as reactive scaffolds for the design of lysine-TCIs.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"397-405"},"PeriodicalIF":3.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thiosulfonate-Based Targeted Covalent Cruzipain Inhibitors with Enhanced Bioactivity Translation for Antichagasic Therapy

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-24 DOI: 10.1021/acsmedchemlett.4c0063110.1021/acsmedchemlett.4c00631

Juan Pablo Cerutti, Lucas Abreu Diniz, Viviane Corrêa Santos, Salomé Catalina Vilchez Larrea, Guillermo Daniel Alonso, Rafaela Salgado Ferreira, Wim Dehaen* and Mario Alfredo Quevedo*,

{"title":"Thiosulfonate-Based Targeted Covalent Cruzipain Inhibitors with Enhanced Bioactivity Translation for Antichagasic Therapy","authors":"Juan Pablo Cerutti, Lucas Abreu Diniz, Viviane Corrêa Santos, Salomé Catalina Vilchez Larrea, Guillermo Daniel Alonso, Rafaela Salgado Ferreira, Wim Dehaen* and Mario Alfredo Quevedo*, ","doi":"10.1021/acsmedchemlett.4c0063110.1021/acsmedchemlett.4c00631","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00631https://doi.org/10.1021/acsmedchemlett.4c00631","url":null,"abstract":"Chagas disease remains a neglected tropical disease with limited therapeutic options and a pressing need for new antichagasic agents. In this context, Cruzipain (CZP), the main cysteine protease of T. cruzi, has been validated as a promising target for reversible targeted covalent inhibitors (TCIs). Building upon our previous research, this study reports phenyl thiosulfonate (TSO)-based TCIs, designed to optimize enzymatic performance and enhance bioactivity translation from in vitro CZP inhibition to T. cruzi-infected cell models. Among ten potent phenyl TSO TCIs, TSO-13 exhibited high CZP inhibitory potency, selectivity over human cathepsin L, and excellent bioactivity translation in parasite-infected cells. Computational studies highlighted the dual benefit of the TSO moiety in combining optimal reactivity with enhanced encounter complexes’ stability. Overall, these findings position triazole-based phenyl TSO derivatives as promising candidates for rational CZP inhibitor design, representing a valuable contribution for developing innovative antichagasic agents.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"464–474 464–474"},"PeriodicalIF":3.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Thiosulfonate-Based Targeted Covalent Cruzipain Inhibitors with Enhanced Bioactivity Translation for Antichagasic Therapy.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-24 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.4c00631

Juan Pablo Cerutti, Lucas Abreu Diniz, Viviane Corrêa Santos, Salomé Catalina Vilchez Larrea, Guillermo Daniel Alonso, Rafaela Salgado Ferreira, Wim Dehaen, Mario Alfredo Quevedo

{"title":"Thiosulfonate-Based Targeted Covalent Cruzipain Inhibitors with Enhanced Bioactivity Translation for Antichagasic Therapy.","authors":"Juan Pablo Cerutti, Lucas Abreu Diniz, Viviane Corrêa Santos, Salomé Catalina Vilchez Larrea, Guillermo Daniel Alonso, Rafaela Salgado Ferreira, Wim Dehaen, Mario Alfredo Quevedo","doi":"10.1021/acsmedchemlett.4c00631","DOIUrl":"10.1021/acsmedchemlett.4c00631","url":null,"abstract":"Chagas disease remains a neglected tropical disease with limited therapeutic options and a pressing need for new antichagasic agents. In this context, Cruzipain (CZP), the main cysteine protease of T. cruzi, has been validated as a promising target for reversible targeted covalent inhibitors (TCIs). Building upon our previous research, this study reports phenyl thiosulfonate (TSO)-based TCIs, designed to optimize enzymatic performance and enhance bioactivity translation from in vitro CZP inhibition to T. cruzi-infected cell models. Among ten potent phenyl TSO TCIs, TSO-13 exhibited high CZP inhibitory potency, selectivity over human cathepsin L, and excellent bioactivity translation in parasite-infected cells. Computational studies highlighted the dual benefit of the TSO moiety in combining optimal reactivity with enhanced encounter complexes' stability. Overall, these findings position triazole-based phenyl TSO derivatives as promising candidates for rational CZP inhibitor design, representing a valuable contribution for developing innovative antichagasic agents.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"464-474"},"PeriodicalIF":3.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912287/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of Ethyl-Hydrazide-Based Selective Histone Deacetylase 6 (HDAC6) PROTACs

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-19 DOI: 10.1021/acsmedchemlett.5c0003310.1021/acsmedchemlett.5c00033

Daniel Stopper, Irina Honin, Felix Feller and Finn K. Hansen*,

{"title":"Development of Ethyl-Hydrazide-Based Selective Histone Deacetylase 6 (HDAC6) PROTACs","authors":"Daniel Stopper, Irina Honin, Felix Feller and Finn K. Hansen*, ","doi":"10.1021/acsmedchemlett.5c0003310.1021/acsmedchemlett.5c00033","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.5c00033https://doi.org/10.1021/acsmedchemlett.5c00033","url":null,"abstract":"Histone deacetylases (HDACs) are promising targets for epigenetic drug discovery. Additionally, targeted degradation of HDACs has emerged as a novel approach in medicinal chemistry and chemical biology. However, most inhibitors and degraders rely on the potentially genotoxic hydroxamate as a zinc-binding group (ZBG). In this study, we present the development of HDAC6-directed proteolysis-targeting chimeras (PROTACs) featuring an ethyl hydrazide moiety as an alternative ZBG. This approach avoids the genotoxicity concerns of hydroxamates while maintaining potent HDAC6 degradation. We synthesized a series of CRBN- and VHL-recruiting PROTACs and identified several potent HDAC6 degraders (HDAC6 Dmax > 80%). Among these, 17c was the most effective, achieving an HDAC6 degradation of 91% and a DC50 value of 14 nM. Further characterization proved that 17c acts via the ubiquitin–proteasome system and chemoproteomics confirmed selective HDAC6 degradation over other HDAC isoforms.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"487–495 487–495"},"PeriodicalIF":3.5,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of Ethyl-Hydrazide-Based Selective Histone Deacetylase 6 (HDAC6) PROTACs.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-19 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.5c00033

Daniel Stopper, Irina Honin, Felix Feller, Finn K Hansen

引用次数: 0

Novel Urea-Containing Compounds as Orexin Receptor Agonists for Treating Sleep Disorders, Namely, Narcolepsy, Hypersomnia, and Sleep Apnea Syndrome. 新型含尿素化合物作为奥列克素受体激动剂用于治疗睡眠障碍，即嗜睡症、失眠症和睡眠呼吸暂停综合征。

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-18 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.5c00067

Ram W Sabnis

引用次数: 0

Novel Urea-Containing Compounds as Orexin Receptor Agonists for Treating Sleep Disorders, Namely, Narcolepsy, Hypersomnia, and Sleep Apnea Syndrome

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-18 DOI: 10.1021/acsmedchemlett.5c0006710.1021/acsmedchemlett.5c00067

Ram W. Sabnis*,

引用次数: 0

Synthesis and SAR Studies of Acyl-Thiourea Platinum(II) Complexes Yield Analogs with Dual-Stage Antiplasmodium Activity.

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-17 eCollection Date: 2025-03-13 DOI: 10.1021/acsmedchemlett.4c00545

Fatima-Zahra Ishmail, Dina Coertzen, Sizwe Tshabalala, Meta Leshabane, Shante da Rocha, Mathew Njoroge, Liezl Gibhard, Lyn-Marie Birkholtz, John G Woodland, Timothy J Egan, Kathryn J Wicht, Kelly Chibale

{"title":"Synthesis and SAR Studies of Acyl-Thiourea Platinum(II) Complexes Yield Analogs with Dual-Stage Antiplasmodium Activity.","authors":"Fatima-Zahra Ishmail, Dina Coertzen, Sizwe Tshabalala, Meta Leshabane, Shante da Rocha, Mathew Njoroge, Liezl Gibhard, Lyn-Marie Birkholtz, John G Woodland, Timothy J Egan, Kathryn J Wicht, Kelly Chibale","doi":"10.1021/acsmedchemlett.4c00545","DOIUrl":"10.1021/acsmedchemlett.4c00545","url":null,"abstract":"Mixed-ligand platinum(II) complexes incorporating bipyridine and acyl-thiourea ligands were synthesized and evaluated for their in vitro growth inhibitory activity against the human malaria parasite Plasmodium falciparum (Pf). The substituents at four distinct sites were varied to identify structure-activity relationships for this series. Most complexes displayed potent PfNF54 activity with IC50 values in the nanomolar range and favorable cytotoxicity profiles. Five complexes (C1, C11, C12, C15, and C17) exhibited activity against both the asexual blood and sexual (gametocyte) stage parasites, with another complex (C8) exhibiting activity against late-stage gametocytes only. In addition, the complexes showed comparable ABS potency against the PfK1 multidrug-resistant strain. The pharmacokinetic parameters of one analog (C6), which displayed good solubility and mouse microsomal metabolic stability, were measured. This work demonstrates the potential of acyl-thiourea platinum(II) complexes as selective, multistage-active antiplasmodium compounds as part of the search for new antimalarial agents.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"428-435"},"PeriodicalIF":3.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11912270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143655625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis and SAR Studies of Acyl-Thiourea Platinum(II) Complexes Yield Analogs with Dual-Stage Antiplasmodium Activity

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-17 DOI: 10.1021/acsmedchemlett.4c0054510.1021/acsmedchemlett.4c00545

Fatima-Zahra Ishmail, Dina Coertzen, Sizwe Tshabalala, Meta Leshabane, Shante da Rocha, Mathew Njoroge, Liezl Gibhard, Lyn-Marie Birkholtz, John G. Woodland, Timothy J. Egan, Kathryn J. Wicht* and Kelly Chibale*,

{"title":"Synthesis and SAR Studies of Acyl-Thiourea Platinum(II) Complexes Yield Analogs with Dual-Stage Antiplasmodium Activity","authors":"Fatima-Zahra Ishmail, Dina Coertzen, Sizwe Tshabalala, Meta Leshabane, Shante da Rocha, Mathew Njoroge, Liezl Gibhard, Lyn-Marie Birkholtz, John G. Woodland, Timothy J. Egan, Kathryn J. Wicht* and Kelly Chibale*, ","doi":"10.1021/acsmedchemlett.4c0054510.1021/acsmedchemlett.4c00545","DOIUrl":"https://doi.org/10.1021/acsmedchemlett.4c00545https://doi.org/10.1021/acsmedchemlett.4c00545","url":null,"abstract":"Mixed-ligand platinum(II) complexes incorporating bipyridine and acyl-thiourea ligands were synthesized and evaluated for their in vitro growth inhibitory activity against the human malaria parasite Plasmodium falciparum (Pf). The substituents at four distinct sites were varied to identify structure–activity relationships for this series. Most complexes displayed potent PfNF54 activity with IC50 values in the nanomolar range and favorable cytotoxicity profiles. Five complexes (C1, C11, C12, C15, and C17) exhibited activity against both the asexual blood and sexual (gametocyte) stage parasites, with another complex (C8) exhibiting activity against late-stage gametocytes only. In addition, the complexes showed comparable ABS potency against the PfK1 multidrug-resistant strain. The pharmacokinetic parameters of one analog (C6), which displayed good solubility and mouse microsomal metabolic stability, were measured. This work demonstrates the potential of acyl-thiourea platinum(II) complexes as selective, multistage-active antiplasmodium compounds as part of the search for new antimalarial agents.","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":"16 3","pages":"428–435 428–435"},"PeriodicalIF":3.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsmedchemlett.4c00545","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143600195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Novel 1,6-Naphthridine Compounds as SMARCA2 Inhibitors for Treating Non-small Cell Lung Cancer

IF 3.5 3区医学

ACS Medicinal Chemistry Letters Pub Date : 2025-02-14 DOI: 10.1021/acsmedchemlett.5c0004810.1021/acsmedchemlett.5c00048

Ram W. Sabnis*,

引用次数: 0