Article
Biochemistry & Molecular Biology
Zhuo-Qi Zhang, Jie Liu, Guang-Yu Zhang, Bo Li, Kang Li, Zhen Jin, Xu Bai, You-Zhi Tang
Summary: Pleuromutilin derivatives with amide side chains were designed and synthesized, and compound 25 showed the strongest antibacterial activity against MRSA and could repress the growth of MRSA in vitro. Molecular docking studies revealed that compound 25 was localized in the binding pocket of 50S ribosomal subunit. Furthermore, compound 25 displayed low cytotoxicity to cells.
CHEMICAL BIOLOGY & DRUG DESIGN
(2022)
Review
Chemistry, Medicinal
Vladimir Finger, Martin Kufa, Ondrej Soukup, Daniele Castagnolo, Jaroslav Roh, Jan Korabecny
Summary: This review provides an overview of recent advances in the hit-to-lead drug discovery studies of pyrimidine-containing compounds with antitubercular activity, focusing on their structural diversity. The review discusses the targets and structure-activity relationships of different pyrimidine families in the first part and categorizes unexplored or speculative targets of antitubercular pyrimidine derivatives based on their structural types in the second part.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Can Yong, Jianglin Yu, Chunxia Wu, Xiujuan Zhang, Yun Li, Chuan Xie, Xiaolong He, Dongfang Liu, Zhouyu Wang, Peng Lai, Yuanyuan Zhang
Summary: The overuse of antibiotics has led to the problem of bacterial drug resistance. This study aimed to develop novel antibiotics, and novel pleuromutilin derivatives were designed and synthesized. The antibacterial activities of these derivatives were evaluated in vitro and in vivo, and compound 6j showed rapid bactericidal effect, low cytotoxicity, and potent antibacterial activity. The results suggest that 6j has significant therapeutic effect on local infections and is comparable to retapamulin.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Medicinal
Rongcai Ding, Xiaoxia Wang, Jianfang Fu, Yaoyao Chang, Yingxue Li, Yajing Liu, Yue Liu, Jinlong Ma, Jinxing Hu
Summary: A series of novel pleuromutilin derivatives with substituted thienopyrimidines were designed, synthesized, and evaluated for their antibacterial activity. Most of the compounds exhibited moderate antibacterial activity against Staphylococcus aureus, Streptococcus agalactiae, and Escherichia coli. Compound A11 showed the most activity and displayed bacteriostatic activities against methicillin-resistant S. aureus.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Guangxu Wu, Zihao Zhu, Jishun Li, Xinyu Luo, Wenyong Zhu, Guoyang Liao, Jie Xia, Wenxuan Zhang, Weidong Pan, Tianlei Li, Song Wu
Summary: This study reports the design, synthesis, and structure-activity relationship studies of pleuromutilin derivatives containing urea/thiourea functionalities. In vitro evaluations showed that these new pleuromutilin derivatives exhibit good antibacterial activities against Gram-positive pathogens and Mycoplasma pneumoniae.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Yuhang Zhou, Yunpeng Yi, Jiangkun Wang, Zheng Yang, Qinqin Liu, Wanxia Pu, Ruofeng Shang
Summary: This study designed and synthesized a series of novel pleuromutilin derivatives with 3,4-dihydropyrimidine and pyrimidine moieties, and evaluated their antibacterial activities. Most of the synthesized derivatives, especially those with pyrimidine moieties, showed potent antibacterial activities against methicillin-resistant Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis. Compound 5h exhibited the highest antibacterial activity and was further evaluated in a mouse systemic infection model, showing significant improvement in mouse survival rate and reduction in bacterial load.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Yu Deng, Yang Zhang, Xiao-Hu Chen, Cheng-Hong Li
Summary: Growing antibiotic resistance has created an urgent need for new antibiotics. The synthesis of novel pleuromutilin derivatives with a 4(3H)-quinazolinone scaffold or its analogues was reported. Furthermore, structure-activity relationship studies revealed the importance of substituted positions on the scaffold for improving antibacterial activity. Compound 23 showed the best in vitro antibacterial activity against MRSA and low cytotoxicity to cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Apeng Wang, Shijie Xu, Yun Chai, Guimin Xia, Bin Wang, Kai Lv, Chao Ma, Dan Wang, Aoyu Wang, Xiaoyu Qin, Mingliang Liu, Yu Lu
Summary: A series of novel benzothiazinone derivatives containing a N-(amino)piperazine moiety, based on the structure of WAP-1902 discovered in the lab, were designed and synthesized as new anti-TB agents. Many compounds showed excellent in vitro activity against drug-sensitive MTB strain H37Rv and multidrug-resistant clinical isolates, with good safety index. Compound 1o, in particular, displayed low hERG cardiac toxicity and acceptable oral pharmacokinetic profiles, indicating its potential as a lead compound for future antitubercular drug discovery.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Dongguang Fan, Bin Wang, Giovanni Stelitano, Karin Savkova, Olga Riabova, Rui Shi, Xiaomei Wu, Laurent R. Chiarelli, Katarina Mikusova, Vadim Makarov, Yu Lu, Yuzhi Hong, Chunhua Qiao
Summary: Compound 37, an analogue of benzothiazinone (BTZ), inhibits the essential enzyme DprE1 and shows improved solubility and bioavailability compared to the lead compound. It exhibits bactericidal activity against Mycobacterium tuberculosis (Mtb) in an acute infection mouse model.
Article
Chemistry, Medicinal
Apeng Wang, Na Du, Huijuan Song, Yuehao Zhang, Xijun Zhong, Jizhou Wu, Tiezheng Xue, Mingliang Liu, Bin Wang, Kai Lv, Yu Lu
Summary: This study focused on the synthesis of novel N-(amino)piperazinyl benzothiazinone derivatives as potential anti-TB agents with reduced in vivo toxicity. Compound 2c showed potent anti-MTB activity, low cardiac toxicity, low cell cytotoxicity, acceptable PK profiles, and low acute toxicity in mice, making it a promising lead compound for further drug discovery against tuberculosis.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Rakesh K. Saunthwal, Maria Schwarz, Rajendra K. Mallick, William Terry-Wright, Jonathan Clayden
Summary: A practical method for enantioselective synthesis of alpha,alpha-diarylmethylamines without using transition metals is achieved through asymmetric alpha-arylation of benzylamines. Enantioselective lithiation of N '-aryl-N-benzyl-N-isopropyl ureas using a chiral lithium amide base generates benzyllithium, which undergoes a stereospecific intramolecular nucleophilic aromatic substitution to form the urea derivative of alpha,alpha-diarylmethylamine with ee up to >99%. Acid treatment induces an azatropic shift with retention of configuration, allowing hydrolysis to yield the target amine.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Pharmacology & Pharmacy
Mikhail V. Khvostov, Elizaveta D. Gladkova, Sergey A. Borisov, Marina S. Fedotova, Nataliya A. Zhukova, Mariya K. Marenina, Yulia V. Meshkova, Nicolae Valutsa, Olga A. Luzina, Tatiana G. Tolstikova, Nariman F. Salakhutdinov
Summary: Several novel 9-N-n-alkyl derivatives of berberine (C5, C7, C10, C12) were synthesized and tested for their hypoglycemic activity in vitro and in vivo. The derivatives with shorter alkyl substitutes showed better stimulation of glucose consumption in HepG2 cells compared to those with longer substitutes. The C5 derivative demonstrated a pronounced hypoglycemic effect, while the C12 derivative was less effective in vivo. However, the C12 derivative also showed adverse effects on hepatosis exacerbation and hepatic aminotransferase levels.
Article
Biochemistry & Molecular Biology
Mashooq A. Bhat, Ahmed M. Naglah, Siddique Akber Ansari, Hanaa M. Al-Tuwajiria, Abdullah Al-Dhfyan
Summary: This study developed an environmentally friendly method using A ChCl: Gly (DESs) to synthesize xanthene analogues from aryl aldehydes and dimedone, showcasing excellent antimycobacterial activity. The compounds showed significant antitubercular activity with low toxicity against various cell lines, confirming their potential as new drug candidates for tuberculosis treatment.
Article
Biochemistry & Molecular Biology
Zhenhua Wu, Xiaoli Zhu, Anjin Hong, Guanghui He, Zheng Wang, Qingyan Xu, Zhiyu Hu, Xiaobing Wu, Yuezhou Wang, Qiufang Chen, Xilin Zhao, Li Li, Xianming Deng
Summary: Inspired by the structural insights from the analysis of lefamulin's cocrystal structure with S. aureus ribosomes, a series of novel pleuromutilin derivatives were designed and synthesized. The study revealed that derivatives with urea in the meta position of phenylene sulfide showed optimal antibacterial activities. Among them, 21h exhibited the most potent activity against MRSA and clinical AMR Gram-positive bacteria, with low resistance frequency and prolonged Post-Antibiotic Effect. It also showed promising antibacterial activity in vivo, making it a potential lead for new antibiotics against Gram-positive pathogens, especially for AMR bacteria.
BIOORGANIC CHEMISTRY
(2023)
Article
Plant Sciences
Hui-Xian Liu, Ge Cui, Dong-Lai Ma, Yue Zhang, Fei-Qun Xue
Summary: A series of novel pleuromutilin derivatives were designed and synthesized based on the twin drugs theory, showing excellent antibacterial activities against drug-sensitive bacteria, with five compounds exhibiting particularly promising results against drug-resistance bacteria. These compounds utilized piperazinyl and thioether linkages to improve biological activity and water solubility.
JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH
(2022)
Article
Chemistry, Medicinal
Shibin Zhao, Julian Maceren, Mia Chung, Samantha Stone, Raphael Geiben, Melissa L. Boby, Bradley S. Sherborne, Derek S. Tan
Summary: Antibiotic resistance is a major threat to public health, with Gram-negative bacteria presenting unique challenges due to their low permeability and efflux pumps. Limited understanding of the chemical rules for overcoming these barriers hinders antibacterial drug discovery. Efforts to address this issue, such as screening compound libraries and using cheminformatic analysis, have led to the design of sulfamidoadenosines with diverse substituents, showing potential utility in accumulation in Escherichia coli.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Jichun Li, Qing Li, Shuai Xia, Jiahuang Tu, Longbo Zheng, Qian Wang, Shibo Jiang, Chao Wang
Summary: This study successfully developed a short peptide mimetic as a MERS-CoV fusion inhibitor by reproducing the key recognition features of the HR2 helix. The resulting 23-mer lipopeptide showed comparable inhibitory effect to the 36-mer HR2 peptide HR2P-M2. This has important implications for developing short peptide-based antiviral agents to treat MERS-CoV infection.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Krista Jaunsleine, Linda Supe, Jana Spura, Sten van Beek, Anna Sandstrom, Jessica Olsen, Carina Halleskog, Tore Bengtsson, Ilga Mutule, Benjamin Pelcman
Summary: Beta(2)-adrenergic receptor agonists can stimulate glucose uptake by skeletal muscle cells and are therefore potential treatments for type 2 diabetes. The chirality of compounds has a significant impact on the activity of these agonists. This study found that certain synthesized compounds showed higher glucose uptake activity. These findings provide important information for the design of novel beta(2)AR agonists for T2D treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Xin Xu, Jia Chen, Guan Wang, Xiaojuan Zhang, Qiang Li, Xiaobo Zhou, Fengying Guo, Min Li
Summary: The study focuses on EZH2, a promising therapeutic target for various types of cancers. Researchers designed and synthesized a series of novel derivatives aiming to enhance the EZH2 inhibition activity. Among them, compound 28 displayed potent EZH2 inhibition activity and showed high anti-proliferative effects in lymphoma cell lines and xenograft mouse models. The study suggests that compound 28 has potential as a therapeutic candidate for EZH2-associated cancers.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Wei Zhang, Wei Liu, Ya-Dong Zhao, Li-Zi Xing, Ji Xu, Rui-Jun Li, Yun-Xiao Zhang
Summary: This study developed a series of aromatic amide derivatives based on Rhein and investigated their inhibitory activity against alpha-Syn aggregation. Two of these compounds showed promising potential in treating Parkinson's disease by stabilizing alpha-Syn's conformation and disassembling alpha-Syn oligomers and fibrils.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)
Article
Chemistry, Medicinal
Mani Sharma, S. S. S. S. Sudha Ambadipudi, Neeraj Kumar Chouhan, V. Lakshma Nayak, Srihari Pabbaraja, Sai Balaji Andugulapati, Ramakrishna Sistla
Summary: Therapeutically active lipids in drug delivery systems can enhance the safety and efficacy of treatment. The liposome formulation created using synthesized biologically active lipids showed additive anti-cancer effects and reduced tumorigenic potential.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2024)