Rejuvenating the [1, 2, 3]-triazolo [1,5-a]quinoxalin-4(5 H)-one scaffold: Synthesis and derivatization in a sustainable guise and preliminary antimicrobial evaluation

Sveva Pelliccia; Antonella Ilenia Alfano; Beatriz Ramos Gomes Da Assunção; Luigia Turco; Francesca Lembo; Vincenzo Summa; Elisabetta Buommino; Margherita Brindisi

doi:10.3389/fchem.2023.1126427

Rejuvenating the [1, 2, 3]-triazolo [1,5-a]quinoxalin-4(5 H)-one scaffold: Synthesis and derivatization in a sustainable guise and preliminary antimicrobial evaluation

Front Chem. 2023 Mar 14:11:1126427. doi: 10.3389/fchem.2023.1126427. eCollection 2023.

Authors

Sveva Pelliccia¹, Antonella Ilenia Alfano¹, Beatriz Ramos Gomes Da Assunção², Luigia Turco^{1

3}, Francesca Lembo¹, Vincenzo Summa¹, Elisabetta Buommino¹, Margherita Brindisi¹

Affiliations

¹ Department of Pharmacy, University of Naples Federico II, Naples, Italy.
² ESTeSL- Lisbon School of Health Technology, Polytechnic Institute of Lisbon, Lisbon, Portugal.
³ Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Abstract

The [1,2,3]-triazolo [1,5-a] quinoxalin-4(5H)-one scaffold and its analogues triazole-fused heterocyclic compounds are relevant structural templates in both natural and synthetic biologically active compounds. However, their medicinal chemistry applications are often limited due to the lack of synthetic protocols combining straightforward generation of the central core while also allowing extensive decoration activity for drug discovery purposes. Herein, we report a "refreshed" synthesis of the [1,2,3]-triazolo [1,5-a]quinoxalin-4(5H)-one core, encompassing the use of eco-compatible catalysts and reaction conditions. We have also performed a sustainable and extensive derivatization campaign at both the endocyclic amide nitrogen and the ester functionality, comprehensively exploring the reaction scope and overcoming some of the previously reported difficulties in introducing functional groups on this structural template. Finally, we unveiled a preliminary biological investigation for the newly generated chemical entities. Our assessment of the compounds on different bacterial species (two S. aureus strains, three P. aeruginosa strains, K. pneumonia), and two fungal C. albicans strains, as well as the evaluation of their activity on S. epidermidis biofilm formation, foster further optimization for the retrieved hit compounds 9, 14, and 20.

Keywords: [1,2,3]-triazolo [1,5-a] quinoxalin-4(5H)-one; antimicrobial agents; drug discovery; green chemistry; privileged scaffold; sustainable synthesis.