Diversity-Orientated Synthesis and Biological Properties of Compounds Based on the N-Phenylquinoneimine Scaffold

Abstract

The N-phenylquinoneimine scaffold is a versatile synthetic platform that has gained significant attention in the field of drug discovery due to its structural diversity and capacity to interact with biologically relevant targets. This review explores established synthetic methodologies and highlights the significant biological activities exhibited by compounds derived from this scaffold, their implications for medicinal chemistry, and the development of novel therapeutics.

Keywords: DNA; N-phenylquinoneimine; biological activity; diversity-orientated synthesis; drugs; reactive metabolites.

Figure 1

Structure of N-phenylquinoneimine 1 (NPQ).

Figure 2

Some of the representative examples of quinoneimines in natural products.

Figure 3

Some subgroups of quinoneimine dyes.

Figure 4

Some of the common quinoneimine dyes.

Figure 5

Structure of Actinomycin D.

Figure 6

Some drugs that form quinoneimine reactive metabolites [56].

Scheme 1

Paracetamol bioactivation to reactive species (quinoneimine) [56].

Scheme 2

Preparation of N-phenylquinoneimine 1 [60].

Scheme 3

Reactions of N-Phenylquinoneimine leading to structural complexity [21].

Scheme 4

Nucleophilic attack via 1,2-addition to the ketone or the imine.

Scheme 5

Nucleophilic attack via 1,4-conjugate addition.

Scheme 6

Addition of aliphatic amine to NPQ [21,66].

Scheme 7

The reaction mechanism of the 1,4-conjugate addition of aromatic amines to the α,β-unsaturated ketone and α,β-unsaturated imine of NPQ [21,76].

Scheme 8

Reaction of aromatic amines with NPQ and subsequent oxidation to phenazinones [76].

Scheme 9

Reactions of thiols with NPQ [78].

Scheme 10

Alternative mode of addition of thiols to NPQ.

Scheme 11

Addition of sodium arenesulfinates to NPQ derivatives [80].

Figure 7

Some useful sulfone-containing compounds.

Scheme 12

Reaction of HBr with NPQ [84].

Scheme 13

Addition of hydrochloric acid to NPQ [85].

Scheme 14

Reaction of NPQ with dimedone [86].

Scheme 15

The reaction of NPQ with organometallic reagents [87].

Scheme 16

Oxidation of NPQ.

Scheme 17

Cycloaddition reaction of NPQ with diphenylketene.

Scheme 18

Suzuki reaction of compound 36 with arylboronic acids.

Scheme 19

Stille reaction of compound 36 with arylstannanes [21,92].

Scheme 20

Reaction of 3-bromo NPQ with isopropylmagnesium chloride [21,91].

Scheme 21

Reaction of 3-bromoNPQ with aniline derivatives [21].