Scaffold-Hopping Strategies in Aurone Optimization: A Comprehensive Review of Synthetic Procedures and Biological Activities of Nitrogen and Sulfur Analogues

Abstract

Aurones, particular polyphenolic compounds belonging to the class of minor flavonoids and overlooked for a long time, have gained significative attention in medicinal chemistry in recent years. Indeed, considering their unique and outstanding biological properties, they stand out as an intriguing reservoir of new potential lead compounds in the drug discovery context. Nevertheless, several physicochemical, pharmacokinetic, and pharmacodynamic (P3) issues hinder their progression in more advanced phases of the drug discovery pipeline, making lead optimization campaigns necessary. In this context, scaffold hopping has proven to be a valuable approach in the optimization of natural products. This review provides a comprehensive and updated picture of the scaffold-hopping approaches directed at the optimization of natural and synthetic aurones. In the literature analysis, a particular focus is given to nitrogen and sulfur analogues. For each class presented, general synthetic procedures are summarized, highlighting the key advantages and potential issues. Furthermore, the biological activities of the most representative scaffold-hopped compounds are presented, emphasizing the improvements achieved and the potential for further optimization compared to the aurone class.

Keywords: aurones; azaaurones; benzothiophenone; biological activities; imidazo [1,2-a]pyridine-3-one; indol-3-one; organic synthesis; scaffold hopping; thioaurones.

Figure 1

General structure of aurones and their higher structural homolog, flavones, with the three rings A–C and enumeration of atoms evidenced.

Figure 2

General chemical structure of natural aurones and of the corresponding nitrogen (indolin-3-ones, imidazo[1,2-a]pyridine-3-ones) and sulfur heterocyclic (benzo[b]thiophen-3-ones) analogues reviewed in this overview. The nitrogen scaffolds are evidenced in blue, whereas the sulfur one in red.

Scheme 1

Main synthetic multi-/one-step procedures to afford the (Z)-azaaurone scaffold. Reagents and conditions: (a) Ac₂O, NaH; (b) [Au] catalyst; (c) base (NaOH, KOH, or aliphatic amine) and aromatic aldehydes; (d) aromatic aldehyde, 20% NaOH; (e) acetic acid, Amberlyst-15; (f) [Pd] catalyst, CO or CO₂, Et₃N; (g) aromatic aldehyde, 8-methylquinoline-N-oxide, HNTf₂, [AuCl(JohnPhos)]/AgNTf₂; (h) tBuXPhosAuNTf₂.

Scheme 2

Synthetic protocols proposed by Aksenov et al. to afford the nitrile-substituted azaaurone scaffold of type 11. Reagents and conditions: (a) KCN followed by AcOH; (b) aromatic aldehydes, KCN, and then AcOH; (c) KOH, DMSO (oxidizing agent).

Scheme 3

Synthetic method for diarylation of azaaurone compounds. Reagents and conditions: (a) N-chlorosuccinimide, MeOH; (b) boronic acid, CsF or CsCO₃, and [Pd^+II] catalyst.

Figure 3

Aurone and azaaurone analogues with potent antimalarial activity against Plasmodium falciparum, with the IC₅₀ values highlighted. The ring A and B of the central scaffold are evidenced.

Figure 4

Chemical structure of several azaaurones with anti-Mycobacterium tuberculosis activity.

Figure 5

Chemical structure of antiviral azaaurones 27a,b, and the corresponding aurones 26a,b; the biological activity (EC₅₀, decrease in cytopathic effect) against influenza A/H1N1pdm09 is evidenced.

Figure 6

Chemical structure of azaaurone derivatives with promising anticancer activity against aggressive and multidrug-resistant cancer cells.

Scheme 4

Main synthetic procedures to isolate the imidazo[1,2-a]pyridin-3-one scaffold, a diaza analogue of natural aurone. Reagents and conditions: (a) PCl₃; (b) ArCHO, base; (c) polyphosphoric acid (PPA); (d) PCy₃. In the right part, an overview of the most interesting features of each synthetic process is given.

Figure 7

Chemical structure of imidazo[1,2-a]pyridin-3-one derivatives endowed with anticancer properties, with the range of antiproliferative activity (expressed as IC₅₀) against multiple cancer cell lines evidenced.

Scheme 5

Main synthetic multi-step procedures to afford the thioaurone scaffold from 1-benzothiophen-3(2H)-one intermediate. Reagents and conditions: (a) (1) SOCl₂, (2) AlCl₃; (b) LDA, −78 °C; (c) ArCHO, with piperidine/NaOH/basic aluminum oxide (basic conditions) or CH₃COONa under acidic catalyst (acid conditions).

Scheme 6

Main synthetic procedures to afford the thioaurone scaffold starting from chalcone analogues as reaction intermediates. Reagents and conditions: (a) S₈, tertiary amine (e.g., Et₃N or N-methylpiperidine), DMSO; (b) I₂, DMSO; (c) CuI, I₂; (d) NBS, pyridine.

Scheme 7

Main synthetic one-pot procedures to afford the thioaurone scaffold. Reagents and conditions: (a) formic acid; (b) LDA.

Figure 8

Chemical structure of thioaurone compounds endowed with biological activity.