Biological and Medicinal Chemistry

Design, Synthesis, and Lead Optimisation of CHVB Series Analogues as Potent Small Molecule Inhibitors of Chikungunya Virus



The worldwide re-emerge of the Chikungunya virus (CHIKV), the high morbidity associated with it, and the lack of an available vaccine or antiviral treatment make the development of a potent CHIKV-inhibitor highly desirable. Therefore, an extensive lead optimisation was performed based on the previously reported CHVB compound 1b and the reported synthesis route was optimised - improving the overall yield in remarkable shorter synthesis and work-up time. 100 CHVB analogues were designed, synthesised, and investigated for their antiviral activity, physiochemistry, and toxicological profile. An extensive structure-activity relationship study (SAR) was performed, which focused mainly on the combination of scaffold changes and revealed the key chemical features for a high anti-CHIKV inhibition. Further, to investigate the druggability of the compound series, a thorough ADMET investigation was carried out: the compounds were screened for their aqueous solubility, lipophilicity, their toxicity in CaCo-2 cells, and possible hERG channel interactions. Additionally, 55 analogues were assessed for their metabolic stability in human liver microsomes (HLMs) which led to a structure-metabolism relationship study (SMR). The compounds showed an excellent safety profile, favourable physicochemical characteristics, and the required metabolic stability. A cross-resistance study confirmed the viral capping machinery (nsP1) to be the viral target of these second-generation CHVB compounds. This study identified five compounds (31b, 31d, 32d, 34, and 35d) as potent, safe, and stable lead compounds for further development as selective CHIKV inhibitors - with 32d as the most promising candidate. Finally, the collected insight led to a successful scaffold hop (64b) for future antiviral research studies.


Thumbnail image of Battisti_Manuscript.pdf

Supplementary material

Thumbnail image of Battisti_Supporting_Information.pdf
Supporting Information - Design, Synthesis, and Lead Optimization of CHVB Series Analogues as Potent Small Molecule Inhibitors of Chikungunya Viru
Molecular Docking study, cytotoxic results, synthesis route for the synthesis of 39 (Scheme S1), experimental procedures, and characterisation data for final compounds and intermediates 20a-64b are reported in the Supporting Information.