Design, synthesis and evaluation of semi- and thiosemicarbazides containing a methylxanthine moiety with in vitro neuroprotective and MAO-B inhibitory activities

Figures & data

Scheme 1. Synthesis of semi- and thiosemicarbazides of 7-theophylline acetic acid [4–13].

Table 1. ID, structures and yields of newly synthesized compounds.

Compound	Z	R	Reaction media	Reaction time, h	Yield, %
4	O	C6H5	DMF	7	97
5	S	CH3	DMF	12	79
6	O	4-Cl–C6H4	DMF	8	99
7	O	3-Cl–C6H4	DMF	8	96
8	O	cyclohehyl	DMF	8	83
9	S	4-Br–C6H4	DMF	15	95
10	S	C2H5	DMF	9	55
11	S	H	H2O/HCl	6	85
12	O	H	H2O/HCl	5	64
13	S	Cyclohehyl	DMF	4	79

Table 2. Yields of the isolated product of 2 under conditions of phase-transfer catalysis.

Reaction media	Phase-transfer catalyst	Reaction temperature, ^оС	Reaction time, h	Yield of 2,%
C6H5CH3	Aliquat 336	111	2	88
C6H5CH3	ТОАВ	111	2	85
C6H5CH3	18-Crown-6	111	2	62
C6H5CH3	Dibenzo-18-Crown-6	111	2	65
C6H6	Aliquat 336	80	2	82
C6H6	ТОАВ	80	2	80
C6H6	18-Crown-6	80	2	63
C6H6	Dibenzo-18-Crown-6	80	2	65
CH2Cl2	Aliquat 336	40	2	57
CH2Cl2	ТОАВ	40	2	55
CH2Cl2	18-Crown-6	40	2	7
CH2Cl2	Dibenzo-18-Crown-6	40	2	10

Figure 1. Effect of compounds 1, 3, 4 - 13 administered alone at a concentration of 100 µmol/L on synaptosomal viability. * р<0.05 compared to control (untreated synaptosomes).

Figure 2. Effect of compounds 1, 3, 4–13 administered alone at a concentration of 100 µM on GSH levels in isolated synaptosomes. **р<0.01 relative to control (untreated synaptosomes).

Figure 3. Effect of compounds 1, 3 and 4–13, applied alone at a concentration of 100 µM, on the production of MDA in isolated microsomes. **р<0.01 relative to control (untreated microsomes).

Figure 4. Effect of compounds 1, 3, 4–13 administered alone at a concentration of 100 µmol/L on GSH levels in isolated mitochondria. **р<0.01 compared to control (untreated mitochondria).

Figure 5. Effect of compounds 1, 3 and 4–13, applied alone at a concentration of 100 µmol/L, on the production of MDA in isolated mitochondria. **р<0.01 compared to control (untreated mitochondria).

Figure 6. Effect of compounds 1, 3, 4–13 (100 µmol/L), in a model of 6-OHDA-induced oxidative stress, on synaptosomal viability in isolated synaptosomes. ***p < 0.001 compared to control (untreated synaptosomes); ⁺⁺p < 0.01 compared to 6-OHDA.

Figure 7. Effect of compounds 1, 3, 4–13 (100 µmol/L), in a model of 6-OHDA-induced oxidative stress, on GSH levels in isolated synaptosomes. ***p < 0.001 compared to control (untreated synaptosomes); ⁺⁺p < 0.01 compared to 6-OHDA.

Figure 8. Influence of compounds 1, 3 and 4–13 (100 µmol/L), in a model of non-enzyme-induced lipid peroxidation, on the production of MDA in isolated brain microsomes. ***p < 0.001 compared to control (untreated microsomes); ⁺⁺p < 0.01 compared to Fe/AA.

Figure 9. Effect of compounds 1, 3 and 4–13 (100 µmol/L), in a model of t-BuOOH-induced oxidative stress, on MDA production in isolated brain mitochondria. ***p < 0.001 compared to control (untreated mitochondria); ⁺⁺p < 0.01 compared to t-BuOOH.

Figure 10. Influence of substances 1, 3 and 4–13 (100 µmol/L), in a model of t-BuOOH-induced oxidative stress, on the GSH level in isolated brain mitochondria. ***p < 0.001 compared to control (untreated mitochondria); ⁺⁺p < 0.01, compared to t-BuOOH.

Figure 11. Influence of a series of compounds 3, 4–13, theophylline [1] and selegiline, administered alone, on the activity of hMAOB. **p < 0.01;***p < 0.001 compared to the control (pure hMAOB).

Bosquesi PL, Melo TRF, Vizioli EO, dos Santos JL, Ching MC. Anti-inflammatory drug design using a molecular hybridization approach. Pharmaceuticals. 2011;4:1450–1474.

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Data Availability Statement

The data used to support the findings of this study are included within the article and Supplementary material.