Design, synthesis, and antihypertensive activity of curcumin-inspired compounds via ACE inhibition and vasodilation, along with a bioavailability study for possible benefit in cardiovascular diseases

Figures & data

Figure 1 Dual mode of action to treat hypertension.

Figure 2 Synthesis of curcumin-inspired derivative.

Notes: Reagents and condition: (a) HCl (g), CH₃COOH; (b) acyl chlorides.

Table 1 ACE inhibitor effect of the designed inhibitors 4 (a–p)

Compound	R	Chain length	IC50 (μM)
4a	H	CH2	50.86
4b	H	CH2CH2	51.14
4c	H	CH2CH2CH2	64.42
4d	H	CH2CH2CH2CH2	78.45
4e	3,4-Dihydroxy	CH2	32.16
4f	3,4-Dihydroxy	CH2CH2	20.15
4g	3,4-Dihydroxy	CH2CH2CH2	41.27
4h	3,4-Dihydroxy	CH2CH2CH2CH2	48.61
4i	3,4,5-Trimethoxy	CH2	3.21
4j	3,4,5-Trimethoxy	CH2CH2	1.23
4k	3,4,5-Trimethoxy	CH2CH2CH2	4.45
4l	3,4,5-Trimethoxy	CH2CH2CH2CH2	6.65
4m	4-Nitro	CH2	95.11
4n	4-Nitro	CH2CH2	90.23
4o	4-Nitro	CH2CH2CH2	131.14
4p	4-Nitro	CH2CH2CH2CH2	120.32
Standard	Captopril		0.094

Abbreviations: ACE, angiotensin-converting enzyme; IC₅₀, half-maximal inhibitory concentrations.

Figure 3 SAR of target compound against ACE inhibition along with most promising inhibitor, 4j.

Abbreviations: ACE, angiotensin-converting enzyme; SAR, structure–activity relationship.

Figure 4 Docking study of compound 4j in the active site of human ACE.

Abbreviation: ACE, angiotensin-converting enzyme.

Figure 5 Effect of compounds on heart rate of experimental rat.

Abbreviation: SNP, sodium nitroprusside.

Figure 6 Effect of compounds on cardiac output in experimental rat.

Abbreviation: SNP, sodium nitroprusside.

Figure 7 Effect of tested compound on stroke volume in experimental rat.

Abbreviation: SNP, sodium nitroprusside.

Figure 8 Effect of tested compounds on NO donor activity.

Abbreviations: NO, nitric oxide; SNP, sodium nitroprusside.

Figure 9 Bioavailability of compound 4j and curcumin in experimental rats.