Design, synthesis, and structure-activity relationships of xanthine derivatives as broad-spectrum inhibitors of coronavirus replication.

Publication date: Dec 01, 2024

Illuminated by insights into the hijacking of host cellular metabolism by coronaviruses, we identified an initial hit compound 7030B-C5, characterized by a xanthine scaffold, via a cellular-level phenotypic screening from a domestic repertoire of lipid-modulating agents. A series of derivatives were synthesized and optimized through comprehensive structure-activity relationship (SAR) studies focusing on the N-1, C-8, and N-7 positions of xanthine and preliminary exploration on the N-3 position and parent nucleus. Compounds 10e, 10f and 10o, featuring modifications at the N-7 position, showed inhibitory activity with half maximal effective concentration (EC) values in the three-digit nanomolar range against human coronavirus-229E (HCoV-229E). In particular, compound 10o exerted superior potency across various coronavirus strains, including HCoV-229E, HCoV-OC43, and the Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Further investigations revealed that 10o acted on the post-entry stages of virus replication and exhibited a distinctive antiviral mechanism from that of clinically approved nirmatrelvir and molnupiravir. Moreover, drug combination study indicates that 10o operates additively with nirmatrelvir, molnupiravir or omicsynin B4, a dual inhibitor of host proteases for S protein priming. Additionally, in vivo assessments show that 10o has favorable pharmacokinetic and safety profiles compared to its parent compound 7030B-C5. These findings underscore the potential of 10o as a promising antiviral candidate for the treatment of current and potential future coronavirus infections.

Concepts Keywords
10e Animals
Coronaviruses Antiviral Agents
Host Antiviral Agents
Nanomolar Antivirals
Pharmacokinetic Coronavirus
Coronavirus 229E, Human
Coronavirus OC43, Human
Dose-Response Relationship, Drug
Drug Design
Humans
Microbial Sensitivity Tests
Molecular Structure
SARS-CoV-2
Structure-Activity Relationship
Structure–activity relationship
Virus Replication
Xanthine
Xanthine
Xanthine
Xanthines
Xanthines

Semantics

Type Source Name
drug DRUGBANK Xanthine
disease IDO replication
disease IDO host
disease MESH coronavirus infections

Original Article

(Visited 1 times, 1 visits today)