Article
Chemistry, Medicinal
Kevin J. Sparrow, Rinu Shrestha, James M. Wood, Keith Clinch, Brett L. Hurst, Hong Wang, Brian B. Gowen, Justin G. Julander, E. Bart Tarbet, Alice M. McSweeney, Vernon K. Ward, Gary B. Evans, Lawrence. D. Harris
Summary: We report the antiviral activities of two iminovirs (antiviral imino-C-nucleosides) 1 and 2, structurally related to galidesivir (Immucillin A, BCX4430), for the first time. An iminovir containing the 4-aminopyrrolo[2,1-f ][1,2,4-triazine] nucleobase found in remdesivir showed submicromolar inhibition against multiple strains of influenza A and B viruses, as well as members of the Bunyavirales order. The ProTide prodrugs of iminovir monophosphates displayed poorer viral inhibition than their parent nucleosides in vitro. A synthesized iminovir 2 containing 4-aminopyrrolo[2,1-f][1,2,4-triazine] was used for preliminary in vivo studies, but it showed significant toxicity in BALB/ c mice and limited protection against influenza, indicating the need for further modification to improve its therapeutic value.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Multidisciplinary
Xiao Jia, Dominique Schols, Chris Meier
Summary: This article describes the synthesis of two types of nucleotide prodrugs containing different nucleoside analogs and their effective inhibition against HIV-2 replication. The prodrugs exhibited high stability and antiviral activity in cell extracts.
Review
Chemistry, Medicinal
Yanping Li, Bo Yang, Yanni Quan, Zhuorong Li
Summary: In the past decades, synthetic nucleoside or nucleotide analogues have been crucial for the development of antiviral agents, but their biological activity is often hindered by low membrane permeability and insufficient cellular phosphorylation. To overcome these limitations, diverse lipophilic prodrug modifications, particularly the ProTide technology, have been successful in delivering nucleosides into the target site and bypassing the rate-limited phosphorylation step, leading to the discovery of FDA-approved antiviral agents.
CURRENT TOPICS IN MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Richard L. Mackman
Summary: Remdesivir is a prodrug that delivers nucleoside monophosphate inhibitors to lung cells, providing antiviral activity against RNA viruses such as coronaviruses. Its potential in respiratory virus treatment warrants further investigation.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Review
Pharmacology & Pharmacy
Michaela Serpi, Fabrizio Pertusati
Summary: The ProTide technology, a phosphate prodrug method, has been successful in delivering new antiviral drugs and shows promise in oncology. Its application to non-nucleoside-based small molecules is emerging and proving effective in various therapeutic areas. Investigations to explain the lack of activity of certain ProTide series and comprehensive structure activity relationship studies are deemed necessary for the future development of these compounds.
EXPERT OPINION ON DRUG DISCOVERY
(2021)
Article
Microbiology
Julia C. LeCher, Keivan Zandi, Vivian Vasconcelos Costa, Franck Amblard, Sijia Tao, Dharmeshkumar Patel, Sujin Lee, Felipe Rocha da Silva Santos, Matheus Rodrigues Goncalves, Celso Martins Queroz-Junior, Fernanda Martins Marim, Katie Musall, Shu Ling Goh, Tamara McBrayer, Jessica Downs-Bowen, Ramyani De, Niloufar Azadi, James Kohler, Mauro Martins Teixeira, Raymond F. Schinazi
Summary: This study reports potential antiviral drugs against yellow fever virus, showing low toxicity, high intracellular metabolism, and strong anti-YFV activity in different models. The findings provide a new therapeutic option for treating yellow fever virus infections.
Editorial Material
Chemistry, Medicinal
Victoria C. Yan
Summary: Remdesivir is an FDA-approved drug for COVID-19 treatment that has shown broad-spectrum antiviral activity in preclinical models. However, its clinical efficacy varies. This study highlights the discordance between humans and non-human primates in the pharmacodynamic effect of remdesivir.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Microbiology
Alexandra Probst, Eugenia Pujol, Cecile Haberli, Jennifer Keiser, Santiago Vazquez
Summary: N,N'-diarylureas have emerged as a promising chemotype for the treatment of schistosomiasis, with low IC50 values observed for both schistosomula and adult worms. However, despite promising in vitro activity, selected compounds did not show significant in vivo efficacy in S. mansoni-infected mice. Further investigations are needed to better understand the underlying mechanisms of SF5-containing N,N'-diarylureas.
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
(2021)
Article
Chemistry, Organic
Jie Yao, Chengjie Huang, Fan Wu, Yufen Zhao, Feng Ni
Summary: Drug development based on phenolic natural products has gained attention, but poor bioavailability limits their clinical use. This paper presents a prodrug approach to improve bioavailability and synthesis of various phosphoramidate prodrugs from phenolic drugs. The method also allows selective phosphorylation of the phenolic hydroxyl group in the presence of nucleophilic functional groups.
SYNTHESIS-STUTTGART
(2022)
Article
Chemistry, Medicinal
Chenglong Zhao, Xiao Jia, Dominique Schols, Jan Balzarini, Chris Meier
Summary: This study presents the design of new nucleoside analogue derivatives with the aim of developing more effective anti-HIV drugs. These compounds were shown to be active against HIV in cell culture experiments, and the hydrolysis of the prodrug masks was investigated.
Article
Chemistry, Multidisciplinary
Christian Prinz, Ludger Starke, Tizian-Frank Ramspoth, Janis Kerkering, Vera Martos Riano, Jerome Paul, Martin Neuenschwander, Andreas Oder, Silke Radetzki, Siegfried Adelhoefer, Paula Ramos Delgado, Mariya Aravina, Jason M. Millward, Ariane Fillmer, Friedemann Paul, Volker Siffrin, Jens-Peter Von Kries, Thoralf Niendorf, Marc Nazare, Sonia Waiczies
Summary: Fluorine (F-19) magnetic resonance imaging (MRI) faces challenges due to low signal-to-noise ratio (SNR), but has potential for label-free theranostic imaging. SF5-substituted TF shows superior F-19 MR SNR efficiency, indicating its suitability as a viable bioisostere for MS drug teriflunomide. Despite chemical modifications, SF5-substituted TF maintains pharmacological and biological activities while improving anti-inflammatory activity.
Article
Chemistry, Medicinal
Pierre-Yves Geant, Malika Kaci, Jean-Pierre Uttaro, Christian Perigaud, Christophe Mathe
Summary: In this study, the racemic synthesis of 3'-fluoro-5'-norcarbocyclic nucleoside phosphonates was reported, and the antiviral activities of the enantiomers were evaluated. The results show that the bis(POM) prodrug (-)-9 exhibits similar or even superior activities compared to (R)-PMPA.
Article
Biochemistry & Molecular Biology
Jirayu Kammarabutr, Panupong Mahalapbutr, Hisashi Okumura, Peter Wolschann, Thanyada Rungrotmongkol
Summary: This study indicates that certain anti-HIV drugs may have higher susceptibility against HBV-RT enzyme, potentially serving as a promising drug option for HBV-infected patients with 3TC resistance.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2021)
Article
Chemistry, Multidisciplinary
Hanglu Ying, Jie Yao, Fan Wu, Yufen Zhao, Feng Ni
Summary: This article describes a synthesis method for aryloxy phosphoramidate prodrug of alcohols using a transesterification strategy. The reaction operates under mild conditions and exhibits excellent functional group tolerance, providing an efficient and practical solution for the rapid construction of the aryloxy phosphoramidate prodrug library for potential SAR studies.
Article
Chemistry, Medicinal
Nicole Pribut, Michael D'Erasmo, Madhuri Dasari, Kyle E. Giesler, Sabrina Iskandar, Savita K. Sharma, Perry W. Bartsch, Akshay Raghuram, Anatoliy Bushnev, Soyon S. Hwang, Samantha L. Burton, Cynthia A. Derdeyn, Adriaan E. Basson, Dennis C. Liotta, Eric J. Miller
Summary: Tenofovir (TFV) is a key drug in HIV/AIDS treatment, with its prodrug TXL originally designed to address metabolic issues but facing substantial hepatic extraction in clinical studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Qingqing Hao, Xu Ling, Christophe Pannecouque, Erik De Clercq, Fener Chen
Summary: A novel series of CHOR-HEPT non-nucleoside HIV-1 reverse transcriptase inhibitors were developed based on structure-based design strategy, using compound 6 as the starting point. These compounds showed moderate to good activity against wild-type HIV-1 strain, with EC50 values ranging from 0.18 to 51.88 mu mol/L and SI values ranging from 4 to 907. Compound 14aj with a CHOH linker and compound 13i with a CHOTMS linker exhibited improved anti-HIV-1 activity (EC50 = 0.18 mu mol/L and 0.20 mu mol/L) and higher selectivity (SI = 907 and 665) compared to the lead compound 6 (EC50 = 0.59 mu mol/L, SI = 9).
CHINESE CHEMICAL LETTERS
(2023)
Article
Chemistry, Medicinal
Da Feng, Xiaofang Zuo, Fabao Zhao, Hao Lin, Jiaojiao Dai, Yangyin Sun, Erik De Clercq, Christophe Pannecouque, Dongwei Kang, Xinyong Liu, Peng Zhan
Summary: We reported a novel series of dual-site binding DAPY derivatives that target both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP). Compound 9e demonstrated strong anti-HIV-1 activity against resistant strains, comparable to etravirine. It also showed low cytotoxicity and high selectivity index towards wild-type HIV-1 strain.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Xu Ling, Qing-Qing Hao, Wen-Juan Huang, Christophe Pannecouque, Erik De Clercq, Shuai Wang, Fen-Er Chen
Summary: A series of S-N3-DABO derivatives F1-F31 were developed as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) by substituting the cyano group of S-CN-DABOs with azide group. These compounds showed significantly increased potency against wild-type HIV-1 and mutant strains. The best compound F10 exhibited a significant improvement in potency and selectivity compared to the parent compound B1, with enhanced activity against mutant strains and no significant inhibition of hERG, CYP, and acute toxicity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Wei Ming, Wen-Long Lu, Christophe Pannecouque, Jiong Chen, Hai-Feng Wang, Ya-Qi Xiao, Sha Hu, Shuang-Xi Gu, Yuan-Yuan Zhu, Fen-Er Chen
Summary: The hybrids of delavirdine and piperdin-4-yl-aminopyrimidine (DPAPYs) were synthesized and evaluated for their anti-HIV activities and inhibitory activities against HIV-1 reverse transcriptase. The results showed that all the compounds demonstrated moderate to excellent potency against wild-type HIV-1 and specific RT inhibitory activity. Compound 4d exhibited the most potent activity against wild-type HIV-1 and showed good to excellent potency against various HIV-1 mutants.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Da Feng, Hao Lin, Liyang Jiang, Jiaojiao Dai, Xiaoying Zhang, Zhongxia Zhou, Yanying Sun, Zhao Wang, Erik De Clercq, Christophe Pannecouque, Dongwei Kang, Peng Zhan, Xinyong Liu
Summary: A series of disubstituted pyrimidine-5-carboxamide derivatives were designed by introducing an amide moiety to the central core of the lead etravirine using crystallographic overlay-based molecular hybridization strategy. These compounds exhibited promising antiviral activities against wild-type and NNRTIs-resistant strains of HIV-1, with compound 21c showing the most potent activity. The compound was proven to target reverse transcriptase and could serve as a lead for developing novel HIV-1 NNRTIs.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Ruo-Lan Zhou, Zhiran Ju, Christophe Pannecouque, Erik De Clercq, Shuai Wang, Fen-Er Chen
Summary: In this study, novel cyclopropyl-substituted HEPT analogs were developed to improve their potency and safety as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Compound 9h exhibited significantly increased inhibitory activity against wild-type HIV-1 (EC50=0.017μM) compared to the lead compound 2. It also showed reduced cytotoxicity with a higher selectivity index (SI>2328) and promising pharmacokinetics profiles.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Jianyang Han, Jakob Arnold, Christophe Pannecouque, Graciela Andrei, Robert Snoeck, Clemens Richert
Summary: Strongly pairing ethynylpyridone C-nucleosides are being explored as substitutes for thymidine in oligonucleotides. However, the strong lipophilicity of ethynylpyridone has been found to limit its antiviral activity. Two strategies are being pursued to overcome this issue, including replacing the ethynyl group with a cyano group and using less lipophilic amino acid esters in a phosphoramidate prodrug design. These findings contribute to the development of next-generation pyridone C-nucleosides as potential antivirals.
HELVETICA CHIMICA ACTA
(2023)
Article
Biochemistry & Molecular Biology
Zhenzhen Zhou, Bairu Meng, Jiaqi An, Fabao Zhao, Yanying Sun, Dan Zeng, Wenna Wang, Shenghua Gao, Yu Xia, Caiyun Dun, Erik De Clercq, Christophe Pannecouque, Peng Zhan, Dongwei Kang, Xinyong Liu
Summary: This study introduces a new HIV-1 covalent inhibitor targeting the highly conserved Tyr318 in the binding pocket of non-nucleoside reverse transcriptase inhibitors to enhance drug resistance. The inhibitor ZA-2, with a fluorosulfate warhead, was found to be a powerful inhibitor (EC50 = 11-246 nM) against HIV-1 IIIB and resistant strains, outperforming NVP and EFV. ZA-2 also showed lower cytotoxicity (CC50 = 125 mu M) and exhibited covalent binding with the enzyme.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Yanying Sun, Da Feng, Zhenzhen Zhou, Tao Zhang, Erik De Clercq, Christophe Pannecouque, Dongwei Kang, Peng Zhan, Xinyong Liu
Summary: In this study, a miniaturized parallel synthesis and in situ biological screening were conducted to develop potent HIV-1 non-nucleoside reverse transcriptase inhibitors. The results showed that 14 compounds exhibited higher or equivalent inhibitory activity compared to the lead compound. Among them, C1N51 showed the most potent anti-HIV-1 activity against wild-type and resistant strains.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Ruo-Lan Zhou, Christophe Pannecouque, Erik De Clercq, Shuai Wang, Fen-Er Chen
Summary: Our recent research on developing HEPT analogs for HIV therapy has identified a potent NNRTI 3 with limited anti-resistance potency. In order to address this limitation, we explored the chemical space of the solvent-protein interface and generated a series of novel HEPT analogs. Some of these analogs showed significant improvements in anti-resistance efficacy, with compound 7g being the most promising, surpassing the activity and selectivity of compound 3 by approximately 2-fold. This study provides new guidance for the development of NNRTIs.
BIOORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Xujie Zhang, Lin Sun, Shujing Xu, Tianguang Huang, Fabao Zhao, Dang Ding, Chuanfeng Liu, Xiangyi Jiang, Yucen Tao, Dongwei Kang, Erik De Clercq, Christophe Pannecouque, Simon Cocklin, Alexej Dick, Xinyong Liu, Peng Zhan
Summary: We report the design, synthesis, and mechanistic study of a novel series of 2-piperazineone peptidomimetics as HIV capsid modulators by mimicking the structure of host factors binding to CA. F-Id-3o was the most potent compound with an anti-HIV-1 EC50 value of 6.0 mu M. The compounds in this series showed a preference for HIV-2 inhibitory activity, with Id-3o having an EC50 value of 2.5 mu M, an improvement over PF74.
RSC MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Shujing Xu, Lin Sun, Waleed A. Zalloum, Xujie Zhang, Tianguang Huang, Dang Ding, Yucen Tao, Fabao Zhao, Shenghua Gao, Dongwei Kang, Erik De Clercq, Christophe Pannecouque, Alexej Dick, Simon Cocklin, Xinyong Liu, Peng Zhan
Summary: A series of phenylalanine derivatives were designed and synthesized by modifying the structure of PF74, which showed potent anti-HIV activity. Compound 7n exhibited 6.25-fold better anti-HIV-1 activity than PF74, while 7h showed nearly 139 times improved anti-HIV-2 activity. The binding target of 7n was identified as HIV-1 capsid protein, and it inhibited virus replication through binding to a vital CA assembly interface.
CHINESE CHEMICAL LETTERS
(2023)
Article
Chemistry, Medicinal
Shujing Xu, Lin Sun, Michael Barnett, Xujie Zhang, Dang Ding, Anushka Gattu, Dazhou Shi, Jamie R. H. Taka, Wenli Shen, Xiangyi Jiang, Simon Cocklin, Erik De Clercq, Christophe Pannecouque, David C. Goldstone, Xinyong Liu, Alexej Dick, Peng Zhan
Summary: Optimization of compound 11L led to the discovery of novel HIV capsid modulators, quinazolin-4-one-bearing phenylalanine derivatives, which exhibited potent antiviral activities against both HIV-1 and HIV-2. These derivatives occupied multiple pockets at the binding site and displayed a dual-stage inhibition profile, making them potential candidates for HIV capsid modulation and paving the way for future anti-HIV drug design.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Rasha Z. Batran, Ahmed Sabt, Mohammed A. Khedr, Abdou K. Allayeh, Christophe Pannecouque, Asmaa F. Kassem
Summary: A series of 4-phenylcoumarin derivatives were synthesized and evaluated for their antiviral activities against HIV-1 and HIV-2, as well as their inhibitory effects on HIV-1 reverse transcriptase. Compound 8b and derivative 4c showed the best inhibition activity against wild-type HIV-1, with compound 8b exhibiting comparable effect to the reference NNRTI Efavirenz. Structure-activity relationship study revealed the importance of 6-chloro and 4-phenyl substituents, as well as the 5-atoms linker at position 7 of the coumarin scaffold.
BIOORGANIC CHEMISTRY
(2023)
Article
Plant Sciences
Ngoc-Thao-Hien Le, Steven De Jonghe, Kristien Erven, Johan Neyts, Christophe Pannecouque, Tom Vermeyen, Wouter A. Herrebout, Luc Pieters, Emmy Tuenter
Summary: A new alkaloid, along with 17 known alkaloids, was isolated and identified from Pancratium maritimum using advanced probabilistic methods and spectroscopic techniques. Assessment of their anti-SARS-CoV-2 activity and cytotoxicity revealed several compounds with weak antiviral potency at non-toxic concentrations, while some compounds showed cytotoxicity.
PHYTOCHEMISTRY LETTERS
(2023)
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)
