An auristatin-based peptide-drug conjugate targeting Kita-Kyushu lung cancer antigen 1 for precision chemoradiotherapy in gastric cancer
Eur J Med Chem. 2022 Jul 19;241:114617. doi: 10.1016/j.ejmech.2022.114617. Online ahead of print.ABSTRACTGastric cancer is a worldwide health problem. Chemotherapy and radiotherapy are of great importance in the management of advanced gastric cancer. However, their therapeutic efficacy is limited by off-target side effects. Peptide-drug conjugates (PDCs) are a novel strategy for tumor-targeted drug delivery to overcome the existing drug resistance mechanisms and improve antitumor effects. Kita-Kyushu lung cancer antigen 1 (KK-LC-1) is exclusively expressed in several types of cancer including gastric cancer, representing a...
Source: European Journal of Medicinal Chemistry - August 6, 2022 Category: Chemistry Authors: Xiaotong Chen Fangcen Liu Xiaoxiao Yu Lin Li Jiayao Yan Xinjie Chen Qin Liu Baorui Liu Source Type: research

Novel analgesic/anti-inflammatory agents: 1,5-Diarylpyrrole nitrooxyethyl sulfides and related compounds as Cyclooxygenase-2 inhibitors containing a nitric oxide donor moiety endowed with vasorelaxant properties
Eur J Med Chem. 2022 Jul 22;241:114615. doi: 10.1016/j.ejmech.2022.114615. Online ahead of print.ABSTRACTThe design of compounds able to combine the selective inhibition of cyclooxygenase-2 (COX-2) with the release of nitric oxide (NO) is a promising strategy to achieve potent anti-inflammatory agents endowed with an overall safer profile and reduced toxicity upon gastrointestinal and cardiovascular systems. With the aim of generating novel and selective COX-2 inhibiting NO-donors (CINOD) and encouraged by the promising results obtained with our nitrooxy- and hydroxyethyl ethers 11 and 12 reported in previous works, we shi...
Source: European Journal of Medicinal Chemistry - August 6, 2022 Category: Chemistry Authors: Mario Saletti Samuele Maramai Annalisa Reale Marco Paolino Simone Brogi Angela Di Capua Andrea Cappelli Gianluca Giorgi Danilo D'Avino Antonietta Rossi Carla Ghelardini Lorenzo Di Cesare Mannelli Roccaldo Sardella Andrea Carotti Gerald Woelkart Burkhard K Source Type: research

β-Nitrostyrene derivatives as broad range potential antifungal agents targeting fungal cell wall
Eur J Med Chem. 2022 Jul 16;240:114609. doi: 10.1016/j.ejmech.2022.114609. Online ahead of print.ABSTRACTThe prevalence of multidrug resistance has been increasingly witnessed during the past few decades. Resistance of human pathogenic fungi against the currently available antifungal agents has increased the frequency of fungal infections and associated mortality rates. The discovery of novel lead antifungal agents is important to challenge multidrug resistance. The present study examined the antifungal potential of chemically synthesized β-Nitrostyrene derivatives. Among the eight β-Nitrostyrene derivatives used in this...
Source: European Journal of Medicinal Chemistry - August 6, 2022 Category: Chemistry Authors: Asiya Ramzan Sajad Ahmad Padder Khalid Z Masoodi Syed Shafi Inayatullah Tahir Reiaz Ul Rehman Rajendra Prasad Abdul Haseeb Shah Source Type: research

Design and synthesis of novel indole and indazole-piperazine pyrimidine derivatives with anti-inflammatory and neuroprotective activities for ischemic stroke treatment
In conclusion, 5j has the potential for the treatment of stroke as an anti-inflammatory and neuroprotective agent.PMID:35931005 | DOI:10.1016/j.ejmech.2022.114597 (Source: European Journal of Medicinal Chemistry)
Source: European Journal of Medicinal Chemistry - August 5, 2022 Category: Chemistry Authors: Hongwei Wang Enjing Cui Jiaming Li Xiaodong Ma Xueyang Jiang Shuaishuai Du Shihu Qian Le Du Source Type: research

Multivalent glucosidase inhibitors based on perylene bisimide and iminosugar conjugates
Eur J Med Chem. 2022 Jul 22;241:114621. doi: 10.1016/j.ejmech.2022.114621. Online ahead of print.ABSTRACTAlthough multivalent glucosidase inhibitors based on iminosugars have shown enhanced inhibition activity, an effective way to improve their hypoglycemic effect in vivo, is still in infancy and needs further development. In this paper, PBI-5DNJ and PBI-6DNJ, with three or four DNJ moieties respectively conjugated at the bay position were synthesized. PBI-6DNJ evidenced stronger π-π stacking interactions and, when self-assembled, a smaller size than that of PBI-5DNJ. It was found that PBI-6DNJ exhibited superior α-gluc...
Source: European Journal of Medicinal Chemistry - August 5, 2022 Category: Chemistry Authors: Jian-Xing Yang Juan-Juan Li Fang-Qian Yin Guang-Yuan Wang Wen-Tong Wei Xiao-Liu Li Ke-Rang Wang Source Type: research

Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold
In this study, we discovered a series of potent Ebola entry inhibitors with the (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl)decahydroisoquinoline-3-carboxamide scaffold from high-throughput screening in reported pseudotyped virus system. Further optimization resulted a most potent compound 28 (IC50= 0.05 μM, SI = 98), which displayed 3-fold potency compared to the known inhibitor Toremifene (IC50= 0.17 μM, SI = 55). Moreover, compound 28 exhibited the remarkable selectivity between EBOV-GP and VSV-G (Spec. Index = 58), thus could exclude nonspecific effects. Structure-activity relationship and molecular docking analysis of t...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Sheng Han Heng Li Weixiong Chen Li Yang Xiankun Tong Jianping Zuo Youhong Hu Source Type: research

Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor
Eur J Med Chem. 2022 Jul 19;241:114601. doi: 10.1016/j.ejmech.2022.114601. Online ahead of print.ABSTRACTTropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a mor...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Zhijie Wang Jiwei Ren Kun Jia Yuming Zhao Li Liang Zitian Cheng Fei Huang Xiaofei Zhao Jie Cheng Shiyu Song Tiancheng Sheng Weiqi Wan Qingqing Shu Donglin Wu Junhao Zhang Tao Lu Yadong Chen Ting Ran Shuai Lu Source Type: research

Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy
Eur J Med Chem. 2022 Jul 20;241:114619. doi: 10.1016/j.ejmech.2022.114619. Online ahead of print.ABSTRACTGamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series. All the compounds were test...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Romain Musti ère Prisca Lagard ère S ébastien Hutter Viviana Dell'Orco Nadia Amanzougaghene Shahin Tajeri Jean-Fran çois Franetich Sophie Corvaisier Marc Since Aur élie Malzert-Fréon Nicolas Masurier Vincent Lisowski Pierre Verhaeghe Dominique Mazie Source Type: research

Design, synthesis and activity evaluation of isopropylsulfonyl-substituted 2,4- diarylaminopyrimidine derivatives as FAK inhibitors for the potential treatment of pancreatic cancer
Eur J Med Chem. 2022 Jul 19;241:114607. doi: 10.1016/j.ejmech.2022.114607. Online ahead of print.ABSTRACTA series of isopropylsulfonyl-substituted 2,4-diarylaminopyrimidine derivatives were designed and synthesized as FAK inhibitors to evaluate their biological activity against pancreatic cancer. One of the most promising compound, 9h, effectively interfered with FAK-mediated phosphorylation and suppressed the proliferation of human pancreatic cancer AsPC-1 cells with half maximal inhibitory concentration (IC50) values of 0.1165 nM and 0.1596 μM, respectively. In addition, 9h also exhibited relatively low toxicity against...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Xu Zheng Xing Li Liangliang Tian Bin Wu Jiawen Yu Changyuan Wang Xiuli Sun Xiaodong Ma Lixue Chen Yanxia Li Source Type: research

Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold
In this study, we discovered a series of potent Ebola entry inhibitors with the (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl)decahydroisoquinoline-3-carboxamide scaffold from high-throughput screening in reported pseudotyped virus system. Further optimization resulted a most potent compound 28 (IC50= 0.05 μM, SI = 98), which displayed 3-fold potency compared to the known inhibitor Toremifene (IC50= 0.17 μM, SI = 55). Moreover, compound 28 exhibited the remarkable selectivity between EBOV-GP and VSV-G (Spec. Index = 58), thus could exclude nonspecific effects. Structure-activity relationship and molecular docking analysis of t...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Sheng Han Heng Li Weixiong Chen Li Yang Xiankun Tong Jianping Zuo Youhong Hu Source Type: research

Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor
Eur J Med Chem. 2022 Jul 19;241:114601. doi: 10.1016/j.ejmech.2022.114601. Online ahead of print.ABSTRACTTropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a mor...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Zhijie Wang Jiwei Ren Kun Jia Yuming Zhao Li Liang Zitian Cheng Fei Huang Xiaofei Zhao Jie Cheng Shiyu Song Tiancheng Sheng Weiqi Wan Qingqing Shu Donglin Wu Junhao Zhang Tao Lu Yadong Chen Ting Ran Shuai Lu Source Type: research

Synthesis of antiplasmodial 2-aminothieno[3,2-d]pyrimidin-4(3H)-one analogues using the scaffold hopping strategy
Eur J Med Chem. 2022 Jul 20;241:114619. doi: 10.1016/j.ejmech.2022.114619. Online ahead of print.ABSTRACTGamhepathiopine (also known as M1), is a multi-stage acting antiplasmodial 2-tert-butylaminothieno[3,2-d]pyrimidin-4(3H)-one hydrochloride that was first described in 2015. The development of this compound is limited by poor microsomal stability, insufficient aqueous solubility and low intestinal permeability. In order to obtain new optimized derivatives, we conducted a scaffold hopping strategy from compound M1, resulting in the synthesis of 20 new compounds belonging to six chemical series. All the compounds were test...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Romain Musti ère Prisca Lagard ère S ébastien Hutter Viviana Dell'Orco Nadia Amanzougaghene Shahin Tajeri Jean-Fran çois Franetich Sophie Corvaisier Marc Since Aur élie Malzert-Fréon Nicolas Masurier Vincent Lisowski Pierre Verhaeghe Dominique Mazie Source Type: research

Design, synthesis and activity evaluation of isopropylsulfonyl-substituted 2,4- diarylaminopyrimidine derivatives as FAK inhibitors for the potential treatment of pancreatic cancer
Eur J Med Chem. 2022 Jul 19;241:114607. doi: 10.1016/j.ejmech.2022.114607. Online ahead of print.ABSTRACTA series of isopropylsulfonyl-substituted 2,4-diarylaminopyrimidine derivatives were designed and synthesized as FAK inhibitors to evaluate their biological activity against pancreatic cancer. One of the most promising compound, 9h, effectively interfered with FAK-mediated phosphorylation and suppressed the proliferation of human pancreatic cancer AsPC-1 cells with half maximal inhibitory concentration (IC50) values of 0.1165 nM and 0.1596 μM, respectively. In addition, 9h also exhibited relatively low toxicity against...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Xu Zheng Xing Li Liangliang Tian Bin Wu Jiawen Yu Changyuan Wang Xiuli Sun Xiaodong Ma Lixue Chen Yanxia Li Source Type: research

Discovery of potent ebola entry inhibitors with (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl) decahydroisoquinoline-3-carboxamide scaffold
In this study, we discovered a series of potent Ebola entry inhibitors with the (3S,4aS,8aS)-2-(3-amino-2-hydroxypropyl)decahydroisoquinoline-3-carboxamide scaffold from high-throughput screening in reported pseudotyped virus system. Further optimization resulted a most potent compound 28 (IC50= 0.05 μM, SI = 98), which displayed 3-fold potency compared to the known inhibitor Toremifene (IC50= 0.17 μM, SI = 55). Moreover, compound 28 exhibited the remarkable selectivity between EBOV-GP and VSV-G (Spec. Index = 58), thus could exclude nonspecific effects. Structure-activity relationship and molecular docking analysis of t...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Sheng Han Heng Li Weixiong Chen Li Yang Xiankun Tong Jianping Zuo Youhong Hu Source Type: research

Identification and structural analysis of a selective tropomyosin receptor kinase C (TRKC) inhibitor
Eur J Med Chem. 2022 Jul 19;241:114601. doi: 10.1016/j.ejmech.2022.114601. Online ahead of print.ABSTRACTTropomyosin receptor kinases (TRKs) are a family of TRKA, TRKB and TRKC isoforms. It has been widely reported that TRKs are implicated in a variety of tumors with several Pan-TRK inhibitors currently being used or evaluated in clinical treatment. However, off-target adverse events frequently occur in the clinical use of Pan-TRK inhibitors, which result in poor patient compliance, even drug discontinuation. Although a subtype-selectivity TRK inhibitor may avert the potential off-target adverse events and can act as a mor...
Source: European Journal of Medicinal Chemistry - July 25, 2022 Category: Chemistry Authors: Zhijie Wang Jiwei Ren Kun Jia Yuming Zhao Li Liang Zitian Cheng Fei Huang Xiaofei Zhao Jie Cheng Shiyu Song Tiancheng Sheng Weiqi Wan Qingqing Shu Donglin Wu Junhao Zhang Tao Lu Yadong Chen Ting Ran Shuai Lu Source Type: research