Benzisoxazole: a privileged scaffold for medicinal chemistry

Abstract

The benzisoxazole analogs represent one of the privileged structures in medicinal chemistry and there has been an increasing number of studies on benzisoxazole-containing compounds. The unique benzisoxazole scaffold also exhibits an impressive potential as antimicrobial, anticancer, anti-inflammatory, anti-glycation agents and so on. This review examines the state of the art in medicinal chemistry as it relates to the comprehensive and general summary of the different benzisoxazole analogs, their use as starting building blocks of multifarious architectures on scales sufficient to drive human drug trials. The number of reports describing benzisoxazole-containing highly active compounds leads to the expectation that this scaffold will further emerge as a potential candidate in the field of drug discovery.

Fig. 1. Some of the representative benzisoxazole analogues with biological potential.

Fig. 2. Compounds with antimicrobial activity: compounds 17–20.

Fig. 3. Potential antimicrobial agents (21–24).

Fig. 4. Potential antimicrobial agents (25–28).

Fig. 5. Potential antimicrobial agents (29–31).

Fig. 6. Benzisoxazole analogues with potential biological activities.

Fig. 7. Synthesized compounds (37–41) with potential antimicrobial activity.

Fig. 8. Synthesized compounds (42–45) with potential antiglycation activity.

Fig. 9. PPARγ ligand binding domain showing ligand–protein interactions of (a) full PPARγ agonists rosiglitazone (green) and pioglitazone (yellow) (PDB access code 2PRG) and (b) PPARγ selective modulator, compound 46 (gray) (PDB access code ; 3TY0). The helix 3 region is marked, and the tyrosine 473 residue is shown in orange.

Fig. 10. Most active synthesized anticonvulsant agents.

Fig. 11. Most active synthesized anti-tuberculosis agents (51–57).

Fig. 12. Protein–ligand interactions between (R)-56 and PS (PDB: ; 2A88): (green) hydrophobic, (light-purple) polar, (blue ring) basic, (red ring) acidic. The tetrahydrobenzoisoxazole ring of 1a occupies the position of the adenine ring (A and B) of the reaction intermediate cocrystallized with PS in PDB1N2H.

Fig. 13. Benzisoxazole analogues with potent antipsychotic activities (58–64).

Fig. 14. Benzisoxazole analogues that are potential anticancer agents (65–74).

Fig. 15. Benzisoxazole analogues that are potential anticancer agents.

Fig. 16. Benzisoxazole analogues that are potential biological agents.

Fig. 17. Benzisoxazole analogues that are potential biological agents.

Fig. 18. Docking of compound 85 to the GSK-3β crystal structure. (A) Ribbon presentation of compound 85 bound to GSK-3β; (B) surface presentation of compound 85 docking into GSK-3β; (C) ribbon presentation of compound 85 bound to GSK-3β; and (D) surface presentation of compound 85 docking into GSK-3β.

Fig. 19. Interaction pattern of the compound 86 with mycobacterial pantothenate synthase enzyme.