Exploration of 6-methyl-7-(Hetero)Aryl-7-Deazapurine ribonucleosides as antileishmanial agents
Eur J Med Chem. 2022 Apr 25;237:114367. doi: 10.1016/j.ejmech.2022.114367. Online ahead of print.ABSTRACTLeishmaniasis causes high mortality and morbidity in tropical and subtropical regions of Africa, Asia, the Americas and southern Europe, and is characterized by diverse clinical manifestations. As a neglected tropical disease, limited resources are allocated for antileishmanial drug discovery. The Leishmania parasite is deficient in de novo purine synthesis, and therefore acquires purines from the host and processes these using a purine salvage pathway. By making use of purine transport systems and interfering with this...
Source: European Journal of Medicinal Chemistry - May 9, 2022 Category: Chemistry Authors: Cai Lin Izet Karalic An Matheeussen Pim-Bart Feijens Fabian Hulpia Louis Maes Guy Caljon Serge Van Calenbergh Source Type: research

Novel hybrid pyrrolidinedione-thiazolidinones as potential anticancer agents: Synthesis and biological evaluation
Eur J Med Chem. 2022 May 2;238:114422. doi: 10.1016/j.ejmech.2022.114422. Online ahead of print.ABSTRACTA series of novel pyrrolidinedione-thiazolidinones was synthesized and subjected to physico-chemical characteristics. They were screened on a panel of cell lines representing different types of cancer, as well as normal human keratynocytes and lymphocytes of peripheral human blood. High antiproliferative activity of 1-(4-chlorophenyl)- and 1-(4-hydroxyphenyl)-3-{5-[(Z,2Z)-2-chloro-3-(4-nitrophenyl)-2-propenylidene]-4-oxo-2-thioxothiazolidin-3-yl}-1-(4-hydroxyphenyl)-pyrrolidine-2,5-diones 2a and 2b was revealed along wit...
Source: European Journal of Medicinal Chemistry - May 9, 2022 Category: Chemistry Authors: Nataliya Finiuk Anna Kryshchyshyn-Dylevych Serhii Holota Olga Klyuchivska Andriy Kozytskiy Olexandr Karpenko Nazar Manko Iryna Ivasechko Rostyslav Stoika Roman Lesyk Source Type: research

Exploration of 6-methyl-7-(Hetero)Aryl-7-Deazapurine ribonucleosides as antileishmanial agents
Eur J Med Chem. 2022 Apr 25;237:114367. doi: 10.1016/j.ejmech.2022.114367. Online ahead of print.ABSTRACTLeishmaniasis causes high mortality and morbidity in tropical and subtropical regions of Africa, Asia, the Americas and southern Europe, and is characterized by diverse clinical manifestations. As a neglected tropical disease, limited resources are allocated for antileishmanial drug discovery. The Leishmania parasite is deficient in de novo purine synthesis, and therefore acquires purines from the host and processes these using a purine salvage pathway. By making use of purine transport systems and interfering with this...
Source: European Journal of Medicinal Chemistry - May 9, 2022 Category: Chemistry Authors: Cai Lin Izet Karalic An Matheeussen Pim-Bart Feijens Fabian Hulpia Louis Maes Guy Caljon Serge Van Calenbergh Source Type: research

Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents
Eur J Med Chem. 2022 Apr 27;238:114377. doi: 10.1016/j.ejmech.2022.114377. Online ahead of print.ABSTRACTThe fluorinated bis-pyridinium oximes were designed and synthesized with the aim of increasing their nucleophilicity and potential to reactivate phosphorylated human recombinant acetylcholinesterase (AChE) and human purified plasmatic butyrylcholinesterase (BChE) in relation to chlorinated and non-halogenated oxime analogues. Compared to non-halogenated oximes, halogenated oximes showed lower pKa of the oxime group (fluorinated < chlorinated < non-halogenated) along with higher level of oximate anion formation at ...
Source: European Journal of Medicinal Chemistry - May 8, 2022 Category: Chemistry Authors: Tamara Zorbaz David Malinak Tereza Hofmanova Nikola Marakovi ć Suzana Žunec Nikolina Ma ček Hrvat Rudolf Andrys Miroslav Psotka Antonio Zandona Jana Svobodova Lukas Prchal Sanja Fingler Maja Katalini ć Zrinka Kovarik Kamil Musilek Source Type: research

Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents
Eur J Med Chem. 2022 Apr 27;238:114377. doi: 10.1016/j.ejmech.2022.114377. Online ahead of print.ABSTRACTThe fluorinated bis-pyridinium oximes were designed and synthesized with the aim of increasing their nucleophilicity and potential to reactivate phosphorylated human recombinant acetylcholinesterase (AChE) and human purified plasmatic butyrylcholinesterase (BChE) in relation to chlorinated and non-halogenated oxime analogues. Compared to non-halogenated oximes, halogenated oximes showed lower pKa of the oxime group (fluorinated < chlorinated < non-halogenated) along with higher level of oximate anion formation at ...
Source: European Journal of Medicinal Chemistry - May 8, 2022 Category: Chemistry Authors: Tamara Zorbaz David Malinak Tereza Hofmanova Nikola Marakovi ć Suzana Žunec Nikolina Ma ček Hrvat Rudolf Andrys Miroslav Psotka Antonio Zandona Jana Svobodova Lukas Prchal Sanja Fingler Maja Katalini ć Zrinka Kovarik Kamil Musilek Source Type: research

Novel bifluorescent Zn(II)-cryptolepine-cyclen complexes trigger apoptosis induced by nuclear and mitochondrial DNA damage in cisplatin-resistant lung tumor cells
Eur J Med Chem. 2022 Apr 30;238:114418. doi: 10.1016/j.ejmech.2022.114418. Online ahead of print.ABSTRACTFour novel bifluorescent Zn(II)-cryptolepine-cyclen complexes, namely [Zn(BQTC)]Cl2 (Zn(BQTC)), [Zn(BQA) (Cur)Cl] (Zn(BQACur)), [Zn (TC)]Cl2 (Zn(TC)), and [Zn (AP) (Cur)Cl] (Zn(APCur)), bearing curcumin (H-Cur), cyclen (TC), 1,10-phenanthrolin-5-amine (AP), and novel cryptolepine-cyclen derivatives (BQTC and BQA) were prepared for cell nucleus- and mitochondria-specific imaging. MTT assay results indicated that Zn(BQTC) and Zn(BQACur) exhibit stronger anticancer activity against cisplatin-resistant A549R lung tumor cell...
Source: European Journal of Medicinal Chemistry - May 7, 2022 Category: Chemistry Authors: Zhen-Feng Wang Xiao-Feng Zhou Qiao-Chang Wei Qi-Pin Qin Jin-Xian Li Ming-Xiong Tan Shu-Hua Zhang Source Type: research

Design, synthesis and antitumor evaluation of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3 η protein
Eur J Med Chem. 2022 Apr 29;238:114402. doi: 10.1016/j.ejmech.2022.114402. Online ahead of print.ABSTRACTIn this work, a series of novel 1H-indole-2-carboxylic acid derivatives targeting 14-3-3η protein were designed and synthesized for treatment of liver cancer. After structural optimization for several rounds, C11 displayed a relatively better affinity with 14-3-3η, as well as the best inhibitory activities against several typical human liver cancer cell lines, including Bel-7402, SMMC-7721, SNU-387, Hep G2 and Hep 3B cells. Compound C11 also displayed best inhibitory activity against chemotherapy-resistant Bel-7402/5-...
Source: European Journal of Medicinal Chemistry - May 7, 2022 Category: Chemistry Authors: Zhenxiong Gao Tingting Fan Linbo Chen Mengchu Yang Vincent Kam Wai Wong Dawei Chen Zijian Liu Yaoyao Zhou Weibin Wu Zixuan Qiu Cunlong Zhang Yuan Li Yuyang Jiang Source Type: research

Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models
Eur J Med Chem. 2022 Apr 27;237:114410. doi: 10.1016/j.ejmech.2022.114410. Online ahead of print.ABSTRACTLSD1 is a histone lysine demethylase proposed as therapeutic target in cancer. Chemical modifications applied at C2, C4 and/or C7 positions of the quinazoline core of the previously reported dual LSD1/G9a inhibitor 1 led to a series of non-covalent, highly active, and selective LSD1 inhibitors (2-4 and 6-30) and to the dual LSD1/G9a inhibitor 5 that was more potent than 1 against LSD1. In THP-1 and MV4-11 leukemic cells, the most potent compounds (7, 8, and 29) showed antiproliferative effects at sub-micromolar level wi...
Source: European Journal of Medicinal Chemistry - May 7, 2022 Category: Chemistry Authors: Martina Menna Francesco Fiorentino Biagina Marrocco Alessia Lucidi Stefano Tomassi Domenica Cilli Mauro Romanenghi Matteo Cassandri Silvia Pomella Michele Pezzella Donatella Del Bufalo Mohammad Salik Zeya Ansari Nevena Toma šević Milan Mladenovi ć Moni Source Type: research

Structure-activity relationship and antitumor activity of 1,4-pyrazine-containing inhibitors of histone acetyltransferases P300/CBP
Eur J Med Chem. 2022 Apr 27;237:114407. doi: 10.1016/j.ejmech.2022.114407. Online ahead of print.ABSTRACTAcetylation of histone lysine residues by histone acetyltransferase (HAT) p300 and its paralog CBP play important roles in gene regulation in health and diseases. The HAT domain of p300/CBP has been found to be a potential drug target for cancer. Compound screening followed by structure-activity relationship studies yielded a novel series of 1,4-pyrazine-containing inhibitors of p300/CBP HAT with their IC50s as low as 1.4 μM. Enzyme kinetics and other studies support the most potent compound 29 is a competitive inhibit...
Source: European Journal of Medicinal Chemistry - May 5, 2022 Category: Chemistry Authors: Shenyou Nie Fangrui Wu Jingyu Wu Xin Li Chao Zhou Yuan Yao Yongcheng Song Source Type: research

Optimization of 4-arylthiophene-3-carboxylic acid derivatives as inhibitors of ANO1: Lead optimization studies toward their analgesic efficacy for inflammatory pain
Eur J Med Chem. 2022 Apr 26;237:114413. doi: 10.1016/j.ejmech.2022.114413. Online ahead of print.ABSTRACTCurrent pain management is largely limited to opioids and non-steroidal anti-inflammatory drugs. Developing new analgesic drugs remains important to address the unmet medical needs of chronic pain patients. Calcium-activated chloride channel anoctamin-1 (ANO1) is a potential analgesic target. ANO1 is activated by noxious stimuli in peripheral sensory neurons and further induced neural depolarization. Downregulation of ANO1 reduced hyperalgesia and allodynia caused by inflammation and nerve injury. Here we developed a se...
Source: European Journal of Medicinal Chemistry - May 5, 2022 Category: Chemistry Authors: Yuxi Wang Xiaoyue Hu Han Huang Zefang Jin Jian Gao Yi Guo Yi Zhong Zhongtang Li Xiaolin Zong Kewei Wang Liangren Zhang Zhenming Liu Source Type: research

Organotropic dendrons with high potency as HIV-1, HIV-2 and EV-A71 cell entry inhibitors
Eur J Med Chem. 2022 Apr 27;237:114414. doi: 10.1016/j.ejmech.2022.114414. Online ahead of print.ABSTRACTWe have recently described a novel family of compounds of reduced size and dual anti-HIV and anti-EV71 activity that encompasses tripodal and tetrapodal derivatives. The tripodal prototype, AL-470, has a nitro group at the focal point of the central scaffold and three attached tryptophan residues, each of which bearing an isophthaloyl moiety at the C2 position of the indole ring. A nitro to amino substitution has allowed us now to introduce a chemically addressable functionality to perform further structural modificatio...
Source: European Journal of Medicinal Chemistry - May 5, 2022 Category: Chemistry Authors: Olaia Mart í-Marí Bel én Martínez-Gualda Irene Fern ández-Barahona Alberto Mills Rana Abdelnabi Sam Noppen Johan Neyts Dominique Schols Mar ía-José Camarasa Fernando Herranz Federico Gago Ana San-F élix Source Type: research

Structure-activity relationship and antitumor activity of 1,4-pyrazine-containing inhibitors of histone acetyltransferases P300/CBP
Eur J Med Chem. 2022 Apr 27;237:114407. doi: 10.1016/j.ejmech.2022.114407. Online ahead of print.ABSTRACTAcetylation of histone lysine residues by histone acetyltransferase (HAT) p300 and its paralog CBP play important roles in gene regulation in health and diseases. The HAT domain of p300/CBP has been found to be a potential drug target for cancer. Compound screening followed by structure-activity relationship studies yielded a novel series of 1,4-pyrazine-containing inhibitors of p300/CBP HAT with their IC50s as low as 1.4 μM. Enzyme kinetics and other studies support the most potent compound 29 is a competitive inhibit...
Source: European Journal of Medicinal Chemistry - May 5, 2022 Category: Chemistry Authors: Shenyou Nie Fangrui Wu Jingyu Wu Xin Li Chao Zhou Yuan Yao Yongcheng Song Source Type: research

Optimization of 4-arylthiophene-3-carboxylic acid derivatives as inhibitors of ANO1: Lead optimization studies toward their analgesic efficacy for inflammatory pain
Eur J Med Chem. 2022 Apr 26;237:114413. doi: 10.1016/j.ejmech.2022.114413. Online ahead of print.ABSTRACTCurrent pain management is largely limited to opioids and non-steroidal anti-inflammatory drugs. Developing new analgesic drugs remains important to address the unmet medical needs of chronic pain patients. Calcium-activated chloride channel anoctamin-1 (ANO1) is a potential analgesic target. ANO1 is activated by noxious stimuli in peripheral sensory neurons and further induced neural depolarization. Downregulation of ANO1 reduced hyperalgesia and allodynia caused by inflammation and nerve injury. Here we developed a se...
Source: European Journal of Medicinal Chemistry - May 5, 2022 Category: Chemistry Authors: Yuxi Wang Xiaoyue Hu Han Huang Zefang Jin Jian Gao Yi Guo Yi Zhong Zhongtang Li Xiaolin Zong Kewei Wang Liangren Zhang Zhenming Liu Source Type: research

Organotropic dendrons with high potency as HIV-1, HIV-2 and EV-A71 cell entry inhibitors
Eur J Med Chem. 2022 Apr 27;237:114414. doi: 10.1016/j.ejmech.2022.114414. Online ahead of print.ABSTRACTWe have recently described a novel family of compounds of reduced size and dual anti-HIV and anti-EV71 activity that encompasses tripodal and tetrapodal derivatives. The tripodal prototype, AL-470, has a nitro group at the focal point of the central scaffold and three attached tryptophan residues, each of which bearing an isophthaloyl moiety at the C2 position of the indole ring. A nitro to amino substitution has allowed us now to introduce a chemically addressable functionality to perform further structural modificatio...
Source: European Journal of Medicinal Chemistry - May 5, 2022 Category: Chemistry Authors: Olaia Mart í-Marí Bel én Martínez-Gualda Irene Fern ández-Barahona Alberto Mills Rana Abdelnabi Sam Noppen Johan Neyts Dominique Schols Mar ía-José Camarasa Fernando Herranz Federico Gago Ana San-F élix Source Type: research

Structure-activity relationship and antitumor activity of 1,4-pyrazine-containing inhibitors of histone acetyltransferases P300/CBP
Eur J Med Chem. 2022 Apr 27;237:114407. doi: 10.1016/j.ejmech.2022.114407. Online ahead of print.ABSTRACTAcetylation of histone lysine residues by histone acetyltransferase (HAT) p300 and its paralog CBP play important roles in gene regulation in health and diseases. The HAT domain of p300/CBP has been found to be a potential drug target for cancer. Compound screening followed by structure-activity relationship studies yielded a novel series of 1,4-pyrazine-containing inhibitors of p300/CBP HAT with their IC50s as low as 1.4 μM. Enzyme kinetics and other studies support the most potent compound 29 is a competitive inhibit...
Source: European Journal of Medicinal Chemistry - May 5, 2022 Category: Chemistry Authors: Shenyou Nie Fangrui Wu Jingyu Wu Xin Li Chao Zhou Yuan Yao Yongcheng Song Source Type: research