Synthesis and antihepatotoxic activity of 2-(substituted-phenyl)-5-(2,3-dihydro-1,4-benzodioxane-2-yl)-1,3,4-oxadiazole derivatives

Figures & data

Table 1.  The chemical structures, melting points and percentage yields for the synthesised compounds in scheme 1.

Compound	R	Molecular Formula	mp (°C)	Yield (%)
3Ai	H	C16H12N2O3	160–62	76
3Aii	2-bromo	C16H11BrN2O3	175–77	68
3Aiii	3-bromo	C16H11BrN2O3	156–58	72
3Aiv	4-bromo	C16H11BrN2O3	135–37	75
3Av	2-chloro	C16H11ClN2O3	189–91	69
3Avi	3-chloro	C16H11ClN2O3	201–203	82
3Avii	4-chloro	C16H11ClN2O3	182–84	73
3Aviii	2,4–dichloro	C16H10Cl2N2O3	148–150	79
3Aix	2–methyl	C17H18N2O4	139–41	70
3Ax	3–methyl	C17H14N2O3	134–36	81
3Axi	4–methyl	C17H14N2O3	142–44	77
3Axii	4–hydroxy	C16H12N2O4	128–30	64
3Axiii	3,4–dihydroxy	C16H11N2O5	165–67	65
3Axiv	4– methoxy	C17H14N2O4	87–89	71
3Axv	3,4–dimethoxy	C18H16N2O5	141–43	74
3Axvi	4–amino	C16H13N3O3	55–57	67
3Axvii	Benzodioxino	C18H14N2O5	160–62	58

Scheme 1.  Reagents and conditions (a) K₂CO₃, acetone, reflux with stirring; (b) NH₂.NH₂.H₂0, ethanol, reflux; (c) POCl₃, stirring.

Table 2.  The effect of the synthesised compound on serum enzymatic activity in CCl₄ induced liver damage in rats.

Groups n=5	Treatment	Dose	SGOT (IU/L)	SGPT (IU/L)	ALP (KA units)	Albumin (g/dl)	Total protein (g/dl)
I	Normal control	–––	34.82 ± 0.697	45.6 ± 1.18	42.08 ± 3.57	3.67 ± 0.123	6.46 ± 0.53
II	Toxic control	1.5ml/kg (po)	74.52 ± 0.695	85.27 ± 2.05	66.157 ± 2.886**	2.41 ± 0.148	3.54 ± 0.57
III	Silymarin (standard drug)	10 mg/kg (po)	56.19 ± 0.808**	61.29 ± 1.78**	48.62 ± 3.385**	3.15 ± 0.181**	4.2 ± 0.23**
IV	Compd. 3Ai	10 mg/kg (po)	64.03 ± 0.995**	69.45 ± 2.35*	53.03 ± 2.462*	4.14 ± 0.125**	3.67 ± 0.37**
V	Compd. 3Avii	10 mg/kg (po)	62.84 ± 0.662**	68.5 ± 1.40**	37.57 ± 2.548**	4.76 ± 0.165**	4.14 ± 0.56*
VI	Compd. 3Axii	10 mg/kg (po)	62.57 ± 0.699**	62.35 ± 2.27***	54.42 ± 2.432**	4.59 ± 0.112*	3.43 ± 0.23**
VII	Compd. 3Axiv	10 mg/kg (po)	63.58 ± 9.061	65.87 ± 2.39	42.83 ± 2.046 **	4.69 ± 0.109**	3.87 ± 0.19**
VIII	Compd. 3Axvii	10 mg/kg (po)	65.87 ± 0.965**	63.15 ± 3.67	42.022 ± 4**	4.71 ± 0.378**	4.32 ± 1. 28

SGOT, Serum glutamate oxaloacetate transaminase; SGPT, Serum glutamate pyruvate transaminase; ALP, alkaline phosphatase: TP, total protein; p.o., per oral.

*** P<0.0001; ** P < 0.01; *P < 0.05 vs CCl₄; P > 0.05 ns.

Values are mean ± SEM (n = 5). ANOVA followed by dunnett’s test was performed.

Table 3.  Histopathological changes in the livers of the Wistar rats.

Groups N=5	Treatment	Microscopic observations
I	Normal control	Normal control liver samples showed normal architecture without any degeneration, necrosis, or inflammation.
II	Toxic control	Toxic control liver samples showed prominent centrilobular necrosis with prominent and enlarged central vein. There is significant periportal inflammation reflecting liver damage.
III	Silymarin (standard drug)	Standard control liver samples showed hepatocytes with uniformly staining cytoplasm and mild dilatation of sinusoidal spaces. The central vein was clearly visible. Liver samples also showed good recovery with the absence of necrosis.
IV	3Ai	Liver samples showed hepatocytes with few sinusoidal spaces and no portal triad inflammation.
V	3Avii	Liver histology of compound 3Avii was almost normal with only very little sinusoidal dilatation seen in some hepatic lobules. The portal vein appeared clearly with the disappearance of necrosis.Thus indicating a potent antihepatotoxic activity.
VI	3Axii	Liver hepatocytes were found almost normal with some sinusoidal dilatation. Portal vein appeared clearly with the disappearance of necrosis thus indicating a potent antihepatotoxic activity.
VII	3Axiv	Pretreatment with compound 3Axiv significantly prevented the CCl4-induced hepatotoxicity as revealed by the hepatic cells with well reserved cytoplasm, and marked decrease in inflammatory cells.
VIII	3Axvii	Some of the 1–2 hepatocyte rows around the central vein demonstrated hepatic cell degeneration, necrosis (loss of nucleus), less injury of endothelial cells around central vein and less fat vacuoles in hepatocytes.