Rational approaches, design strategies, structure activity relationship and mechanistic insights for therapeutic coumarin hybrids

Abstract

Hybrid molecules, furnished by combining two or more pharmacophores is an emerging concept in the field of medicinal chemistry and drug discovery that has attracted substantial traction in the past few years. Naturally occurring scaffolds such as coumarins display a wide spectrum of pharmacological activities including anticancer, antibiotic, antidiabetic and others, by acting on multiple targets. In this view, various coumarin-based hybrids possessing diverse medicinal attributes were synthesized in the last five years by conjugating coumarin moiety with other therapeutic pharmacophores. The current review summarizes the recent development (2014 and onwards) of these pharmacologically active coumarin hybrids and demonstrates rationale behind their design, structure-activity relationships (SAR) and mechanistic studies performed on these hybrid molecules. This review will be beneficial for medicinal chemist and chemical biologist, and in general to the drug discovery community and will facilitate the synthesis and development of novel, potent coumarin hybrid molecules serving as lead molecules for the treatment of complex disorders.

Keywords: Anti-Alzheimer’s; Anti-inflammatory; Anticancer; Antidiabetic; Antimicrobial; Antioxidant; Coumarin hybrids; Design strategies; Mechanistic insights; Structure-activity relationship.

Figure 1.

(A) Marketed formulations of coumarin derivatives and their clinical uses; (B) General structure-activity relationship of coumarins

Figure 2a.

Mechanism of actions of coumarin derivatives against cancer

Figure 2b.

Mechanism of actions of coumarin derivatives against various diseases

Figure 3.

(A) Hybrid molecule CUDC-907 in clinical trial; (B) Various hybrid molecules as drug candidates

Figure 4.

Recently reported coumarin-based anticancer hybrid molecules

Figure 5.

Recently reported Coumarin based hybrid molecules having anti-Alzheimer’s properties

Figure 6.

Coumarin based antidiabetic and anti-microbial hybrid molecules

Figure 7.

Various coumarin-based bioactive hybrid molecules

Figure 8.

Isatin-coumarin hybrids as tubulin inhibitors

Figure 9.

Indole-coumarin hybrids as anticancer agents

Figure 10.

Coumarin-chalcone hybrids as anticancer agents

Figure 11.

Naphthoquinone-coumarin hybrid molecule topoisomerase II inhibitor

Figure 12.

Coumarin-chalcone/acrylohydrazide/pyridine hybrids as anticancer agents

Figure 13.

Triazole-coumarin hybrids as 5-LO and ceramidase inhibitors

Figure 14.

C₅-curcuminoid-coumarin bifunctional hybrids as tubulin inhibitors

Figure 15.

(A) bis-coumarin–iminothiazole hybrids as anticancer agents; (B) indole-coumarin hybrid molecules as anticancer agents

Figure 16.

Imidazo[1,2-a]pyrazine-coumarin hybrids as B-Raf Kinase inhibitors

Figure 17.

Coumarin-pyrimidine hybrids as anticancer agents

Figure 18.

Chalcone-coumarin hybrids linked via 1,2,3-triazole as tubulin inhibitors

Figure 19.

(A) Triphenylethylene-coumarin hybrids active against leukemic cancer cell line; (B) Coumarin-1,2,3-triazole dithiocarbamate hybrids as LSD1 inhibitors

Figure 20.

Coumarin-hydrazide-hydrazone hybrids as anticancer agents

Figure 21.

Coumarin-N-benzylpyridinium hybrids as anti-Alzheimer’s agents

Figure 22.

Coumarin-pargyline hybrids as MAO-B inhibitors that prevent amyloid aggregation

Figure 23.

Donepezil-coumarin hybrids as cholinesterase and MAO-B inhibitors

Figure 24.

Hybrid molecules of coumarin and various aromatic amines as AChE inhibitors

Figure 25.

Tacrine-coumarin hybrids as cholinesterase inhibitors

Figure 26.

3,4-dimethylcoumarin-piperidine hybrid as anti-Alzheimer’s agents

Figure 27.

Coumarin-tryptamine hybrids as cholinesterase inhibitors

Figure 28.

Tacrine-coumarin hybrids tethered through piperazine as cholinesterase inhibitors

Figure 29.

Coumarin-tacrine hybrids using methylene chain linker as dual AChE/β-secretase inhibitors

Figure 30.

(A) Coumarin-thiazolidinediones hybrid molecules as novel glucosidase inhibitors; (B) Flavonoid-coumarin hybrids as antidiabetic agents

Figure 31.

Thiazole-coumarin hybrids as α-glucosidase inhibitors

Figure 32.

Coumarin-thiazole and coumarin-oxadiazole hybrids as ALR inhibitors

Figure 33.

Coumarin-pyrimidine as anti-microbial agents

Figure 34.

Coumarin-theophylline hybrids as anti-microbial and antitubercular agents

Figure 35.

(A) Coumarin and phenyl glyoxal hybrids; (B) Triazole-coumarin hybrids as anti-microbial agents

Figure 36.

Various coumarin hybrid molecules as anti-microbial agents

Figure 37.

Various coumarin hybrid molecules with antioxidant activity

Figure 38.

Arylpyrazoline-coumarin hybrids as anti-inflammatory agents

Figure 39.

Various coumarin hybrid molecules as anti-inflammatory agents

Figure 40.

Coumarin-chalcone hybrid as a blood coagulator agent with antioxidant property

Figure 41.

Phenylamide-coumarins as FXIIa enzyme inhibitors

Figure 42.

Coumarin-aminopyran based hybrids as an antidepressant