Emerging impact of triazoles as anti-tubercular agent
Eur J Med Chem. 2022 May 13;238:114454. doi: 10.1016/j.ejmech.2022.114454. Online ahead of print.ABSTRACTTuberculosis, a disease of poverty is a communicable infection with a reasonably high mortality rate worldwide. 10 Million new cases of TB were reported with approx 1.4 million deaths in the year 2019. Due to the growing number of drug-sensitive and drug-resistant tuberculosis cases, there is a vital need to develop new and effective candidates useful to combat this deadly disease. Despite tremendous efforts to identify a mechanism-based novel antitubercular agent, only a few have entered into clinical trials in the las...
Source: European Journal of Medicinal Chemistry - May 21, 2022 Category: Chemistry Authors: Anindra Sharma Anand K Agrahari Sanchayita Rajkhowa Vinod K Tiwari Source Type: research

New peptidomimetic rhodesain inhibitors with improved selectivity towards human cathepsins
Eur J Med Chem. 2022 May 14;238:114460. doi: 10.1016/j.ejmech.2022.114460. Online ahead of print.ABSTRACTParasitic cysteine proteases such as rhodesain (TbCatL) from Trypanosoma brucei rhodesiense are relevant targets for developing new potential drugs against parasitic diseases (e. g. Human African Trypanosomiasis). Designing selective inhibitors for parasitic cathepsins can be challenging as they share high structural similarities with human cathepsins. In this paper, we describe the development of novel peptidomimetic rhodesain inhibitors by applying a structure-based de novo design approach and molecular docking protoc...
Source: European Journal of Medicinal Chemistry - May 21, 2022 Category: Chemistry Authors: Sascha Jung Natalie Fuchs Christoph Grathwol Ute A Hellmich Annika Wagner Erika Diehl Thomas Willmes Christoph Sotriffer Tanja Schirmeister Source Type: research

Identification and development of a series of disubstituted piperazines for the treatment of Chagas disease
Eur J Med Chem. 2022 May 6;238:114421. doi: 10.1016/j.ejmech.2022.114421. Online ahead of print.ABSTRACTApproximately 6-7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potency against the target parasite but is hampered by poor metabolic stability. We outline the strategies used to mitigate this issue such as lowering logD, bioisosteric replacement...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Kate McGonagle Gary J Tarver Juan Cantizani Ignacio Cotillo Peter G Dodd Liam Ferguson Ian H Gilbert Maria Marco Tim Miles Claire Naylor Maria Osuna-Cabello Christy Paterson Kevin D Read Erika G Pinto Jennifer Riley Paul Scullion Yoko Shishikura Frederick Source Type: research

Design, synthesis and antitumour activity of novel 5(6)-amino-benzimidazolequinones containing a fused morpholine
Eur J Med Chem. 2022 May 11;238:114420. doi: 10.1016/j.ejmech.2022.114420. Online ahead of print.ABSTRACTBased on the previous synthesis of tetracyclic and tricyclic benzimidazoles starting from 1,4:3,6-dianhydro-d-fructose and o-phenylenediamines, a series of 5(6)-amino substituted tetracyclic and tricyclic benzimidazolequinones were obtained through the oxidation of 4,7-dimethoxy-benzimidazole analogues with bis(trifluoroacetoxy)iodobenzene (PIFA) and subsequent substitution with various aliphatic and aromatic amines. Biological evaluations of the target benzimidazolequinones indicated that all the arylamino-substituted ...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Haixia Wang Yao Meng Jing Yang Hao Huang Yifan Zhao Chuantao Zhu Cong Wang Feng-Wu Liu Source Type: research

Design and synthesis of proteolysis targeting chimeras (PROTACs) as an EGFR degrader based on CO-1686
Eur J Med Chem. 2022 May 12;238:114455. doi: 10.1016/j.ejmech.2022.114455. Online ahead of print.ABSTRACTEpidermal growth factor receptor (EGFR) inhibitors represent the first-line treatment of non-small-cell lung cancer (NSCLC). However, the emergence of acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Herein, we reported the discovery of EGFRL858R/T790M degraders based on CO-1686. Promising PROTAC 1q could effectively and selectively inhibit the growth of PC-...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Qinlan Li Qian Guo Shuyi Wang Shanhe Wan Zhonghuang Li Jiajie Zhang Xiaoyun Wu Source Type: research

Identification and development of a series of disubstituted piperazines for the treatment of Chagas disease
Eur J Med Chem. 2022 May 6;238:114421. doi: 10.1016/j.ejmech.2022.114421. Online ahead of print.ABSTRACTApproximately 6-7 million people around the world are estimated to be infected with Trypanosoma cruzi, the causative agent of Chagas disease. The current treatments are inadequate and therefore new medical interventions are urgently needed. In this paper we describe the identification of a series of disubstituted piperazines which shows good potency against the target parasite but is hampered by poor metabolic stability. We outline the strategies used to mitigate this issue such as lowering logD, bioisosteric replacement...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Kate McGonagle Gary J Tarver Juan Cantizani Ignacio Cotillo Peter G Dodd Liam Ferguson Ian H Gilbert Maria Marco Tim Miles Claire Naylor Maria Osuna-Cabello Christy Paterson Kevin D Read Erika G Pinto Jennifer Riley Paul Scullion Yoko Shishikura Frederick Source Type: research

Design, synthesis and antitumour activity of novel 5(6)-amino-benzimidazolequinones containing a fused morpholine
Eur J Med Chem. 2022 May 11;238:114420. doi: 10.1016/j.ejmech.2022.114420. Online ahead of print.ABSTRACTBased on the previous synthesis of tetracyclic and tricyclic benzimidazoles starting from 1,4:3,6-dianhydro-d-fructose and o-phenylenediamines, a series of 5(6)-amino substituted tetracyclic and tricyclic benzimidazolequinones were obtained through the oxidation of 4,7-dimethoxy-benzimidazole analogues with bis(trifluoroacetoxy)iodobenzene (PIFA) and subsequent substitution with various aliphatic and aromatic amines. Biological evaluations of the target benzimidazolequinones indicated that all the arylamino-substituted ...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Haixia Wang Yao Meng Jing Yang Hao Huang Yifan Zhao Chuantao Zhu Cong Wang Feng-Wu Liu Source Type: research

Design and synthesis of proteolysis targeting chimeras (PROTACs) as an EGFR degrader based on CO-1686
Eur J Med Chem. 2022 May 12;238:114455. doi: 10.1016/j.ejmech.2022.114455. Online ahead of print.ABSTRACTEpidermal growth factor receptor (EGFR) inhibitors represent the first-line treatment of non-small-cell lung cancer (NSCLC). However, the emergence of acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Herein, we reported the discovery of EGFRL858R/T790M degraders based on CO-1686. Promising PROTAC 1q could effectively and selectively inhibit the growth of PC-...
Source: European Journal of Medicinal Chemistry - May 20, 2022 Category: Chemistry Authors: Qinlan Li Qian Guo Shuyi Wang Shanhe Wan Zhonghuang Li Jiajie Zhang Xiaoyun Wu Source Type: research

Structure-based discovery and development of novel O-GlcNAcase inhibitors for the treatment of Alzheimer's disease
Eur J Med Chem. 2022 May 13;238:114444. doi: 10.1016/j.ejmech.2022.114444. Online ahead of print.ABSTRACTThe neurofibrillary tangles (NFTs) formed from hyperphosphorylation of tau protein are closely associated with Alzheimer's disease (AD). O-GlcNAcylation of tau can negatively regulate hyperphosphorylation and the O-GlcNAcase (OGA) catalyzes the removal of O-linked β-N-acetylglucosamine (O-GlcNAc) from tau protein. Therefore, preventing tau hyperphosphorylation by increasing the levels of tau O-GlcNAcylation via OGA inhibitors could be a promising approach. Based on Thiamet-G, a potent OGA inhibitor, and its binding mod...
Source: European Journal of Medicinal Chemistry - May 19, 2022 Category: Chemistry Authors: Xiaoli Li Jinhe Han Sheshurao Bujaranipalli Jie He Eun Young Kim Hee Kim Jae Hong Im Won-Jea Cho Source Type: research

Structure-based discovery and development of novel O-GlcNAcase inhibitors for the treatment of Alzheimer's disease
Eur J Med Chem. 2022 May 13;238:114444. doi: 10.1016/j.ejmech.2022.114444. Online ahead of print.ABSTRACTThe neurofibrillary tangles (NFTs) formed from hyperphosphorylation of tau protein are closely associated with Alzheimer's disease (AD). O-GlcNAcylation of tau can negatively regulate hyperphosphorylation and the O-GlcNAcase (OGA) catalyzes the removal of O-linked β-N-acetylglucosamine (O-GlcNAc) from tau protein. Therefore, preventing tau hyperphosphorylation by increasing the levels of tau O-GlcNAcylation via OGA inhibitors could be a promising approach. Based on Thiamet-G, a potent OGA inhibitor, and its binding mod...
Source: European Journal of Medicinal Chemistry - May 19, 2022 Category: Chemistry Authors: Xiaoli Li Jinhe Han Sheshurao Bujaranipalli Jie He Eun Young Kim Hee Kim Jae Hong Im Won-Jea Cho Source Type: research

Discovery, enantioselective synthesis of myrtucommulone E analogues as tyrosyl-DNA phosphodiesterase 2 inhibitors and their biological activities
Eur J Med Chem. 2022 May 10;238:114445. doi: 10.1016/j.ejmech.2022.114445. Online ahead of print.ABSTRACTAs a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 2 (TDP2) can specifically repair topoisomerase 2 (TOP2)-mediated DNA damage, resulting in cancer cell resistance to TOP2 inhibitors. Its inhibitors can enhance the anticancer efficacy of TOP2 inhibitors. In this work, we report the discovery of natural product myrtucommulone E as selective TDP2 inhibitor and its first enantioselective total synthesis through a pivotal CPA-catalyzed Michael addition reaction. A series of myrtucommulone E analogues ...
Source: European Journal of Medicinal Chemistry - May 17, 2022 Category: Chemistry Authors: Yu Zhang Hao Yang Fang-Ting Wang Xing Peng Hai-Yang Liu Qing-Jiang Li Lin-Kun An Source Type: research

Study of the anticancer potential of Cd complexes of selenazoyl-hydrazones and their sulfur isosters
Eur J Med Chem. 2022 May 12;238:114449. doi: 10.1016/j.ejmech.2022.114449. Online ahead of print.ABSTRACTThe biological activity of Cd compounds has been investigated scarce since Cd has been recognized as a human carcinogen. However, the toxicity of cadmium is comparable to the toxicity of noble metals such as Pt and Pd. The paradigm of metal toxicity has been challenged suggesting that metal toxicity is not a constant property, yet it depends on many factors like the presence of appropriate ligands. Studies on anticancer activity of cadmium complexes showed that the complexation of various ligands resulted in complexes t...
Source: European Journal of Medicinal Chemistry - May 17, 2022 Category: Chemistry Authors: Sanja B Markovi ć Natalia Maciejewska Mateusz Olszewski Aleksandar Vi šnjevac Adri án Puerta Jos é M Padrón Irena Novakovi ć Sne žana Kojić Henrique S Fernandes S érgio F Sousa Sandra Ramotowska Agnieszka Chylewska Mariusz Makowski Tamara R Todor Source Type: research

Discovery, enantioselective synthesis of myrtucommulone E analogues as tyrosyl-DNA phosphodiesterase 2 inhibitors and their biological activities
Eur J Med Chem. 2022 May 10;238:114445. doi: 10.1016/j.ejmech.2022.114445. Online ahead of print.ABSTRACTAs a recently discovered DNA repair enzyme, tyrosyl-DNA phosphodiesterase 2 (TDP2) can specifically repair topoisomerase 2 (TOP2)-mediated DNA damage, resulting in cancer cell resistance to TOP2 inhibitors. Its inhibitors can enhance the anticancer efficacy of TOP2 inhibitors. In this work, we report the discovery of natural product myrtucommulone E as selective TDP2 inhibitor and its first enantioselective total synthesis through a pivotal CPA-catalyzed Michael addition reaction. A series of myrtucommulone E analogues ...
Source: European Journal of Medicinal Chemistry - May 17, 2022 Category: Chemistry Authors: Yu Zhang Hao Yang Fang-Ting Wang Xing Peng Hai-Yang Liu Qing-Jiang Li Lin-Kun An Source Type: research

Study of the anticancer potential of Cd complexes of selenazoyl-hydrazones and their sulfur isosters
Eur J Med Chem. 2022 May 12;238:114449. doi: 10.1016/j.ejmech.2022.114449. Online ahead of print.ABSTRACTThe biological activity of Cd compounds has been investigated scarce since Cd has been recognized as a human carcinogen. However, the toxicity of cadmium is comparable to the toxicity of noble metals such as Pt and Pd. The paradigm of metal toxicity has been challenged suggesting that metal toxicity is not a constant property, yet it depends on many factors like the presence of appropriate ligands. Studies on anticancer activity of cadmium complexes showed that the complexation of various ligands resulted in complexes t...
Source: European Journal of Medicinal Chemistry - May 17, 2022 Category: Chemistry Authors: Sanja B Markovi ć Natalia Maciejewska Mateusz Olszewski Aleksandar Vi šnjevac Adri án Puerta Jos é M Padrón Irena Novakovi ć Sne žana Kojić Henrique S Fernandes S érgio F Sousa Sandra Ramotowska Agnieszka Chylewska Mariusz Makowski Tamara R Todor Source Type: research

Novel 1,3,4-oxadiazole chalcogen analogues: Synthesis and cytotoxic activity
Eur J Med Chem. 2022 May 10;238:114440. doi: 10.1016/j.ejmech.2022.114440. Online ahead of print.ABSTRACTA small library of novel 1,3,4-oxadiazole bioisosteres was synthesized and their cytotoxic activity evaluated in vitro. Five of the new derivatives (3, 6, 11, 14 and 15) showed high potency against different human cancer cell lines, with 14 being the most interesting compound endowed with IC50 ranging from 0.005 to 0.091 μM. Preliminary SAR studies have suggested that the-chlorine atom in ortho position of the phenyl ring on the 1,3,4-selenadiazole is important for antitumor potency in vitro. Notably, these new compoun...
Source: European Journal of Medicinal Chemistry - May 16, 2022 Category: Chemistry Authors: Stefano Zoroddu Paola Corona Luca Sanna Federica Borghi Valentina Bordoni Battistina Asproni Gerard A Pinna Luigi Bagella Gabriele Murineddu Source Type: research