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1.
J Med Chem ; 65(4): 2880-2904, 2022 02 24.
Article in English | MEDLINE | ID: mdl-34347470

ABSTRACT

Starting from the MLPCN probe compound ML300, a structure-based optimization campaign was initiated against the recent severe acute respiratory syndrome coronavirus (SARS-CoV-2) main protease (3CLpro). X-ray structures of SARS-CoV-1 and SARS-CoV-2 3CLpro enzymes in complex with multiple ML300-based inhibitors, including the original probe ML300, were obtained and proved instrumental in guiding chemistry toward probe compound 41 (CCF0058981). The disclosed inhibitors utilize a noncovalent mode of action and complex in a noncanonical binding mode not observed by peptidic 3CLpro inhibitors. In vitro DMPK profiling highlights key areas where further optimization in the series is required to obtain useful in vivo probes. Antiviral activity was established using a SARS-CoV-2-infected Vero E6 cell viability assay and a plaque formation assay. Compound 41 demonstrates nanomolar activity in these respective assays, comparable in potency to remdesivir. These findings have implications for antiviral development to combat current and future SARS-like zoonotic coronavirus outbreaks.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/metabolism , Chlorocebus aethiops , Coronavirus 3C Proteases/isolation & purification , Coronavirus 3C Proteases/metabolism , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/chemistry , Dose-Response Relationship, Drug , Glutamine/chemistry , Glutamine/pharmacology , Humans , Ketones/chemistry , Ketones/pharmacology , Microbial Sensitivity Tests , Models, Molecular , Molecular Structure , Peptidomimetics/chemistry , SARS-CoV-2/enzymology , Vero Cells , Virus Replication/drug effects , COVID-19 Drug Treatment
2.
Bioorg Med Chem ; 22(21): 5776-82, 2014 Nov 01.
Article in English | MEDLINE | ID: mdl-25305010

ABSTRACT

An efficient and practical strategy for the synthesis of (3R,4s,5S)-4-(2-hydroxyethyl) piperidine-3,4,5-triol and its N-alkyl derivatives 8a-f, starting from the D-glucose, is reported. The chiral pool methodology involves preparation of the C-3-allyl-α-D-ribofuranodialdose 10, which was converted to the C-5-amino derivative 11 by reductive amination. The presence of C-3-allyl group gives an easy access to the requisite hydroxyethyl substituted compound 13. Intramolecular reductive aminocyclization of C-5 amino group with C-1 aldehyde provided the γ-hydroxyethyl substituted piperidine iminosugar 8a that was N-alkylated to get N-alkyl derivatives 8b-f. Iminosugars 8a-f were screened against glycosidase enzymes. Amongst synthetic N-alkylated iminosugars, 8b and 8c were found to be α-galactosidase inhibitors while 8d and 8e were selective and moderate α-mannosidase inhibitors. In addition, immunomodulatory activity of compounds 8a-f was examined. These results were substantiated by molecular docking studies using AUTODOCK 4.2 programme.


Subject(s)
Enzyme Inhibitors/chemistry , Imino Sugars/chemistry , Immunosuppressive Agents/chemistry , Piperidines/chemistry , alpha-Galactosidase/antagonists & inhibitors , Alkylation , Binding Sites , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Humans , Imino Sugars/chemical synthesis , Imino Sugars/pharmacology , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/pharmacology , Jurkat Cells , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Molecular Docking Simulation , Protein Structure, Tertiary , alpha-Galactosidase/metabolism
3.
J Org Chem ; 79(10): 4398-404, 2014 May 16.
Article in English | MEDLINE | ID: mdl-24735108

ABSTRACT

We report herein a newly developed domino reaction that facilitates the synthesis of new 1,5-dideoxy-1,5-iminoribitol iminosugar C-glycosides 7a-e and 8. The key intermediate in this approach is a six-membered cyclic sugar nitrone that is generated in situ and trapped by an alkene dipolarophile via a [2 + 3] cycloaddition reaction to give the corresponding isooxazolidines 10a-e in a "one-pot" protocol. The iminoribitol C-glycosides 7a-e and 8 were found to be modest ß-galactosidase (bGal) inhibitors. However, compounds 7c and 7e showed "pharmacological chaperone" activity for mutant lysosomal bGal activity and facilitated its recovery in GM1 gangliosidosis patient fibroblasts by 2-6-fold.


Subject(s)
Alkenes/chemistry , Fibroblasts/chemistry , Gangliosidosis, GM1/drug therapy , Lysosomes/chemistry , Molecular Chaperones/pharmacology , Molecular Chaperones/therapeutic use , Monosaccharides/chemical synthesis , Nitrogen Oxides/chemistry , beta-Galactosidase/antagonists & inhibitors , beta-Galactosidase/chemistry , Cycloaddition Reaction , Gangliosidosis, GM1/enzymology , Gangliosidosis, GM1/metabolism , Glycosides , Humans , Lysosomes/metabolism , Monosaccharides/chemistry
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