Male contraceptive development: A medicinal chemistry perspective
Eur J Med Chem. 2022 Aug 25;243:114709. doi: 10.1016/j.ejmech.2022.114709. Online ahead of print.ABSTRACTThere is a need for non-hormonal contraceptives. One area that needs further investigation is the development of male contraceptives. Comparatively little is understood about potential drug targets in men to achieve a reversible contraceptive effect. In this article, we review the need for male contraceptives and some thoughts around the characteristics of a male contraceptive and the potential development pathway. We then discuss different potential approaches to discovering male contraceptives and then highlight poten...
Source: European Journal of Medicinal Chemistry - September 10, 2022 Category: Chemistry Authors: Neil R Norcross Irene Georgiou Zoe C Johnston Franz S Gruber Jason R Swedlow Kevin D Read Christopher Lr Barratt Ian H Gilbert Source Type: research

Molecular networking assisted discovery and combinatorial biosynthesis of new antimicrobial pleuromutilins
Eur J Med Chem. 2022 Sep 1;243:114713. doi: 10.1016/j.ejmech.2022.114713. Online ahead of print.ABSTRACTPleuromutilins, the unique fungal metabolites possessing 5/6/8 tricyclic skeleton, are potent antibacterial leading compounds for the development of new antibiotics. We applied the MS/MS molecular networking technique and the combinatorial biosynthesis approach to discover new pleuromutilin analogues. Ten pleuromutilin derivatives including seven new compounds (1-7) were obtained from the solid culture of Omphalina mutila. The gene cluster for the biosynthesis of pleuromutilins in the mushroom of O. mutila was identified...
Source: European Journal of Medicinal Chemistry - September 10, 2022 Category: Chemistry Authors: Cui Guo Huanqin Dai Mengting Zhang Huan Liao Rui Zhang Baosong Chen Junjie Han Hongwei Liu Source Type: research

NIR phosphorescent cyclometalated platinum (II) complexes with CAIX targeted and nuclear penetration as potent anticancer theragnostic agents
Eur J Med Chem. 2022 Aug 31;243:114702. doi: 10.1016/j.ejmech.2022.114702. Online ahead of print.ABSTRACTAlthough cisplatin drugs have achieved great success in cancer therapy, they also easily cause drug resistance and other side effects. Non-classical platinum (II) complexes with targeted therapy characteristics have become one of the hotspots in the research of new anticancer drugs. In the present work, a series of carbonic anhydrase IX (CAIX)-targeted and inhibited cyclometalated platinum (II) complexes with near-infrared (NIR) phosphorescent emission have been developed, due to the calculation of Molecular docking and...
Source: European Journal of Medicinal Chemistry - September 9, 2022 Category: Chemistry Authors: Jing Yang Da-Lei Chen Peng-Chao Wang Bo Yang Chuan-Zhu Gao Source Type: research

Benzo[b]thiophene-2-carboxamides as novel opioid receptor agonists with potent analgesic effect and reduced constipation
In this study, we carried out structural modification of a hit compound previously identified in an artificial-intelligence (AI) virtual screening and discovered the potent analgesic, benzo[b]thiophene-2-carboxamide analog (compound 25) with new structural scaffold. We investigated the signaling pathways of opioid receptors mediated by compound 25, and found this racemic compound activated mu-opioid receptor through the cyclic adenosine monophosphate (cAMP) and β-arrestin-2-mediated pathways with strong potency and efficacy, and accompanying nociceptin-orphanin FQ opioid peptide and delta-opioid receptors through the cAMP...
Source: European Journal of Medicinal Chemistry - September 9, 2022 Category: Chemistry Authors: Ramajayam Kuppusamy Ying-Ting Hsu Yi-Yu Ke Po-Wei Chang Yung-Chiao Chang Hsiao-Fu Chang Pei-Chen Wang Yu-Hao Lin Yu-Chen Huang Teng-Kuang Yeh Jian-Ying Chuang Horace H Loh Chuan Shih Chiung-Tong Chen Shiu-Hwa Yeh Shau-Hua Ueng Source Type: research

Design, synthesis, and biological evaluation of aromatic tertiary amine derivatives as selective butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease
Eur J Med Chem. 2022 Sep 2;243:114729. doi: 10.1016/j.ejmech.2022.114729. Online ahead of print.ABSTRACTButyrylcholinesterase (BChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD), the development of selective BChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Previously, an aromatic tertiary amine derivative (S17-1001) was screened and validated as a selective BChE inhibitor. Structured-based molecular modification guided the synthesis of 43 analogs. Biological test of cholinesterase inhibition, in vitro blood brain barrier permeation assay, ...
Source: European Journal of Medicinal Chemistry - September 9, 2022 Category: Chemistry Authors: Xin Lu Nan Qin Yijun Liu Chenxi Du Feng Feng Wenyuan Liu Yao Chen Haopeng Sun Source Type: research

NIR phosphorescent cyclometalated platinum (II) complexes with CAIX targeted and nuclear penetration as potent anticancer theragnostic agents
Eur J Med Chem. 2022 Aug 31;243:114702. doi: 10.1016/j.ejmech.2022.114702. Online ahead of print.ABSTRACTAlthough cisplatin drugs have achieved great success in cancer therapy, they also easily cause drug resistance and other side effects. Non-classical platinum (II) complexes with targeted therapy characteristics have become one of the hotspots in the research of new anticancer drugs. In the present work, a series of carbonic anhydrase IX (CAIX)-targeted and inhibited cyclometalated platinum (II) complexes with near-infrared (NIR) phosphorescent emission have been developed, due to the calculation of Molecular docking and...
Source: European Journal of Medicinal Chemistry - September 9, 2022 Category: Chemistry Authors: Jing Yang Da-Lei Chen Peng-Chao Wang Bo Yang Chuan-Zhu Gao Source Type: research

Benzo[b]thiophene-2-carboxamides as novel opioid receptor agonists with potent analgesic effect and reduced constipation
In this study, we carried out structural modification of a hit compound previously identified in an artificial-intelligence (AI) virtual screening and discovered the potent analgesic, benzo[b]thiophene-2-carboxamide analog (compound 25) with new structural scaffold. We investigated the signaling pathways of opioid receptors mediated by compound 25, and found this racemic compound activated mu-opioid receptor through the cyclic adenosine monophosphate (cAMP) and β-arrestin-2-mediated pathways with strong potency and efficacy, and accompanying nociceptin-orphanin FQ opioid peptide and delta-opioid receptors through the cAMP...
Source: European Journal of Medicinal Chemistry - September 9, 2022 Category: Chemistry Authors: Ramajayam Kuppusamy Ying-Ting Hsu Yi-Yu Ke Po-Wei Chang Yung-Chiao Chang Hsiao-Fu Chang Pei-Chen Wang Yu-Hao Lin Yu-Chen Huang Teng-Kuang Yeh Jian-Ying Chuang Horace H Loh Chuan Shih Chiung-Tong Chen Shiu-Hwa Yeh Shau-Hua Ueng Source Type: research

Design, synthesis, and biological evaluation of aromatic tertiary amine derivatives as selective butyrylcholinesterase inhibitors for the treatment of Alzheimer's disease
Eur J Med Chem. 2022 Sep 2;243:114729. doi: 10.1016/j.ejmech.2022.114729. Online ahead of print.ABSTRACTButyrylcholinesterase (BChE) is recently regarded as a biomarker in progressed Alzheimer's disease (AD), the development of selective BChE inhibitors has attracted a great deal of interest and may be a viable therapeutic strategy for AD. Previously, an aromatic tertiary amine derivative (S17-1001) was screened and validated as a selective BChE inhibitor. Structured-based molecular modification guided the synthesis of 43 analogs. Biological test of cholinesterase inhibition, in vitro blood brain barrier permeation assay, ...
Source: European Journal of Medicinal Chemistry - September 9, 2022 Category: Chemistry Authors: Xin Lu Nan Qin Yijun Liu Chenxi Du Feng Feng Wenyuan Liu Yao Chen Haopeng Sun Source Type: research

Discovery of pimozide derivatives as novel T-type calcium channel inhibitors with little binding affinity to dopamine D < sub > 2 < /sub > receptors for treatment of somatic and visceral pain
Eur J Med Chem. 2022 Aug 27;243:114716. doi: 10.1016/j.ejmech.2022.114716. Online ahead of print.ABSTRACTT-type Ca2+ channels (T-channels), particularly Cav3.2 and Cav3.1 isoforms, are promising targets for treating various diseases including intractable pain. Given the potent inhibitory activity of pimozide, an antipsychotic, against T-channels, we conducted structure-activity relationship studies of pimozide derivatives, and identified several compounds including 3a, 3s, and 4 that had potency comparable to that of pimozide in inhibiting T-channels, but little binding affinity to dopamine D2 receptors. The introduction o...
Source: European Journal of Medicinal Chemistry - September 8, 2022 Category: Chemistry Authors: Yoshihito Kasanami Chihiro Ishikawa Takahiro Kino Momoka Chonan Naoki Toyooka Yasuhiro Takashima Yuriko Iba Fumiko Sekiguchi Maho Tsubota Tsuyako Ohkubo Shigeru Yoshida Atsushi Kawase Takuya Okada Atsufumi Kawabata Source Type: research

Identification of L. infantum trypanothione synthetase inhibitors with leishmanicidal activity from a (non-biased) in-house chemical library
Eur J Med Chem. 2022 Aug 18;243:114675. doi: 10.1016/j.ejmech.2022.114675. Online ahead of print.ABSTRACTRedox homeostasis in trypanosomatids is based on the low-molecular-weight trypanothione, an essential dithiol molecule that is synthetized by trypanothione synthetase (TryS) and maintained in its reduced state by trypanothione disulfide reductase (TryR). The fact that both enzymes are indispensable for parasite survival and absent in the mammalian hosts makes them ideal drug targets against leishmaniasis. Although many efforts have been directed to developing TryR inhibitors, much less attention has been focused on TryS...
Source: European Journal of Medicinal Chemistry - September 8, 2022 Category: Chemistry Authors: Mercedes Alc ón-Calderón H éctor de Lucio Juan Carlos Garc ía-Soriano Alejandro Revuelto Sonia de Castro Celia L ópez-Gutiérrez Ana San-F élix Ernesto Quesada Federico Gago Mar ía-José Camarasa Antonio Jim énez-Ruiz Sonsoles Vel ázquez Source Type: research

Discovery of new macrophage M2 polarization modulators as multiple sclerosis treatment agents that enable the inflammation microenvironment remodeling
Eur J Med Chem. 2022 Sep 2;243:114732. doi: 10.1016/j.ejmech.2022.114732. Online ahead of print.ABSTRACTThe M2 polarized macrophages modulation has been described as a beneficial approach to facilitate the myelin repairing and inflammation microenvironment remodeling of multiple sclerosis (MS). Whereas, the M2 polarization involves complex mechanisms, and the modulators are still limited. As a protein kinase B (Akt) inhibitor, compound 2 was found promoting M2 polarization activity in our previous research, here we report the identification of a new modulator B9 with high M2-marker Arg1 upregulation activity, M1 polarizati...
Source: European Journal of Medicinal Chemistry - September 8, 2022 Category: Chemistry Authors: Jinxin Che Dan Li Wenxiang Hong Longling Wang Yu Guo Mingfei Wu Jialiang Lu Lexian Tong Qinjie Weng Jiajia Wang Xiaowu Dong Source Type: research

Rational design of molecular rotor-based fluorescent probes with bi-aromatic rings for efficient in vivo detection of amyloid- β plaques in Alzheimer's disease
Eur J Med Chem. 2022 Aug 30;243:114715. doi: 10.1016/j.ejmech.2022.114715. Online ahead of print.ABSTRACTThe presence of Aβ plaques in the brain is a hallmark of Alzheimer's disease. Here, we designed and synthesized a series of molecular rotors with various bi-aromatic rings and investigated their applications as near-infrared (NIR) probes for Aβ plaques. We found that the interaction with Aβ aggregates hindered the rotational freedom of the molecular rotors, which brought about a noticeable enhancement in fluorescence intensity. Among them, probe 4b (Kd = 8.5 nM) with a phenyl-pyridine ring showed a 98-fold increase i...
Source: European Journal of Medicinal Chemistry - September 7, 2022 Category: Chemistry Authors: Nan Yue Hualong Fu Yimin Chen Xi Gao Jiapei Dai Mengchao Cui Source Type: research

Spiro[benzoxazine-piperidin]-one derivatives as chitin synthase inhibitors and antifungal agents: Design, synthesis and biological evaluation
Eur J Med Chem. 2022 Aug 31;243:114723. doi: 10.1016/j.ejmech.2022.114723. Online ahead of print.ABSTRACTFour series of spiro[benzoxazine-piperidin]-one derivatives were designed and synthesized. Their inhibition percentages against chitin synthase and antifungal activities were evaluated. Based on the preliminary biological assays, the series of derivatives containing α, β-unsaturated carbonyl fragment which had moderate to excellent CHS inhibitory activity and antifungal activity were further researched. In this series of compounds, eight out of twenty-one compounds had good to excellent inhibitory activity against chi...
Source: European Journal of Medicinal Chemistry - September 7, 2022 Category: Chemistry Authors: Yajie Xu Yangli Shen Chuanbiao Du Lige Liu Hu Wu Qingggang Ji Source Type: research

Discovery of small-molecules targeting the CCL20/CCR6 axis as first-in-class inhibitors for inflammatory bowel diseases
Eur J Med Chem. 2022 Aug 29;243:114703. doi: 10.1016/j.ejmech.2022.114703. Online ahead of print.ABSTRACTThe CCL20/CCR6 axis is implicated in the migration of CCR6+ immune cells towards CCL20, its sole ligand, whose expression is increased during inflammatory processes and is known to play a pivotal role in triggering different autoimmune-mediated inflammatory diseases. Herein, we report a drug discovery effort focused on the development of a new pharmacological approach for the treatment of inflammatory bowel diseases (IBDs) based on small-molecule CCR6 antagonists. The most promising compound 1b was identified by combini...
Source: European Journal of Medicinal Chemistry - September 6, 2022 Category: Chemistry Authors: Maria Grazia Martina Carmine Giorgio Marika Allodi Simone Palese Elisabetta Barocelli Vigilio Ballabeni Martyna Szpakowska Andy Chevign é Jan Piet van Hamburg Nadine Davelaar Erik Lubberts Simona Bertoni Marco Radi Source Type: research

Discovery of small-molecules targeting the CCL20/CCR6 axis as first-in-class inhibitors for inflammatory bowel diseases
Eur J Med Chem. 2022 Aug 29;243:114703. doi: 10.1016/j.ejmech.2022.114703. Online ahead of print.ABSTRACTThe CCL20/CCR6 axis is implicated in the migration of CCR6+ immune cells towards CCL20, its sole ligand, whose expression is increased during inflammatory processes and is known to play a pivotal role in triggering different autoimmune-mediated inflammatory diseases. Herein, we report a drug discovery effort focused on the development of a new pharmacological approach for the treatment of inflammatory bowel diseases (IBDs) based on small-molecule CCR6 antagonists. The most promising compound 1b was identified by combini...
Source: European Journal of Medicinal Chemistry - September 6, 2022 Category: Chemistry Authors: Maria Grazia Martina Carmine Giorgio Marika Allodi Simone Palese Elisabetta Barocelli Vigilio Ballabeni Martyna Szpakowska Andy Chevign é Jan Piet van Hamburg Nadine Davelaar Erik Lubberts Simona Bertoni Marco Radi Source Type: research