<abstract xmlns="http://www.w3.org/1999/xhtml">Phosphoinositide 3-kinase α (PI3Kα) is a propitious target for designing anticancer drugs. A series of new <italic>N</italic>’-(diphenylmethylene)benzenesulfonohydrazide was synthesized and characterized using FT-IR, NMR (1H and 13C), HRMS, and elemental analysis. Target compounds exhibited an antiproliferative effect against the human colon carcinoma (HCT-116) cell line. Our cheminformatics analysis indicated that the <italic>para</italic>-tailored derivatives [<italic>p</italic>-NO2 (<bold>3</bold>) and <italic>p</italic>-CF3 (<bold>7</bold>)] have better ionization potentials based on calculated Moran autocorrelations and ionization potentials. Subsequent <italic>in vitro</italic> cell proliferation assays validated our cheminformatics results by providing experimental evidence that both derivatives <bold>3</bold> and <bold>7</bold> exhibited improved antiproliferative activities against HCT-116. Hence, our results emphasized the importance of electron-withdrawing groups and hydrogen bond-acceptors in the rational design of small-molecule chemical ligands targeting PI3Kα. These results agreed with the induced-fit docking against PI3Kα, highlighting the role of <italic>p</italic>-substituted aromatic rings in guiding the ligand-PI3Kα complex formation, by targeting a hydrophobic pocket in the ligand-binding site and forming π-stacking interactions with a nearby tryptophan residue.</abstract>

Phosphoinositide 3-kinase α (PI3Kα) is a propitious target for designing anticancer drugs. A series of new N’-(diphenylmethylene)benzenesulfonohydrazide was synthesized and characterized using FT-IR, NMR (1H and 13C), HRMS, and elemental analysis. Target compounds exhibited an antiproliferative effect against the human colon carcinoma (HCT-116) cell line. Our cheminformatics analysis indicated that the para-tailored derivatives [p-NO2 (3) and p-CF3 (7)] have better ionization potentials based on calculated Moran autocorrelations and ionization potentials. Subsequent in vitro cell proliferation assays validated our cheminformatics results by providing experimental evidence that both derivatives 3 and 7 exhibited improved antiproliferative activities against HCT-116. Hence, our results emphasized the importance of electron-withdrawing groups and hydrogen bond-acceptors in the rational design of small-molecule chemical ligands targeting PI3Kα. These results agreed with the induced-fit docking against PI3Kα, highlighting the role of p-substituted aromatic rings in guiding the ligand-PI3Kα complex formation, by targeting a hydrophobic pocket in the ligand-binding site and forming π-stacking interactions with a nearby tryptophan residue.

New derivatives of sulfonylhydrazone as potential antitumor agents: Design, synthesis and cheminformatics evaluation

Department of Pharmacy, Faculty of Pharmacy

Department of Clinical Pharmacy and Therapeutics

Acta Pharmaceutica

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Phosphoinositide 3-kinase α (PI3Kα) is a propitious target for designing anticancer drugs. A series of new N’-(diphenylmethylene)benzenesulfonohydrazide was...

New derivatives of sulfonylhydrazone as potential antitumor agents: Design, synthesis and cheminformatics evaluation

Published Online: Apr 03, 2021

Page range: 545 - 565

Accepted: Dec 08, 2020

DOI: https://doi.org/10.2478/acph-2021-0043

Keywords
sulfonylhydrazones, antitumor, HCT-116, PI3Kα-inhibitors, cheminformatics, docking

© 2021 Dima A. Sabbah et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

New derivatives of sulfonylhydrazone as potential antitumor agents: Design, synthesis and cheminformatics evaluation

Published Online: Apr 03, 2021

Page range: 545 - 565

Accepted: Dec 08, 2020

DOI: https://doi.org/10.2478/acph-2021-0043

Keywordssulfonylhydrazones, antitumor, HCT-116, PI3Kα-inhibitors, cheminformatics, docking

© 2021 Dima A. Sabbah et al., published by Sciendo

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Keywords
sulfonylhydrazones, antitumor, HCT-116, PI3Kα-inhibitors, cheminformatics, docking