Rapid Synthesis of Novel Pyrazino-Pyrido-Pyrimidinones Derived from Fumiquinazoline Alkaloids

2,5-Diketopiperazines (2,5-DKPs) are valued in Medicinal Chemistry for their diverse properties and are considered privileged structures. The natural alkaloids class of fumiquinazolines, combining 2,5-DKP and quinazolinone cores within a pyrazino[1,2-b]quinazoline-3,6-dione framework, is known for its broad biological activity. Although few synthetic approaches to such structures have been explored, this study focuses on synthesizing novel fumiquinazolines analogs featuring a pyrazinopyrido[2,3-d]pyrimidine-5,7-dione core bearing various substituents on the pyrazine moiety (C-6 and C-9), classified into three series (A, B, and C). To investigate an efficient sequential one-pot method, we used a pyridine precursor and L-amino acids in two condensation and cyclization reactions, under controlled microwave irradiations at lower temperatures than previously reported. This approach generated protected bicyclic intermediates, particularly pyrido[2,3-d]pyrimidin-4(3H)-one derivatives, which were smoothly deprotected, allowing for final intramolecular cyclization to yield disubstituted fumiquinazoline analogs (series A) without observed epimerization. The optimized protocol revealed greater efficiency for monosubstituted analogs (series B and C), speeding up the tricyclic products synthesis without the need for intermediates isolation and deprotection. Overall, this study demonstrates the incorporation of diverse protected amino acids, featuring different electronic and structural side chains, via a rapid and effective sequential one-pot strategy, resulting in the synthesis of 19 novel fumiquinazoline analogs.