Novel Aldimine‐Type Schiff Bases of 4‐Amino‐5‐[(3,4,5‐trimethoxyphenyl)methyl]‐1,2,4‐triazole‐3‐thione/thiol: Docking Study, Synthesis, Biological Evaluation, and Anti‐Tubulin Activity

Abstract

The present study was planned to design some novel aldimine-type Schiff bases bearing 3,4,5-trimethoxyphenyl and 1,2,4-triazole-3-thione/thiol as potential tubulin polymerization inhibitors. The obtained results of the molecular docking study using the tubulin complex (PDB code: 1SA0) showed that compounds H-25 and H-26 were well fitted in the colchicine binding site of tubulin with binding energies of -8.68 and -8.40 kcal/mol, respectively, in comparison to the main ligand (-8.20 kcal/mol). In parallel, molecular simulations were also performed on five other 3,4,5-trimethoxyphenyl-containing ligand targets including hsp90, VEGFR2, and human and microbial (Staphylococcus aureus and Candida albicans) dihydrofolate reductase, among which H-17, H-45, H-27, H-02, and H-19 were the most suitable compounds, respectively. Evaluation of the cytotoxic effect of the most efficient compounds of the docking steps (H-25) revealed IC50 values of 12.48 ± 1.10, 4.25 ± 0.22, 3.33 ± 0.31, and 9.71 ± 0.75 µM against the HT1080, HT29, MCF-7, and A549 cell lines, respectively, compared to doxorubicin (12.69 ± 1.23, 6.12 ± 0.47, 3.51 ± 0.32, and 6.40 ± 0.31 µM, respectively). The in vitro tubulin polymerization investigation launched compounds H-25 and H-26 as potent antitubulin agents due to their IC50 values of 0.17 ± 0.01 and 10.93 ± 0.43 µM, respectively.

Schiff Bases and Triazolothiadiazines Derived from A Thiophene-Substituted 4-Amino-3-Mercapto-1,2,4-Triazole

“…34 Reduction of triazolothiadiazines (9) and 10 (substituted)phenyl. 37,38 Reaction of azomethine (8) with phenacyl bromides in the presence of TEA led to the isolation of the desired dihydrotriazolothiadiazines (13) and (14) in excellent yields (Figure 2).…”

“…4,7 In addition, the proximity of the aforementioned reactive sites in 4-amino-1,2,4-triazole-3-thiones is inducive of ring closure reactions in which both amino and mercapto groups are involved. 2,8,9 Formation of Schiff bases through the condensation of 4-amino-1,2,4-triazole-3-thiones with aldehydes is one of the most investigated reaction of these substrates, a process that leads to biologically active compounds [10][11][12][13][14][15][16][17][18][19] and ligands for metal complexes, [20][21][22][23][24][25][26] to mention only two significant applications of these derivatives of 4-amino-1,2,4-triazole-3-thiones. On the other hand, the proximity of the reactive amino and mercapto groups in these triazole derivatives could be exploited in ring closure reactions leading to fused heterocycles.…”

Hybrid Pharmacophore Design, Molecular Docking, Synthesis, and Biological Evaluation of Novel Aldimine‐Type Schiff Base Derivatives as Tubulin Polymerization Inhibitor

“…A series of selected aldimine‐type Schiff base derivatives obtained from docking studies were synthesized following the reaction outlined in Scheme 1 . The both methods (A) and B) in Scheme 1 ) were modified for the synthesis of compound 2 but method B) (fusion method) was applied for synthesis of recent compound because of the higher reaction yield (the yields of methods A) and B) were 24% and 43%, respectively). The crude product was recrystallized from methanol to give compound 2 as precursor for aldimine‐type Schiff base derivatives.…”

“…Solvent Free (fusion) Method (B). [31] General Procedure for the Synthesis of Thiocarbazide (7). A solution of hydrazine hydrate 80% (30 ml) was stirred at 0 -5°C for 10 min and consequently, carbon disulfide (10 ml) was added dropwise over 30 min.…”

“…Compound 7 was purified by 4 times recrystallization from water and stored in the darkness (Scheme 1). [31] General Procedure for the Synthesis of 4-Amino-3-[(3,4,5-trimethoxyphenyl)methyl]-4,5-dihydro-1H-1,2,4triazole-5-thione (Tn), 4-Amino-5-[(3,4,5-trimethoxyphenyl)methyl]-4H-1,2,4-triazole-3-thiol (Tl; 2). An equimolar mixture of compounds 3 (2.262 g, 10 mmol) and 7 (1.062 g, 10 mmol) was firstly heated and stirred on an oil bath at 130 -140°C for 5.5 h and then at 160 -170°C for 20 min.…”