Chromatographic and computational lipophilicity assessment of novel antibiofilm agents

Abstract

In this study, lipophilicity of five newly designed molecules with antibiofilm properties was estimated for the first time. The overall goal of lipophilicity evaluation in lead generation phase is to decrease the traditionally high attrition rates for compounds entering clinical trials. Lipophilicity was assessed using RP-HPLC and in silico methods. Chromatographic analyses were performed on BDS Thermo Scientific Hypersil C18 and Phenomenex Kinetex C8 columns with mobile phase consisting of acetonitrile and 20 mmol/L ammonium-acetate solution in different ratios. Retention data was used to derivatize the lipophilicity estimates $\mathit{log}{k}_w,$ $S$ and ${\phi }_0.$ Computational substructure-based and property-based methods were employed to calculate the logP, logD, milogP, AlogP, XlogP2, XlogP3, AlogPs, AClogP and MlogP descriptors. Due to the incongruent trends of increasing hydrophobicity observed among the scales, the Sum of Ranking Differences was used to fairly evaluate the prediction ability of each method. This test unambiguously recognized $S_{(C18)},$ AlogP and XlogP2 as the best lipophilicity measures. By virtue of the respective scales, compound denoted as DIRL PIP was identified as the most lipophilic one. Out of concern related to the DIRL PIP’s anticipated toxicity, less hydrophobic MHK 9a should be subjected to the further drug development.

Graphical Abstract

Keywords:

• Antibiofilm agents
• in silico
• lipophilicity
• RP-HPLC
• Sum of Ranking Differences

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Ministry of Education, Science and Technological Development of Republic of Serbia (project no. 172033).