Structural development of salicylanilide-based SPAK inhibitors as candidate antihypertensive agents
ChemMedChem. 2021 Jun 9. doi: 10.1002/cmdc.202100273. Online ahead of print.ABSTRACTHypertension is an important target for drug discovery. We have focused on the with-no-lysine kinase (WNK)-oxidative stress-responsive 1 (OSR1) and STE20/SPS1-related proline-alanine-rich protein kinase (SPAK)-NaCl cotransporter (NCC) signal cascade as a potential target, and we previously developed a screening system for inhibitors of WNK-OSR1/SPAK-NCC signaling. Herein we used this system to examine the structure-activity relationship (SAR) of salicylanilide derivatives as SPAK kinase inhibitors. Structural design and development based on...
Source: ChemMedChem - June 10, 2021 Category: Chemistry Authors: Shinya Fujii Eriko Kikuchi Honoka Suzuyama Yuko Watanabe Mari Ishigami-Yuasa Hiroyuki Masuno Takayasu Mori Kiyoshi Isobe Shinichi Uchida Hiroyuki Kagechika Source Type: research

Autophagy-dependent ferroptosis as a therapeutic target in cancer
ChemMedChem. 2021 Jun 10. doi: 10.1002/cmdc.202100334. Online ahead of print.ABSTRACTFerroptosis is an iron-dependent form of cell death associated with the accumulation of labile iron and cytotoxic lipid peroxides. Increasing evidence reveals that ferroptosis isn't a self-standing phenomenon and has close connections with other cellular events. Remarkably, recent insights show that ferroptosis is dependent on autophagy, which is a lysosomal degradation pathway responsible for the recycling of damaged cellular components under survival stress. Autophagy is capable of contributing to ferroptosis through degradation of the f...
Source: ChemMedChem - June 10, 2021 Category: Chemistry Authors: Li Liu Liqi Li Menghuan Li Zhong Luo Source Type: research

Med Chem Remote: The Frontiers in Medicinal Chemistry 2021
This report presents a summary of the key lectures and activities at the event.PMID:34101362 | DOI:10.1002/cmdc.202100355 (Source: ChemMedChem)
Source: ChemMedChem - June 8, 2021 Category: Chemistry Authors: Fabian H Knaup Christian Meyners Anna Charalampidou Patryk Krajczy Patrick L Purder Tatjana Ross Felix Hausch Source Type: research

Fragment-based drug discovery for RNA targets
ChemMedChem. 2021 Jun 8. doi: 10.1002/cmdc.202100324. Online ahead of print.ABSTRACTRapid development within the fields of both fragment-based drug discovery (FBDD) and medicinal targeting of RNA provides possibilities for combining technologies and methods in novel ways. This review provides an overview of fragment-based screening (FBS) against RNA targets, including a discussion of the most recently used screening and hit validation methods such as NMR, X-ray crystallography, and virtual screening methods. A discussion of fragment library design based on research from small molecule RNA binders provides an overview on bo...
Source: ChemMedChem - June 8, 2021 Category: Chemistry Authors: Kasper Plenov Lundquist Vipul Panchal Charlotte Held Gotfredsen Ruth Brenk Mads Hartvig Clausen Source Type: research

Med Chem Remote: The Frontiers in Medicinal Chemistry 2021
This report presents a summary of the key lectures and activities at the event.PMID:34101362 | DOI:10.1002/cmdc.202100355 (Source: ChemMedChem)
Source: ChemMedChem - June 8, 2021 Category: Chemistry Authors: Fabian H Knaup Christian Meyners Anna Charalampidou Patryk Krajczy Patrick L Purder Tatjana Ross Felix Hausch Source Type: research

Fragment-based drug discovery for RNA targets
ChemMedChem. 2021 Jun 8. doi: 10.1002/cmdc.202100324. Online ahead of print.ABSTRACTRapid development within the fields of both fragment-based drug discovery (FBDD) and medicinal targeting of RNA provides possibilities for combining technologies and methods in novel ways. This review provides an overview of fragment-based screening (FBS) against RNA targets, including a discussion of the most recently used screening and hit validation methods such as NMR, X-ray crystallography, and virtual screening methods. A discussion of fragment library design based on research from small molecule RNA binders provides an overview on bo...
Source: ChemMedChem - June 8, 2021 Category: Chemistry Authors: Kasper Plenov Lundquist Vipul Panchal Charlotte Held Gotfredsen Ruth Brenk Mads Hartvig Clausen Source Type: research

Pyrazole-Thiazole Core-Containing Analogs Exhibit Adjunctive Activity with Meropenem against Carbapenem-Resistant Enterobacteriaceae (CRE)
ChemMedChem. 2021 Jun 6. doi: 10.1002/cmdc.202100321. Online ahead of print.ABSTRACTPyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram-negative bacteria evidenced by a range of fractional inhibitory concentration (FIC = 0.5 - 0.25) and minimum adjunctive concentration (MAC = 128 - 32 μM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover, the solubility ...
Source: ChemMedChem - June 7, 2021 Category: Chemistry Authors: Chungsik Kim Mintesinot Kassu Kenneth P Smith James E Kirby Roman Manetsch Source Type: research

Pyrazole-Thiazole Core-Containing Analogs Exhibit Adjunctive Activity with Meropenem against Carbapenem-Resistant Enterobacteriaceae (CRE)
ChemMedChem. 2021 Jun 6. doi: 10.1002/cmdc.202100321. Online ahead of print.ABSTRACTPyrazole-thiazole core-containing compound KP-40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram-negative bacteria evidenced by a range of fractional inhibitory concentration (FIC = 0.5 - 0.25) and minimum adjunctive concentration (MAC = 128 - 32 μM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover, the solubility ...
Source: ChemMedChem - June 7, 2021 Category: Chemistry Authors: Chungsik Kim Mintesinot Kassu Kenneth P Smith James E Kirby Roman Manetsch Source Type: research

Poly-L-lysine Glycoconjugates Inhibit DC-SIGN-mediated Attachment of Pandemic Viruses
ChemMedChem. 2021 Jun 1. doi: 10.1002/cmdc.202100348. Online ahead of print.ABSTRACTThe C-type lectin receptor DC-SIGN mediates interactions with envelope glycoproteins of many viruses such as SARS-CoV-2, ebola, and HIV and contributes to virus internalization and dissemination. In the context of the recent SARS-CoV-2 pandemic, involvement of DC-SIGN has been linked to severe cases of COVID-19. Inhibition of the interaction between DC-SIGN and viral glycoproteins has the potential to generate broad spectrum antiviral agents. Here, we demonstrate that mannose-functionalized poly- l -lysine glycoconjugates efficiently inhibi...
Source: ChemMedChem - June 1, 2021 Category: Chemistry Authors: Beat Ernst Jonathan Cramer Butrint Aliu Xiaohua Jiang Timothy Sharpe Lijuan Pang Adrian Hadorn Said Rabbani Source Type: research

Poly-L-lysine Glycoconjugates Inhibit DC-SIGN-mediated Attachment of Pandemic Viruses
ChemMedChem. 2021 Jun 1. doi: 10.1002/cmdc.202100348. Online ahead of print.ABSTRACTThe C-type lectin receptor DC-SIGN mediates interactions with envelope glycoproteins of many viruses such as SARS-CoV-2, ebola, and HIV and contributes to virus internalization and dissemination. In the context of the recent SARS-CoV-2 pandemic, involvement of DC-SIGN has been linked to severe cases of COVID-19. Inhibition of the interaction between DC-SIGN and viral glycoproteins has the potential to generate broad spectrum antiviral agents. Here, we demonstrate that mannose-functionalized poly- l -lysine glycoconjugates efficiently inhibi...
Source: ChemMedChem - June 1, 2021 Category: Chemistry Authors: Beat Ernst Jonathan Cramer Butrint Aliu Xiaohua Jiang Timothy Sharpe Lijuan Pang Adrian Hadorn Said Rabbani Source Type: research

Poly-L-lysine Glycoconjugates Inhibit DC-SIGN-mediated Attachment of Pandemic Viruses
ChemMedChem. 2021 Jun 1. doi: 10.1002/cmdc.202100348. Online ahead of print.ABSTRACTThe C-type lectin receptor DC-SIGN mediates interactions with envelope glycoproteins of many viruses such as SARS-CoV-2, ebola, and HIV and contributes to virus internalization and dissemination. In the context of the recent SARS-CoV-2 pandemic, involvement of DC-SIGN has been linked to severe cases of COVID-19. Inhibition of the interaction between DC-SIGN and viral glycoproteins has the potential to generate broad spectrum antiviral agents. Here, we demonstrate that mannose-functionalized poly- l -lysine glycoconjugates efficiently inhibi...
Source: ChemMedChem - June 1, 2021 Category: Chemistry Authors: Beat Ernst Jonathan Cramer Butrint Aliu Xiaohua Jiang Timothy Sharpe Lijuan Pang Adrian Hadorn Said Rabbani Source Type: research

Poly-L-lysine Glycoconjugates Inhibit DC-SIGN-mediated Attachment of Pandemic Viruses
ChemMedChem. 2021 Jun 1. doi: 10.1002/cmdc.202100348. Online ahead of print.ABSTRACTThe C-type lectin receptor DC-SIGN mediates interactions with envelope glycoproteins of many viruses such as SARS-CoV-2, ebola, and HIV and contributes to virus internalization and dissemination. In the context of the recent SARS-CoV-2 pandemic, involvement of DC-SIGN has been linked to severe cases of COVID-19. Inhibition of the interaction between DC-SIGN and viral glycoproteins has the potential to generate broad spectrum antiviral agents. Here, we demonstrate that mannose-functionalized poly- l -lysine glycoconjugates efficiently inhibi...
Source: ChemMedChem - June 1, 2021 Category: Chemistry Authors: Beat Ernst Jonathan Cramer Butrint Aliu Xiaohua Jiang Timothy Sharpe Lijuan Pang Adrian Hadorn Said Rabbani Source Type: research

Poly-L-lysine Glycoconjugates Inhibit DC-SIGN-mediated Attachment of Pandemic Viruses
ChemMedChem. 2021 Jun 1. doi: 10.1002/cmdc.202100348. Online ahead of print.ABSTRACTThe C-type lectin receptor DC-SIGN mediates interactions with envelope glycoproteins of many viruses such as SARS-CoV-2, ebola, and HIV and contributes to virus internalization and dissemination. In the context of the recent SARS-CoV-2 pandemic, involvement of DC-SIGN has been linked to severe cases of COVID-19. Inhibition of the interaction between DC-SIGN and viral glycoproteins has the potential to generate broad spectrum antiviral agents. Here, we demonstrate that mannose-functionalized poly- l -lysine glycoconjugates efficiently inhibi...
Source: ChemMedChem - June 1, 2021 Category: Chemistry Authors: Beat Ernst Jonathan Cramer Butrint Aliu Xiaohua Jiang Timothy Sharpe Lijuan Pang Adrian Hadorn Said Rabbani Source Type: research

Polysubstituted Pyrimidines as Potent Inhibitors of Prostaglandin E2 Production: Increasing Their Aqueous Solubility
ChemMedChem. 2021 May 31. doi: 10.1002/cmdc.202100263. Online ahead of print.ABSTRACTWater-solubility is one of the key features of potential therapeutic agents. In order to enhance poor water-solubility of parent 5-butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine, a potent inhibitor of prostaglandin E 2 (PGE 2 ) production, we synthesized and evaluated a new series of derivatives where the butyl group in the C5 position of pyrimidine ring was replaced with less lipophilic substituent, preferably with a hydrophilic aliphatic moiety. Except for the 5-cyanopyrimidine derivative, all target compounds exhibited increased (2...
Source: ChemMedChem - May 31, 2021 Category: Chemistry Authors: Filip Kal čic Viktor Kolman Zden ěk Zídek Zlatko Janeba Source Type: research

Polysubstituted Pyrimidines as Potent Inhibitors of Prostaglandin E2 Production: Increasing Their Aqueous Solubility
ChemMedChem. 2021 May 31. doi: 10.1002/cmdc.202100263. Online ahead of print.ABSTRACTWater-solubility is one of the key features of potential therapeutic agents. In order to enhance poor water-solubility of parent 5-butyl-4-(4-methoxyphenyl)-6-phenylpyrimidin-2-amine, a potent inhibitor of prostaglandin E 2 (PGE 2 ) production, we synthesized and evaluated a new series of derivatives where the butyl group in the C5 position of pyrimidine ring was replaced with less lipophilic substituent, preferably with a hydrophilic aliphatic moiety. Except for the 5-cyanopyrimidine derivative, all target compounds exhibited increased (2...
Source: ChemMedChem - May 31, 2021 Category: Chemistry Authors: Filip Kal čic Viktor Kolman Zden ěk Zídek Zlatko Janeba Source Type: research

Synthesis and biological evaluation of dantrolene-like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases
ChemMedChem. 2021 May 28. doi: 10.1002/cmdc.202100209. Online ahead of print.ABSTRACTDantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one novel dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newl...
Source: ChemMedChem - May 28, 2021 Category: Chemistry Authors: Isabella Bolognino Nicola Giangregorio Annamaria Tonazzi Ant ón L Martínez Cosimo D Altomare Mar ía I Loza Sara Sablone Saverio Cellamare Marco Catto Source Type: research

Targeting the S100A2-p53 interactions with a series of novel 3,5-bistrifluoromethylbenzene sulfonamides: Synthesis and cytotoxicity
ChemMedChem. 2021 May 27. doi: 10.1002/cmdc.202000949. Online ahead of print.ABSTRACTIn silico approaches identified 1 , N -(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 µM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused lib...
Source: ChemMedChem - May 28, 2021 Category: Chemistry Authors: Jufeng Sun Joey I Ambrus Cecilia C Russell Jennifer R Baker Peter J Cossar Melanie J Pirinen Jennette A Sakoff Christopher J Scarlett Adam McCluskey Source Type: research

Novel cytotoxic 1,2,3-triazoles as potential new leads targeting the S100A2-p53complex
ChemMedChem. 2021 May 27. doi: 10.1002/cmdc.202000950. Online ahead of print.ABSTRACTIn silico approaches identified 1, N-(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 µM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused libra...
Source: ChemMedChem - May 28, 2021 Category: Chemistry Authors: Jufeng Sun Jennifer R Baker Cecilia C Russell Peter J Cossar Hong Ngoc Thuy Pham Jennette A Sakoff Christopher J Scarlett Adam McCluskey Source Type: research

Synthesis and biological evaluation of dantrolene-like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases
ChemMedChem. 2021 May 28. doi: 10.1002/cmdc.202100209. Online ahead of print.ABSTRACTDantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one novel dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newl...
Source: ChemMedChem - May 28, 2021 Category: Chemistry Authors: Isabella Bolognino Nicola Giangregorio Annamaria Tonazzi Ant ón L Martínez Cosimo D Altomare Mar ía I Loza Sara Sablone Saverio Cellamare Marco Catto Source Type: research

Targeting the S100A2-p53 interactions with a series of novel 3,5-bistrifluoromethylbenzene sulfonamides: Synthesis and cytotoxicity
ChemMedChem. 2021 May 27. doi: 10.1002/cmdc.202000949. Online ahead of print.ABSTRACTIn silico approaches identified 1 , N -(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 µM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused lib...
Source: ChemMedChem - May 28, 2021 Category: Chemistry Authors: Jufeng Sun Joey I Ambrus Cecilia C Russell Jennifer R Baker Peter J Cossar Melanie J Pirinen Jennette A Sakoff Christopher J Scarlett Adam McCluskey Source Type: research

Novel cytotoxic 1,2,3-triazoles as potential new leads targeting the S100A2-p53complex
ChemMedChem. 2021 May 27. doi: 10.1002/cmdc.202000950. Online ahead of print.ABSTRACTIn silico approaches identified 1, N-(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 µM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused libra...
Source: ChemMedChem - May 28, 2021 Category: Chemistry Authors: Jufeng Sun Jennifer R Baker Cecilia C Russell Peter J Cossar Hong Ngoc Thuy Pham Jennette A Sakoff Christopher J Scarlett Adam McCluskey Source Type: research

Synthesis and biological evaluation of dantrolene-like hydrazide and hydrazone analogues as multitarget agents for neurodegenerative diseases
ChemMedChem. 2021 May 28. doi: 10.1002/cmdc.202100209. Online ahead of print.ABSTRACTDantrolene, a drug used for the management of malignant hyperthermia, had been recently evaluated for prospective repurposing as multitarget agent for neurodegenerative syndromes, including Alzheimer's disease (AD). Herein, twenty-one novel dantrolene-like hydrazide and hydrazone analogues were synthesized with the aim of exploring structure-activity relationships (SARs) for the inhibition of human monoamine oxidases (MAOs) and acetylcholinesterase (AChE), two well-established target enzymes for anti-AD drugs. With few exceptions, the newl...
Source: ChemMedChem - May 28, 2021 Category: Chemistry Authors: Isabella Bolognino Nicola Giangregorio Annamaria Tonazzi Ant ón L Martínez Cosimo D Altomare Mar ía I Loza Sara Sablone Saverio Cellamare Marco Catto Source Type: research

Targeting the S100A2-p53 interactions with a series of novel 3,5-bistrifluoromethylbenzene sulfonamides: Synthesis and cytotoxicity
ChemMedChem. 2021 May 27. doi: 10.1002/cmdc.202000949. Online ahead of print.ABSTRACTIn silico approaches identified 1 , N -(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 µM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused lib...
Source: ChemMedChem - May 28, 2021 Category: Chemistry Authors: Jufeng Sun Joey I Ambrus Cecilia C Russell Jennifer R Baker Peter J Cossar Melanie J Pirinen Jennette A Sakoff Christopher J Scarlett Adam McCluskey Source Type: research

Novel cytotoxic 1,2,3-triazoles as potential new leads targeting the S100A2-p53complex
ChemMedChem. 2021 May 27. doi: 10.1002/cmdc.202000950. Online ahead of print.ABSTRACTIn silico approaches identified 1, N-(6-((4-bromo- benzyl)amino)hexyl)-3,5-bis(trifluoromethyl)benzene sulfonamide, as a potential inhibitor of S100A2-p53 protein-protein interaction, a validated pancreatic cancer drug target. Subsequent cytotoxicity screening revealed it to be a 2.97 µM cell growth inhibitor of the MiaPaCa-2 pancreatic cell line. This is in keeping with our hypothesis that inhibiting this interaction would have an anti-pancreatic cancer effect with S100A2, the validated PC drug target. A combination of focused libra...
Source: ChemMedChem - May 28, 2021 Category: Chemistry Authors: Jufeng Sun Jennifer R Baker Cecilia C Russell Peter J Cossar Hong Ngoc Thuy Pham Jennette A Sakoff Christopher J Scarlett Adam McCluskey Source Type: research

Novel pyridine-containing sultones: Structure-activity relationship and biological evaluation as selective AChE inhibitors for the treatment of Alzheimer's disease
ChemMedChem. 2021 May 25. doi: 10.1002/cmdc.202100272. Online ahead of print.ABSTRACTNovel pyridine-containing sultones were synthesized and evaluated for their ChE inhibitory activity. Most of compounds showed selective AChE inhibitory activity. The structure-activity relationship (SAR) showed: (i) fused pyridine-containing sultones increased the AChE inhibition, series B> series A ; (ii) series B with halo-phenyl had better activity. Compound B4 was identified as a selective AChE inhibitor (IC 50 = 8.93 μM), which was nicely fallen into Tc AChE via hydrogen interactions between δ-pyridylsultone scaffold with ...
Source: ChemMedChem - May 26, 2021 Category: Chemistry Authors: Wenjian Tang Hong Zhang Chengyao Wu Xing Chen Ziwen Zhang Xia Jiang Hua-Li Qin Source Type: research

Novel pyridine-containing sultones: Structure-activity relationship and biological evaluation as selective AChE inhibitors for the treatment of Alzheimer's disease
ChemMedChem. 2021 May 25. doi: 10.1002/cmdc.202100272. Online ahead of print.ABSTRACTNovel pyridine-containing sultones were synthesized and evaluated for their ChE inhibitory activity. Most of compounds showed selective AChE inhibitory activity. The structure-activity relationship (SAR) showed: (i) fused pyridine-containing sultones increased the AChE inhibition, series B> series A ; (ii) series B with halo-phenyl had better activity. Compound B4 was identified as a selective AChE inhibitor (IC 50 = 8.93 μM), which was nicely fallen into Tc AChE via hydrogen interactions between δ-pyridylsultone scaffold with ...
Source: ChemMedChem - May 26, 2021 Category: Chemistry Authors: Wenjian Tang Hong Zhang Chengyao Wu Xing Chen Ziwen Zhang Xia Jiang Hua-Li Qin Source Type: research

Novel pyridine-containing sultones: Structure-activity relationship and biological evaluation as selective AChE inhibitors for the treatment of Alzheimer's disease
ChemMedChem. 2021 May 25. doi: 10.1002/cmdc.202100272. Online ahead of print.ABSTRACTNovel pyridine-containing sultones were synthesized and evaluated for their ChE inhibitory activity. Most of compounds showed selective AChE inhibitory activity. The structure-activity relationship (SAR) showed: (i) fused pyridine-containing sultones increased the AChE inhibition, series B> series A ; (ii) series B with halo-phenyl had better activity. Compound B4 was identified as a selective AChE inhibitor (IC 50 = 8.93 μM), which was nicely fallen into Tc AChE via hydrogen interactions between δ-pyridylsultone scaffold with ...
Source: ChemMedChem - May 26, 2021 Category: Chemistry Authors: Wenjian Tang Hong Zhang Chengyao Wu Xing Chen Ziwen Zhang Xia Jiang Hua-Li Qin Source Type: research

β-Actin Peptide-Based Inhibitors of Histidine Methyltransferase SETD3
ChemMedChem. 2021 May 25. doi: 10.1002/cmdc.202100296. Online ahead of print.ABSTRACTSETD3 was recently identified as the histidine methyltransferase responsible for N 3 -methylation of His73 of β-actin in humans. Overexpression of SETD3 is associated with several diseases, including breast cancer. Here, we report a development of actin-based peptidomimetics as inhibitors of recombinantly expressed human SETD3. Substitution of His73 by simple natural and unnatural amino acids led to selected β-actin peptides with high potency against SETD3 in MALDI-TOF MS assays. The selenomethionine-containing β-actin pepti...
Source: ChemMedChem - May 25, 2021 Category: Chemistry Authors: Jordi C J Hintzen Laust Moesgaard Sebastian Kwiatkowski Jakub Drozak Jacob Kongsted Jasmin Mecinovic Source Type: research

From quinoline to quinazoline-based S. aureus NorA efflux pump inhibitors by coupling focused scaffold hopping approach and pharmacophore search
ChemMedChem. 2021 May 25. doi: 10.1002/cmdc.202100282. Online ahead of print.ABSTRACTAntibiotic resistance breakers, such as efflux pump inhibitors (EPIs), represent a powerful alternative to the development of new antimicrobials. Recently, by using previously described EPIs, we developed pharmacophore models able to identify inhibitors of NorA, the most studied efflux pump of the Staphylococcus aureus. Herein, we reported a pharmacophore-based virtual screening of a library of new potential NorA EPIs generated by an in-silico scaffold hopping approach of the quinoline core. After chemical synthesis and biological evaluati...
Source: ChemMedChem - May 25, 2021 Category: Chemistry Authors: Nicholas Cedraro Rolando Cannalire Andrea Astolfi Gianmarco Mangiaterra Tommaso Felicetti Salvatore Vaiasicca Giada Cernicchi Serena Massari Giuseppe Manfroni Oriana Tabarrini Violetta Cecchetti Maria Letizia Barreca Francesca Biavasco Stefano Sabatini Source Type: research

Design, Synthesis and Evaluation of a Series of 1,5-Diaryl-1,2,3-triazole-4-carbohydrazones as Inhibitors of the YAP-TAZ/TEAD Complex
ChemMedChem. 2021 May 25. doi: 10.1002/cmdc.202100153. Online ahead of print.ABSTRACTStarting from our previously reported hit, a series of 1,5-diaryl-1,2,3-triazole-4-carbohydrazones was synthesized and evaluated as inhibitors of the YAP/TAZ-TEAD complex. Binding to hTEAD2 of our compounds was evidenced by nanodifferential scanning fluorimetry and they were also shown by polarization fluorescence to disrupt to some extent YAP-TEAD interaction. They displayed micromolar inhibition in a luciferase gene reporter assay in transfected HEK293T cells and decreased mRNAs levels of TEAD target genes measured by RTqPCR in MDA-MB231...
Source: ChemMedChem - May 25, 2021 Category: Chemistry Authors: Fabrice Bailly Floriane Gibault Manon Sturbaut Mathilde Coevoet Martine Pugni ère Ashley Burtscher Fr édéric Allemand Patricia Melnyk Wanjin Hong Brian P Rubin Ajaybabu V Pobbati Jean-Fran çois Guichou Philippe Cotelle Source Type: research

Metal-based Catalytic Drug Development for Next-generation Cancer Therapy
ChemMedChem. 2021 May 24. doi: 10.1002/cmdc.202100297. Online ahead of print.ABSTRACTConsidering the very high increase in mortality caused by cancer in recent years, new cancer drugs with novel anticancer mechanism are of urgent prerequisite for overcoming the drawbacks of platinum-based chemotherapeutics. Very recently, in the area of metal-based cancer drug development research, the concept of catalytic cancer drugs has been introduced with the organometallic Ru(II), Os(II), Rh(III) and Ir(III) complexes. These complexes are reported as catalysts for many important biological transformations in cancer cells such as nico...
Source: ChemMedChem - May 24, 2021 Category: Chemistry Authors: Huaiyi Huang Zhongxian Fan Samya Banerjee Juyang Huang Source Type: research

Metal-based Catalytic Drug Development for Next-generation Cancer Therapy
ChemMedChem. 2021 May 24. doi: 10.1002/cmdc.202100297. Online ahead of print.ABSTRACTConsidering the very high increase in mortality caused by cancer in recent years, new cancer drugs with novel anticancer mechanism are of urgent prerequisite for overcoming the drawbacks of platinum-based chemotherapeutics. Very recently, in the area of metal-based cancer drug development research, the concept of catalytic cancer drugs has been introduced with the organometallic Ru(II), Os(II), Rh(III) and Ir(III) complexes. These complexes are reported as catalysts for many important biological transformations in cancer cells such as nico...
Source: ChemMedChem - May 24, 2021 Category: Chemistry Authors: Huaiyi Huang Zhongxian Fan Samya Banerjee Juyang Huang Source Type: research

Platinum Cyclooctadiene Complexes with Activity against Gram-positive Bacteria
ChemMedChem. 2021 May 21. doi: 10.1002/cmdc.202100157. Online ahead of print.ABSTRACTAntimicrobial resistance is a looming health crisis, and it is becoming increasingly clear that organic chemistry alone is not sufficient to continue to provide the world with novel and effective antibiotics. Recently there has been an increased number of reports describing promising antimicrobial properties of meta-containing compounds. Platinum complexes are well known in the field of inorganic medicinal chemistry for their tremendous success as anticancer agents. Here we report on the promising antibacterial properties of platinum cyclo...
Source: ChemMedChem - May 21, 2021 Category: Chemistry Authors: Angelo Frei Soumya Ramu Gabrielle J Lowe Hue Dinh Lucie Semenec Alysha G Elliott Johannes Zuegg Anke Deckers Nicole Jung Stefan Braese Amy K Cain Mark A T Blaskovich Source Type: research

Platinum Cyclooctadiene Complexes with Activity against Gram-positive Bacteria
ChemMedChem. 2021 May 21. doi: 10.1002/cmdc.202100157. Online ahead of print.ABSTRACTAntimicrobial resistance is a looming health crisis, and it is becoming increasingly clear that organic chemistry alone is not sufficient to continue to provide the world with novel and effective antibiotics. Recently there has been an increased number of reports describing promising antimicrobial properties of meta-containing compounds. Platinum complexes are well known in the field of inorganic medicinal chemistry for their tremendous success as anticancer agents. Here we report on the promising antibacterial properties of platinum cyclo...
Source: ChemMedChem - May 21, 2021 Category: Chemistry Authors: Angelo Frei Soumya Ramu Gabrielle J Lowe Hue Dinh Lucie Semenec Alysha G Elliott Johannes Zuegg Anke Deckers Nicole Jung Stefan Braese Amy K Cain Mark A T Blaskovich Source Type: research

Platinum Cyclooctadiene Complexes with Activity against Gram-positive Bacteria
ChemMedChem. 2021 May 21. doi: 10.1002/cmdc.202100157. Online ahead of print.ABSTRACTAntimicrobial resistance is a looming health crisis, and it is becoming increasingly clear that organic chemistry alone is not sufficient to continue to provide the world with novel and effective antibiotics. Recently there has been an increased number of reports describing promising antimicrobial properties of meta-containing compounds. Platinum complexes are well known in the field of inorganic medicinal chemistry for their tremendous success as anticancer agents. Here we report on the promising antibacterial properties of platinum cyclo...
Source: ChemMedChem - May 21, 2021 Category: Chemistry Authors: Angelo Frei Soumya Ramu Gabrielle J Lowe Hue Dinh Lucie Semenec Alysha G Elliott Johannes Zuegg Anke Deckers Nicole Jung Stefan Braese Amy K Cain Mark A T Blaskovich Source Type: research

Structure-activity relationship and mode of action studies highlight 1-(4-biphenylylmethyl)-1H-imidazole derived small molecules as potent CYP121 inhibitors
ChemMedChem. 2021 May 19. doi: 10.1002/cmdc.202100283. Online ahead of print.ABSTRACTCYP121 of Mycobacterium tuberculosis (Mtb) is an essential target for the development of novel potent drugs against Tuberculosis (TB). Besides known antifungal azoles, further compounds of the azole class were recently identified as CYP121 inhibitors with antimycobacterial activity. Herein we report the screening of a similarity-oriented library based on the former hit compound, the evaluation of affinity towards CYP121 and activity against M. bovis BCG. The results enabled a comprehensive SAR study, which was extended through the synthesi...
Source: ChemMedChem - May 19, 2021 Category: Chemistry Authors: Sebastian Adam Isabell Walter Rolf Hartmann Andreas Kany Jesko K öhnke Maria Virginia Gentilini Tim Sparwasser Christian Brengel Andreas Thomann Source Type: research

Corrigendum: Synthesis and Evaluation of 2-Aminothiophene Derivatives as Staphylococcus aureus Efflux Pump Inhibitors
ChemMedChem. 2021 May 18;16(10):1680. doi: 10.1002/cmdc.2020100124.NO ABSTRACTPMID:34010522 | DOI:10.1002/cmdc.2020100124 (Source: ChemMedChem)
Source: ChemMedChem - May 19, 2021 Category: Chemistry Authors: Rayssa M D da Cruz Renaud Zelli Sarah Benhsain Ryldene M D da Cruz Jos é P Siqueira-Júnior Jean-Luc D écout Marie-Paule Mingeot-Leclercq Francisco J B Mendon ça-Junior Source Type: research

Structure-activity relationship and mode of action studies highlight 1-(4-biphenylylmethyl)-1H-imidazole derived small molecules as potent CYP121 inhibitors
ChemMedChem. 2021 May 19. doi: 10.1002/cmdc.202100283. Online ahead of print.ABSTRACTCYP121 of Mycobacterium tuberculosis (Mtb) is an essential target for the development of novel potent drugs against Tuberculosis (TB). Besides known antifungal azoles, further compounds of the azole class were recently identified as CYP121 inhibitors with antimycobacterial activity. Herein we report the screening of a similarity-oriented library based on the former hit compound, the evaluation of affinity towards CYP121 and activity against M. bovis BCG. The results enabled a comprehensive SAR study, which was extended through the synthesi...
Source: ChemMedChem - May 19, 2021 Category: Chemistry Authors: Sebastian Adam Isabell Walter Rolf Hartmann Andreas Kany Jesko K öhnke Maria Virginia Gentilini Tim Sparwasser Christian Brengel Andreas Thomann Source Type: research

Corrigendum: Synthesis and Evaluation of 2-Aminothiophene Derivatives as Staphylococcus aureus Efflux Pump Inhibitors
ChemMedChem. 2021 May 18;16(10):1680. doi: 10.1002/cmdc.2020100124.NO ABSTRACTPMID:34010522 | DOI:10.1002/cmdc.2020100124 (Source: ChemMedChem)
Source: ChemMedChem - May 19, 2021 Category: Chemistry Authors: Rayssa M D da Cruz Renaud Zelli Sarah Benhsain Ryldene M D da Cruz Jos é P Siqueira-Júnior Jean-Luc D écout Marie-Paule Mingeot-Leclercq Francisco J B Mendon ça-Junior Source Type: research

Small Molecule with Bridged Carbonyl and Tri-fluoro-aceto-phenone Groups Impedes Microtubule Dynamics and Subsequently Triggers Cancer Cell Apoptosis
ChemMedChem. 2021 May 13. doi: 10.1002/cmdc.202100192. Online ahead of print.ABSTRACTWe identified a new class of microtubule targeted small molecule, which showed significant anticancer activity and induces apoptotic death of cancer cells. Precisely the central bridged carbonyl group and trifluoro-acetophenone group of a bis-benzothiazole molecule (BBT) interacts with tubulin close to the curcumin site and perturbs microtubule dynamics as well as causes microtubule depolymerization. We observed a significant enhancement of fluorescence while BBT interacts with the tubulin through bridged carbonyl moiety, a similar phenome...
Source: ChemMedChem - May 13, 2021 Category: Chemistry Authors: Saswat Mohapatra Varsha Gupta Prasenjit Mondal Shreyam Chatterjee Debmalya Bhunia Surajit Ghosh Source Type: research

Small Molecule with Bridged Carbonyl and Tri-fluoro-aceto-phenone Groups Impedes Microtubule Dynamics and Subsequently Triggers Cancer Cell Apoptosis
ChemMedChem. 2021 May 13. doi: 10.1002/cmdc.202100192. Online ahead of print.ABSTRACTWe identified a new class of microtubule targeted small molecule, which showed significant anticancer activity and induces apoptotic death of cancer cells. Precisely the central bridged carbonyl group and trifluoro-acetophenone group of a bis-benzothiazole molecule (BBT) interacts with tubulin close to the curcumin site and perturbs microtubule dynamics as well as causes microtubule depolymerization. We observed a significant enhancement of fluorescence while BBT interacts with the tubulin through bridged carbonyl moiety, a similar phenome...
Source: ChemMedChem - May 13, 2021 Category: Chemistry Authors: Saswat Mohapatra Varsha Gupta Prasenjit Mondal Shreyam Chatterjee Debmalya Bhunia Surajit Ghosh Source Type: research

Small Molecule with Bridged Carbonyl and Tri-fluoro-aceto-phenone Groups Impedes Microtubule Dynamics and Subsequently Triggers Cancer Cell Apoptosis
ChemMedChem. 2021 May 13. doi: 10.1002/cmdc.202100192. Online ahead of print.ABSTRACTWe identified a new class of microtubule targeted small molecule, which showed significant anticancer activity and induces apoptotic death of cancer cells. Precisely the central bridged carbonyl group and trifluoro-acetophenone group of a bis-benzothiazole molecule (BBT) interacts with tubulin close to the curcumin site and perturbs microtubule dynamics as well as causes microtubule depolymerization. We observed a significant enhancement of fluorescence while BBT interacts with the tubulin through bridged carbonyl moiety, a similar phenome...
Source: ChemMedChem - May 13, 2021 Category: Chemistry Authors: Saswat Mohapatra Varsha Gupta Prasenjit Mondal Shreyam Chatterjee Debmalya Bhunia Surajit Ghosh Source Type: research

Small Molecule with Bridged Carbonyl and Tri-fluoro-aceto-phenone Groups Impedes Microtubule Dynamics and Subsequently Triggers Cancer Cell Apoptosis
ChemMedChem. 2021 May 13. doi: 10.1002/cmdc.202100192. Online ahead of print.ABSTRACTWe identified a new class of microtubule targeted small molecule, which showed significant anticancer activity and induces apoptotic death of cancer cells. Precisely the central bridged carbonyl group and trifluoro-acetophenone group of a bis-benzothiazole molecule (BBT) interacts with tubulin close to the curcumin site and perturbs microtubule dynamics as well as causes microtubule depolymerization. We observed a significant enhancement of fluorescence while BBT interacts with the tubulin through bridged carbonyl moiety, a similar phenome...
Source: ChemMedChem - May 13, 2021 Category: Chemistry Authors: Saswat Mohapatra Varsha Gupta Prasenjit Mondal Shreyam Chatterjee Debmalya Bhunia Surajit Ghosh Source Type: research

Small Molecule with Bridged Carbonyl and Tri-fluoro-aceto-phenone Groups Impedes Microtubule Dynamics and Subsequently Triggers Cancer Cell Apoptosis
ChemMedChem. 2021 May 13. doi: 10.1002/cmdc.202100192. Online ahead of print.ABSTRACTWe identified a new class of microtubule targeted small molecule, which showed significant anticancer activity and induces apoptotic death of cancer cells. Precisely the central bridged carbonyl group and trifluoro-acetophenone group of a bis-benzothiazole molecule (BBT) interacts with tubulin close to the curcumin site and perturbs microtubule dynamics as well as causes microtubule depolymerization. We observed a significant enhancement of fluorescence while BBT interacts with the tubulin through bridged carbonyl moiety, a similar phenome...
Source: ChemMedChem - May 13, 2021 Category: Chemistry Authors: Saswat Mohapatra Varsha Gupta Prasenjit Mondal Shreyam Chatterjee Debmalya Bhunia Surajit Ghosh Source Type: research

Albumin conjugates of thiosemicarbazone and imidazole-2-thione prochelators: Iron coordination and antiproliferative activity
ChemMedChem. 2021 May 11. doi: 10.1002/cmdc.202100278. Online ahead of print.ABSTRACTThe central role of iron in tumor progression and metastasis motivates the development of iron-binding approaches in cancer chemotherapy. Disulfide-based prochelators are reductively activated upon cellular uptake to liberate thiol chelators responsible for iron sequestration. Herein, a trimethyl thiosemicarbazone moiety and the imidazole-2-thione heterocycle are incorporated in this prochelator design. Iron binding of the corresponding tridentate chelators leads to the stabilization of a low-spin ferric center in 2:1 ligand-to-metal compl...
Source: ChemMedChem - May 11, 2021 Category: Chemistry Authors: Yu-Shien Sung Wangbin Wu Megan A Ewbank Rachel D Utterback Michael T Marty Elisa Tomat Source Type: research

Albumin conjugates of thiosemicarbazone and imidazole-2-thione prochelators: Iron coordination and antiproliferative activity
ChemMedChem. 2021 May 11. doi: 10.1002/cmdc.202100278. Online ahead of print.ABSTRACTThe central role of iron in tumor progression and metastasis motivates the development of iron-binding approaches in cancer chemotherapy. Disulfide-based prochelators are reductively activated upon cellular uptake to liberate thiol chelators responsible for iron sequestration. Herein, a trimethyl thiosemicarbazone moiety and the imidazole-2-thione heterocycle are incorporated in this prochelator design. Iron binding of the corresponding tridentate chelators leads to the stabilization of a low-spin ferric center in 2:1 ligand-to-metal compl...
Source: ChemMedChem - May 11, 2021 Category: Chemistry Authors: Yu-Shien Sung Wangbin Wu Megan A Ewbank Rachel D Utterback Michael T Marty Elisa Tomat Source Type: research

Albumin conjugates of thiosemicarbazone and imidazole-2-thione prochelators: Iron coordination and antiproliferative activity
ChemMedChem. 2021 May 11. doi: 10.1002/cmdc.202100278. Online ahead of print.ABSTRACTThe central role of iron in tumor progression and metastasis motivates the development of iron-binding approaches in cancer chemotherapy. Disulfide-based prochelators are reductively activated upon cellular uptake to liberate thiol chelators responsible for iron sequestration. Herein, a trimethyl thiosemicarbazone moiety and the imidazole-2-thione heterocycle are incorporated in this prochelator design. Iron binding of the corresponding tridentate chelators leads to the stabilization of a low-spin ferric center in 2:1 ligand-to-metal compl...
Source: ChemMedChem - May 11, 2021 Category: Chemistry Authors: Yu-Shien Sung Wangbin Wu Megan A Ewbank Rachel D Utterback Michael T Marty Elisa Tomat Source Type: research

Synthesis of Chimeric Thiazolo-Nootkatone Derivatives as Potent Antimicrobial Agents
ChemMedChem. 2021 May 6. doi: 10.1002/cmdc.202100230. Online ahead of print.ABSTRACTNootkatone, an approved insecticide, is a well-known natural product from grapefruit. A series of fused-thiazole derivatives of nootkatone have been synthesized and these new compounds were tested against several strains of bacteria. Some of these compounds (15 and 16) are found to be potent antimicrobial agents against Staphylococcus aureus and Enterococcus faecium with minimum inhibitory concentration (MIC) values as low as 1.56 µg/ml. The lead compound (16) is bactericidal and very potent against S. aureus persisters. These compoun...
Source: ChemMedChem - May 6, 2021 Category: Chemistry Authors: Ibrahim Alkhaibari Hansa Raj Kc Rawan Alnufaie David F Gilmore Mohammad Abrar Alam Source Type: research

Corrigendum: Synthesis of Novel Hybrids of Thymoquinone and Artemisinin with High Activity and Selectivity Against Colon Cancer
ChemMedChem. 2021 May 6;16(9):1513. doi: 10.1002/cmdc.202100088. Epub 2021 Apr 6.NO ABSTRACTPMID:33956398 | DOI:10.1002/cmdc.202100088 (Source: ChemMedChem)
Source: ChemMedChem - May 6, 2021 Category: Chemistry Authors: Tony Fr öhlich Benardina Ndreshkjana Julienne K Muenzner Christoph Reiter Elisabeth Hofmeister Sandra Mederer Maamoun Fatfat Chirine El-Baba Hala Gali-Muhtasib Regine Schneider-Stock Svetlana B Tsogoeva Source Type: research

Synthesis of Chimeric Thiazolo-Nootkatone Derivatives as Potent Antimicrobial Agents
ChemMedChem. 2021 May 6. doi: 10.1002/cmdc.202100230. Online ahead of print.ABSTRACTNootkatone, an approved insecticide, is a well-known natural product from grapefruit. A series of fused-thiazole derivatives of nootkatone have been synthesized and these new compounds were tested against several strains of bacteria. Some of these compounds (15 and 16) are found to be potent antimicrobial agents against Staphylococcus aureus and Enterococcus faecium with minimum inhibitory concentration (MIC) values as low as 1.56 µg/ml. The lead compound (16) is bactericidal and very potent against S. aureus persisters. These compoun...
Source: ChemMedChem - May 6, 2021 Category: Chemistry Authors: Ibrahim Alkhaibari Hansa Raj Kc Rawan Alnufaie David F Gilmore Mohammad Abrar Alam Source Type: research