Exploratory applications of 2-nitrobenzaldehyde-derived Morita-Baylis-Hillman adducts as synthons in the construction of drug-like scaffolds

Abstract

Morita-Baylis-Hillman adducts, prepared from 2-nitrobenzaldehyde precursors and either methyl acrylate or methyl vinyl ketone, have been used as critical synthons in the preparation of α-[(alkylamino)methyl]cinnamate esters and their but-3-en-2-one analogs, cinnamate ester-azidothymidine (AZT) conjugates, 2-quinolone and quinoline derivatives. Computer docking studies have been conducted to explore the potential of the cinnamate ester-AZT conjugates as potential dual-action HIV-1 integrase-reverse transcriptase (IN-RT) inhibitors. The results further demonstrate the applicability of Morita-Baylis-Hillman methodology in the construction of complex drug-like scaffolds.

GRAPHICAL ABSTRACT

KEYWORDS:

• Antimalarial
• azidothymidine (AZT)
• dual-action drugs
• HIV-1 integrase-reverse transcriptase inhibitors
• Morita-Baylis-Hillman reaction
• quinoline
• quinololone

Note

Acknowledgements

The authors thank Rhodes University for bursary support (K.C.I.) and the National Research Foundation (NRF: GUN 2069255), the Medical Research Council of South Africa (SAMRC) and Rhodes University for generous financial support. Any opinion, findings and conclusions or recommendations expressed in this material are those of the authors and therefore the NRF does not accept any liability in regard thereto. Prof K.A. Lobb’s guidance in computer modelling and ligand docking is appreciated.

Notes

1 Systematic name: 4{[2-methoxycarbonyl-3-(2-nitrophenyl)-2-propenylamino]methyl}-1-[(2S,3R,5R)-5-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)-2-(hydroxymethyl)tetrahydrofuran-3-yl]-1H-1,2,3-triazole.

Additional information

Funding

The authors thank Rhodes University for bursary support (K.C.I.), the National Research Foundation (NRF: GUN 2069255), and the South African Medical Research Council (SAMRC) for generous financial support.