Synthesis and antiviral evaluation of a novel series of homoserine-based inhibitors of the hepatitis C virus NS3/4A serine protease

Alexandre, François-René; Brandt, Guillaume; Caillet, Catherine; Chaves, Dominique; Convard, Thierry; Derock, Michel; Gloux, Damien; Griffon, Yann; Lallos, L.; Leroy, Frédéric; Liuzzi, Michel; Loi, Anna-Giulia; Moulat, Laure; Montaldo, Chiara; Parsy, Christophe; Rahali, Houcine; Roques, Virginie; Seifer, Maria; Standring, David N.; Surleraux, Dominique

doi:10.1016/j.bmcl.2015.07.020

Cited by 11 publications

(4 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Suzuki-Miyaura cross-coupling reaction of compound 6 with thiophene boronic acid produced ((4-methoxy-2-methyl-5-(thiophene)yl)phenyl)sulfonyl) tert-butyl carbamate (6) [9]. The resulting compound 7 was subjected to halogenation of the thiophene ring using benzoyl peroxide and NBS, and the protecting group attached to the amino group was removed using trifluoroacetic acid to obtain 5-(5-bromothiophen-2-yl)-4-methoxy-2-methylbenzenesulfonamide (8) [9,38]. Under the catalysis of cuprous iodide, triethylamine, and the 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex, compound 8 was cross-coupled with propargyloxytetrahydropyran to obtain the key intermediate 9 [39].…”

Section: Synthesismentioning

confidence: 99%

Design, Synthesis, Evaluation and Molecular Dynamics Simulation of Dengue Virus NS5-RdRp Inhibitors

Zong,

Li,

et al. 2023

Pharmaceuticals

View full text Add to dashboard Cite

Dengue virus (DENV) is a major mosquito-borne human pathogen in tropical countries; however, there are currently no targeted antiviral treatments for DENV infection. Compounds 27 and 29 have been reported to be allosteric inhibitors of DENV RdRp with potent inhibitory effects. In this study, the structures of compounds 27 and 29 were optimized using computer-aided drug design (CADD) approaches. Nine novel compounds were synthesized based on rational considerations, including molecular docking scores, free energy of binding to receptor proteins, predicted Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) parameters, structural diversity, and feasibility of synthesis. Subsequently, the anti-DENV activity was assessed. In the cytopathic effect (CPE) assay conducted on BHK-21 cells using the DENV2 NGC strain, both SW-b and SW-d demonstrated comparable or superior activity against DENV2, with IC50 values of 3.58 ± 0.29 μM and 23.94 ± 1.00 μM, respectively, compared to that of compound 27 (IC50 = 19.67 ± 1.12 μM). Importantly, both SW-b and SW-d exhibited low cytotoxicity, with CC50 values of 24.65 μmol and 133.70 μmol, respectively, resulting in selectivity indices of 6.89 and 5.58, respectively. Furthermore, when compared to the positive control compound 3′-dATP (IC50 = 30.09 ± 8.26 μM), SW-b and SW-d displayed superior inhibitory activity in an enzyme inhibitory assay, with IC50 values of 11.54 ± 1.30 μM and 13.54 ± 0.32 μM, respectively. Molecular dynamics (MD) simulations elucidated the mode of action of SW-b and SW-d, highlighting their ability to enhance π–π packing interactions between benzene rings and residue W795 in the S1 fragment, compared to compounds 27 and 29. Although the transacylsulphonamide fragment reduced the interaction between T794 and NH, it augmented the interaction between R729 and T794. In summary, our study underscores the potential of SW-b and SW-d as allosteric inhibitors targeting the DENV NS5 RdRp domain. However, further in vivo studies are warranted to assess their pharmacology and toxicity profiles.

show abstract

Section: Synthesismentioning

confidence: 99%

Design, Synthesis, Evaluation and Molecular Dynamics Simulation of Dengue Virus NS5-RdRp Inhibitors

Zong,

Li,

et al. 2023

Pharmaceuticals

View full text Add to dashboard Cite

show abstract

“…Nearly the same method was also used for the synthesis of α-fluorinated sulfonamide 37 (Scheme 13). [56] In the case of ketones 40 and 41, direct fluorination with Selectfluor or Accufluor [57] reagents was possible, without preliminary enolate formation ( Scheme 14).…”

Section: Chemmedchemmentioning

confidence: 99%

“…Nearly the same method was also used for the synthesis of α‐fluorinated sulfonamide 37 (Scheme 13). [56] …”

Section: Synthesis Of Monofluorinated Cycloalkyl Building Blocksmentioning

confidence: 99%

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

et al. 2022

View full text Add to dashboard Cite

The review covers various aspects of fluorinated cycloalkyl (C3−C7) building blocks for drug discovery, including their synthesis, key physicochemical properties, and biological and medicinal applications of their derivatives. The discussed synthetic methods include classical nucleophilic fluorinations of various substrates, the addition of fluorine and another heteroatom to double bonds, cycloadditions and other transformations of fluorine‐containing substrates, as well as some newer reactions like fluorination of non‐activated and remotely activated C−H bonds, decarboxylative and deborylative fluorinations, etc. The known data on the effect of introducing the fluorinated cycloalkyl groups on the compound's key in vitro parameters (such as acidity/basicity, lipophilicity, conformational behavior, and short contact capabilities) are surveyed. Finally, applications of fluorinated cycloalkyl building block derivatives in the design of biologically active compounds (including marketed drugs Maraviroc, Ivosidenib, and Sitafloxacin) are covered, with a focus on the fluorination impact.

show abstract

“…206 Alternatively, the hydroxyPro residue has been replaced with a cyclopentane-1,2-dicarboxylic acid residue in 256, which again was cyclized to the vinyl-ACC residue to give simeprevir (257) (TMC435) (Scheme 28). 207 The hydroxy-Pro residue has also been replaced with an O-arylated homoserine residue in 258, 208 or with a ring-expanded hydroxypipecolic acid residue in 261 (IDX320), 209 which was derived from a series of different ring sizes in 259 and 260.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Unusual Amino Acids in Medicinal Chemistry

2016

View full text Add to dashboard Cite

Unusual amino acids are fundamental building blocks of modern medicinal chemistry. The combination of readily functionalized amine and carboxyl groups attached to a chiral central core along with one or two potentially diverse side chains provides a unique three-dimensional structure with a high degree of functionality. This makes them invaluable as starting materials for syntheses of complex molecules, highly diverse elements for SAR campaigns, integral components of peptidomimetic drugs, and potential drugs on their own. This Perspective highlights the diversity of unnatural amino acid structures found in hit-to-lead and lead optimization campaigns and clinical stage and approved drugs, reflecting their increasingly important role in medicinal chemistry.

show abstract

Synthesis and antiviral evaluation of a novel series of homoserine-based inhibitors of the hepatitis C virus NS3/4A serine protease

Cited by 11 publications

References 23 publications

Design, Synthesis, Evaluation and Molecular Dynamics Simulation of Dengue Virus NS5-RdRp Inhibitors

Design, Synthesis, Evaluation and Molecular Dynamics Simulation of Dengue Virus NS5-RdRp Inhibitors

Fluorinated Cycloalkyl Building Blocks for Drug Discovery

Unusual Amino Acids in Medicinal Chemistry

Contact Info

Product

Resources

About