2H/4H-Chromenes-A Versatile Biologically Attractive Scaffold

Abstract

2H/4H-chromene (2H/4H-ch) is an important class of heterocyclic compounds with versatile biological profiles, a simple structure, and mild adverse effects. Researchers discovered several routes for the synthesis of a variety of 2H/4H-ch analogs that exhibited unusual activities by multiple mechanisms. The direct assessment of activities with the parent 2H/4H-ch derivative enables an orderly analysis of the structure-activity relationship (SAR) among the series. Additionally, 2H/4H-ch have numerous exciting biological activities, such as anticancer, anticonvulsant, antimicrobial, anticholinesterase, antituberculosis, and antidiabetic activities. This review is consequently an endeavor to highlight the diverse synthetic strategies, synthetic mechanism, various biological profiles, and SARs regarding the bioactive heterocycle, 2H/4H-ch. The presented scaffold work compiled in this article will be helpful to the scientific community for designing and developing potent leads of 2H/4H-ch analogs for their promising biological activities.

Keywords: 2H/4H-chromenes; biological activities; reaction mechanism; structure-activity relationship; synthetic strategies.

Figure 1

(A) Four possible structures of chromenes; (B) Plausible reaction mechanisms for the 4H-ch formation; and (C) 2H-ch.

Figure 2

Diverse synthetic strategies of 4H-ch derivatives via several catalyzed one-pot reactions as following: (A) using resorcinols and 2-benzylidene malononitriles in the presence of Ca(OH)₂ base; (B) by condensation of malononitrile, aryl aldehydes, and resorcinol in the presence of diethylamine; (C) by simple mixing of malononitrile, α-naphthol, and aromatic aldehydes in water and catalyzed by expanded Perlite; (D) using amino-functionalized silica gel as a base catalyst; (E) by using 2-aminopyridine as an organo-base-catalyst; (F) by MgO as a base-catalyst; (G) using Ca(OH)₂ base-catalyst; and (H) using PoPINO.

Figure 3

Synthesis of 4H-ch derivatives: (I) DBU catalyzed, (J) 3-nitrophenylboronic acid as a green catalyst, (K) lipase-catalyzed synthesis, (L) baker's yeast catalytic one port synthesis, (M) metal-organic framework catalyzed synthesis, and (N) potassium-titanium-oxalate-catalyzed ultrasonic synthesis.

Figure 4

Synthesis of 2H-ch derivatives: (O) Witting-Horner-Emmons and Suzuki-Miyaura cross-coupling pallado-catalyzed, (i)-chromenes, (ii)- chromenes fused-retinoids hybrids; (P) rhodium-catalyzed (5+1) annulations; (Q) microwave-assisted catalyst-free synthesis; (R) TMSCN catalyzed Michael addition/elimination; and (S) unexpected [4+2] annulation of alkynyl thioethers.

Figure 5

Substituted potent chromenes possess significant anticancer potency.

Figure 6

Potent 2H/4H-ch analogs for significant anticancer activities.

Figure 7

Potent 2H/4H-ch derivatives possess various significant biological activities.

Figure 8

SAR features: (A) substituted N-(6-chloro-3-cyano-4-phenyl-4H-chromen-2-yl)-2-(4-chloro-phenoxy)-acetamides, (B) 4H-chromene-3-carboxylate analogs.

Figure 9

SAR features (A) 1H-1,2,3-triazole containing tethered 4H-chromene-D-glucose conjugates, (B) 4H-chromen-4-one analogs, (C) 3-(Benzimidazol-2-yl)-4H-chromen-4-one analogs, and (D) 2-glyco-3-nitro-2H-ch.