Synthesis and biological evaluation of 4H-benzo[e][1,3]oxazin-4-ones analogues of TGX-221 as inhibitors of PI3Kβ

Ehtesham U R Mohammed; Zoe J Porter; Ian G Jennings; Jasim M A Al-Rawi; Philip E Thompson; Michael J Angove

doi:10.1016/j.bmc.2022.116832

Synthesis and biological evaluation of 4H-benzo[e][1,3]oxazin-4-ones analogues of TGX-221 as inhibitors of PI3Kβ

Bioorg Med Chem. 2022 Sep 1:69:116832. doi: 10.1016/j.bmc.2022.116832. Epub 2022 May 17.

Authors

Ehtesham U R Mohammed¹, Zoe J Porter², Ian G Jennings², Jasim M A Al-Rawi³, Philip E Thompson², Michael J Angove³

Affiliations

¹ Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia. Electronic address: ehteshamchem@gmail.com.
² Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.
³ Pharmacy and Biomedical Sciences, La Trobe Institute for Molecular Science, La Trobe University, P.O. Box 199, Bendigo, VIC 3552, Australia.

PMID: 35752141
DOI: 10.1016/j.bmc.2022.116832

Abstract

A novel series of TGX-221 analogues was prepared that include isosteric replacement of the 4H-pyrido[1,2-a]pyrimidin-4-one with a 4H-benzo[e][1,3]oxazin-4-one scaffold. The compounds that included an CH(CH₃)NH type linker showed comparable activity to TGX-221 analogues with the isosterism supported by the comparative SAR analysis. The analogues containing an CH(CH₃)O linker were less active but still showed useful SAR including a favoured o-methyl substitution.

Keywords: 1,3-Benzoxazin-4-ones; Anticancer; PI3Kβ.

MeSH terms

Morpholines*
Pyrimidinones* / pharmacology
Structure-Activity Relationship

Substances

Morpholines
Pyrimidinones
TGX 221