Recent Trends in the Synthesis and Bioactivity of Coumarin, Coumarin-Chalcone, and Coumarin-Triazole Molecular Hybrids.

Molecular hybridization represents a new approach in drug discovery in which specific chromophores are strategically combined to create novel drugs with enhanced therapeutic effects. This innovative strategy leverages the strengths of individual chromophores to address complex biological challenges, synergize beneficial properties, optimize pharmacokinetics, and overcome limitations associated with single-agent therapies. Coumarins are documented to possess several bioactivities and have therefore been targeted for combination with other active moieties to create molecular hybrids. This review summarizes recent (2013-2023) trends in the synthesis of coumarins, as well as coumarin-chalcone and coumarin-triazole molecular hybrids. To cover the wide aspects of this area, we have included differently substituted coumarins, chalcones, 1,2,3- and 1,2,4-triazoles in this review and considered the point of fusion/attachment with coumarin to show the diversity of these hybrids. The reported syntheses mainly relied on well-established chemistry without the need for strict reaction conditions and usually produced high yields. Additionally, we discussed the bioactivities of the reported compounds, including antioxidative, antimicrobial, anticancer, antidiabetic, and anti-cholinesterase activities and commented on their IC50 where possible. Promising bioactivity results have been obtained so far. It is noted that mechanistic studies are infrequently found in the published work, which was also mentioned in this review to give the reader a better understanding. This review aims to provide valuable information to enable further developments in this field.

Syntheses of cytotoxic novel arctigenin derivatives bearing halogen and alkyl groups on aromatic rings.

The new lignano-9,9'-lactones (α,ß-dibenzyl-γ-butyrolactone lignans), which showed the higher cytotoxicity than arctigenin, were synthesized. The well-known cytotoxic arctigenin showed activity against HL-60 cells (EC50=12µM), however, it was inactive against HeLa cells (EC50>100µM). The synthesized (3,4-dichloro, 2'-butoxy)-derivative 55 and (3,4-dichloro, 4'-butyl)-derivative 66 bearing the lignano-9,9'-lactone structures showed the EC50 values of 10µM and 9.4µM against HL-60 cells, respectively. Against HeLa cells, the EC50 value of the derivative 66 was 27µM. By comparing the activities with the corresponding 9,9'-epoxy structure (tetrahydrofuran compounds), the importance of the lactone structure of 55 and 66 for the higher activities was shown. The substituents on the aromatic ring of the lignano-9,9'-lactones affected the cytotoxicity level, observing more than 10-fold difference.

Effect of the structure of dietary epoxylignan on its cytotoxic activity: relationship between the structure and the activity of 7,7'-epoxylignan and the introduction of apoptosis by caspase 3/7.

We compared the cytotoxic activities of dietary epoxylignans and their stereoisomers and found (-)-verrucosin, which is (7S,7'R,8R,8'R)-7,7'-epoxylignan, to be the most cytotoxic epoxylignan against HeLa cells (IC50 = 6.6 µM). On the other hand, the activity was about a factor of 10 less against HL-60. In this research on the relationship between the structure and cytotoxic activity of (-)-verrucosin 13, the 7-(4-methoxyphenyl)-7'-(3,4-dimethoxyphenyl) derivative 60, for which the activity (IC50 = 2.4 µM) is three times greater than (-)-verrucosin 13, was discovered. The induction of apoptosis by caspase 3/7 was observed upon treatment with the (-)-verrucosin derivative.

Revised stereochemistry of ficifolidione and its biological activities against insects and cells.

Ficifolidione (1), a moderately active insecticidal compound from two species of Myrtaceae, and its derivatives were synthesized to evaluate their insecticidal activity. X-ray crystallographic analyses and specific rotation values of ficifolidione and its C-4 (2) demonstrated that the structure of ficifolidione differs from the reported absolute structure; that is, the C-4 configuration of ficifolidione should have an S configuration. The reported insecticidal activity of ficifolidione (1) and its C-4 epimer (2) against adult houseflies (Musca domestica), mosquito larvae (Culex pipiens), and cutworms (Spodoptera litura) was not observed. The cytotoxicities of ficifolidione and its derivatives (1-4) against four cell lines, Sf9, Colon26, HL60, and Vero, were also measured because ficifolidione has a phloroglucinol-derived moiety, a motif that is often present in the structure of cytotoxic chemicals. Compound 1 exhibited IC50 values of ca. 32, 9, 3, and 12 µM for Sf9, Colon26, HL60, and Vero cells, respectively, indicating that ficifolidione possesses selective cytotoxicity against the four cell lines. In HL60 cells treated with 1, DNA fragmentation and the activation of procaspase 3 were observed, suggesting that the cytotoxicity is induced by apoptosis.

Cytotoxic activity of butane type of 1,7-seco-2,7'-cyclolignanes and apoptosis induction by Caspase 9 and 3.

All stereoisomers of methoxybutane and fluorobutane type of 1,7-seco-2,7'-cyclolignane were synthesized and cytotoxic activities of these compounds were compared with those of all stereoisomers of butane and butanol type compounds. Both enantiomers of butane type secocyclolignane showed higher cytotoxic activity (IC50=16-20 µM) than methoxy type compounds, whereas none was observed for all the stereoisomers of butanol type secocyclolignane, however, (-)-Kadangustin J showed stereospecific cytotoxic activity (IC50=47-67 µM). Since (R)-9'-fluoro derivative 23 was most potent (IC50=19 µM) among the corresponding fluoro stereoisomers, (R)-9'-alkyl derivatives were synthesized, hydrophobic 9'-heptyl derivative 27 showing highest activity (IC50=3.7 µM against HL-60, IC50=3.1 µM against HeLa) in this experiment. Apoptosis induction caused by Caspase 3 and 9 for (R)-9'-heptyl derivative 27 was observed in the research on the mechanism. A degradation of DNA into small fragments was also shown by DNA ladder assay.

Syntheses of all the stereoisomers of butanol type 1,7-seco-2,7'-cyclolignane.

All the stereoisomers of butanol type 1,7-seco-2,7'-cyclolignane were stereoselectively synthesized by employing (S)- and (R)-Evans' auxiliaries to construct the stereochemistry. (+)- and (-)-Kadangustin J and their diastereomers were also prepared. The optical purity of the synthesized butanol type 1,7-seco-2,7'-cyclolignane was more than 99%ee.

Cytotoxic activity of dietary lignan and its derivatives: structure-cytotoxic activity relationship of dihydroguaiaretic acid.

Cytotoxic activities of synthesized lignan derivatives were estimated by WST-8 reduction assay against HL-60 and HeLa cells to show the structure-activity relationship. The activities of some effective compounds were examined against Colon 26 and Vero cells. Dietary secoisolariciresinol (SECO, 1) and its metabolite, 9,9'-anhydrosecoisolariciresinol (2), did not show the cytotoxic activity. On the other hand, all stereoisomers of dihydroguaiaretic acid (DGA, 9,9'-dehydroxysecoisolariciresinol, 3-5) exhibited the activity (IC50: around 30 µM). The IC50 value of (8R,8'R)-9-butyl DGA derivative 13 was around 6 µM. This fact means that the hydrophobic group was advantageous for higher activity at 9- and 9'-positions. By the evaluation of the effect of 7and 7'-aryl group on the activity, we discovered the highest activity of (8R,8'R)-7-(3-hydroxy-4-methoxyphenyl)-7'-(2-ethoxyphenyl) DGA derivative 47 showing around 1 µM of IC50 value, which is about 24-fold higher activity than that of natural (8R,8'R)-DGA. The derivative of dietary lignan showed the high cytotoxic activity.

Structure-cytotoxic activity relationship of sesquilignan, morinol A.

The cytotoxic activities of sesquilignans, (7S,8S,7'R,8'R)- and (7R,8R,7'S,8'S)-morinol A and (7S,8S,7'S,8'S)- and (7R,8R,7'R,8'R)-morinol B were compared, showing no significant difference between stereoisomers (IC50=24-35 µM). As a next stage, the effect of substituents at 7, 7', and 7"-aromatic ring on the activity was evaluated to find out the higher activity of (7S,8S,7'R,8'R)-7,7',7"-phenyl derivative 18 (IC50=6-7 µM). In the research on the structure-activity relationship of 7"-position of (7S,8S,7'R,8'R)-7,7',7"-phenyl derivative 18, the most potent compounds were 7,7',7"-phenyl derivative 18 (IC50=6 µM) against HeLa cells. Against HL-60 cells, 7"-(4-nitrophenyl)-7,7'-phenyl derivative 33 and 7"-hexyl-7,7'-phenyl derivative 37 (IC50=5 µM) showed highest activity. We discovered the compounds showed four to sevenfold potent activity than that of natural (7S,8S,7'R,8'R)-morinol A. It was also confirmed that the 7'-benzylic hydroxy group have an important role for exhibiting activity, on the other hand, the resonance system of cinnamyl structure is not crucial for the potent activity.

First discovery of insecticidal activity of 9,9'-epoxylignane and dihydroguaiaretic acid against houseflies and the structure-activity relationship.

The insecticidal activity of (-)-(8R,8'R)-3,3'-dimethoxy-9,9'-epoxylignane-4,4'-diol (1) against houseflies was clarified for the first time. The activities of other stereoisomers were weaker than that of the (8R,8'R)-stereoisomer. In the course of research into structure-activity relationships involving 30 newly synthesized (8R,8'R)-derivatives, 5-fold higher activity (ED50 = 0.91 nmol/fly) was observed for (-)-(8R,8'R)-3,3',4-trimethoxy-9,9'-epoxylignan-4'-ol (21) than for the naturally occurring compound (1). The activity of 1 was weaker than that of (-)-(8R,8'R)-dihydroguaiaretic acid ((-)-DGA) (4); however, compound 21 showed almost the same level of activity as 4.