Submission Details
Molecule(s):
O=C(Cn1ccc2c(c1=O)NCO2)NC(CC1CCNC1=O)C(=O)C(=O)NC12CCC(C1)C2
N#CC(C1CCNC1=O)C(NC(=O)Cn1ccc2c(c1=O)NCO2)C(=O)C(=O)NC12CCC(C1)C2
O=C(Cn1ccc2cc[nH]c2c1=O)NC(CC1CCNC1=O)C(=O)C(=O)NC12CCC(C1)C2
Design Rationale:
Here, the approach was to improve the physicochemical property of the lead (published on March 20, cited below) by retaining the activity (IC50 = 0.67 ± 0.18 µM for compound 13b). The replacement of the phenyl ring to the bicyclo-pentane would increase the solubility. Also, it can prevent the para-hydroxylation of the phenyl ring. Moreover, these compounds showed increase bioavailability scores, a decrease in the rotatable bonds and molecular weight as compared to the lead molecule (Compound 13b). However, docking studies would help to understand the binding efficacy of these molecules.
Other Notes:
The physicochemical properties were checked through SwissADME (http://www.swissadme.ch/index.php) Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors, published on March 20. (https://science.sciencemag.org/content/early/2020/03/20/science.abb3405 )