New triazole-based hybrids as neurotropic agents

Abstract

Herein, we describe the synthesis of new hybrids linked to 1,2,3- and 1,2,4-triazole units. Hybrids connected to a 1,2,3-triazole ring were synthesized using the well-known click reaction. The synthesis of the 1,2,4-triazole-based hybrids was carried out using 2-[(4-cyano-1-methyl(2-furyl)-5,6,7,8-tetrahydroisoquinolin-3-yl)oxy]acetohydrazides as starting compounds. The compounds were evaluated for their anticonvulsive activity via antagonism towards pentylenetetrazole (PTZ) - and thiosemicarbazide (TSC)-induced convulsion and maximal electroshock-induced seizure (MES). Furthermore, the most active compounds were studied for their locomotory and anxiolytic activity via the "open field" and elevated plus maze (EPM) assays. Finally, their antidepressant activity was studied via the "forced swim" method. All the hybrids displayed pentylenetetrazole antagonism, ranging from 40% to 80%, while in the TSC model, the most active compounds increased latency of thiosemicarbazide seizures to 1.9-4.65 times compared to that of the control. Some of the tested compounds exhibited a pronounced anxiolytic and antidepressant effect. Docking study demonstrated complete agreement with experimental pharmacological data. It was revealed that the most active compounds have a pyrano[3,4-c]pyridine ring in their structure.

Fig. 1. Alkaloids: gentianine I, gentianidine II and drugs bearing piperazine core III and IV.

Scheme 1. Synthesis of compounds 2a–g and 3a–g. (a) CICH₂COCI, C₆H₆, Et₃N, 35 °C, 6 h; (b) NaN₃, MeCOMe, reflux, 15 h. 1–3. a, b: X = CH₂, n = 0, R = H, a: R¹ = n-Pr; b: R¹ = i-Bu; c–e: X = CH₂, n = 1, R = H, c: R¹ = Me; d: R¹ = i-Pr; e: R¹ = 2-furyl; f, g: X = O, n = 1, R = Me, f: R¹ = Me; g: R¹ = Et.

Scheme 2. Synthesis of compounds 5a–i. 4, 5: a: X = CH₂, n = 0, R = H, R¹ = i-Pr; b: X = CH₂, n = 1, R = H: R¹ = Me; c: R¹ = Et; d: R¹ = i-Pr; e: R¹ = Ph; f: R¹ = 2-furyl; g: X = O, n = 1, R = Me: R¹ = i-Pr; h: R¹ = p-MeOC₆H₄; i: R¹ = 2-furyl.

Scheme 3. Synthesis of 1,4-disubstituted 1,2,3-triazoles 6a–q.

Scheme 4. Synthesis of compounds 9a–c. 7–9. a: X = CH₂, R = H, R¹ = Me; b: X = CH₂, R = H, R¹ = 2-furyl; c: X = O, R = Me, R¹ = 2-furyl.

Scheme 5. Synthesis of 3,5-disubstituted 1,2,4-triazoles 10a–g.

Chart 1. Graphical representation of the anticonvulsant activity and TI of hybrids 6a–c, e–j, l, and n–q. The ordinate axis shows the obtained data on PTZ activity and the therapeutic index values, and the abscissa axis shows the number of compounds.

Fig. 2. Structure–activity relationship for the anticonvulsant activity via antagonism towards pentylenetetrazole for compounds 6.

Chart 2. Graphical representation of the activity of compounds 6a–c, e–j, l, and n–q, ethosuximide and diazepam in the “open field” model. The ordinate axis shows the obtained data in the ‘’open field’’ model and the abscissa axis shows the number of compounds.

Chart 3. Graphical representation of the influence of compounds 6a–c, e–j, l, and n–q and compared drugs on the EPM model (5 min of research). The ordinate axis shows the obtained data on the EPM model and the abscissa axis shows the number of compounds.

Chart 4. Graphical representation of the effect of compounds 6a–c, e–j, l, and n–q and reference preparations on “forced swim” (study for 6 min). The ordinate axis shows the obtained data on “forced swim” and the abscissa axis shows the number of compounds.

Fig. 3. Alignment of the docked conformation of the re-docked initial inhibitor benzamidine (blue) and the co-crystalized ligand to the 4COF structure (RMSD: 0.34 Å).

Fig. 4. Docked conformation of diazepam and the GABA_A receptor complex.

Fig. 5. Docked pose of compound 6n and the GABA_A receptor complex. Red lines show hydrogen bonds and yellow spheres represent hydrophobic interactions.

Fig. 6. Alignment of the docked conformation of the re-docked initial inhibitor l-tryptophan (blue) and the co-crystallized 3F3A structure (magenta, RMSD: 0.86 Å).

Fig. 7. (A) Docked pose of compound 6q and the SERT complex. (B) 2D ligand interaction diagram for the docked ligand.

Fig. 8. Alignment of the docked conformation of the re-docked initial inhibitor alprenolol (blue) and the co-crystalized ligand (green) to the 3NYA structure (RMSD: 0.98 Å).

Fig. 9. (A) 2D ligand interaction diagram for docked compound 6q. (B) Docked pose of compound 6q (blue) and alprenolol (magenta) into the 5-HT_1A receptor.