Synthesis and Biological Activities of Some New Benzotriazinone Derivatives Based on Molecular Docking; Promising HepG2 Liver Carcinoma Inhibitors

Abstract

In one-pot strategy, diazotization of methyl anthranilate 5 followed by addition of amino acid ester hydrochloride, we have prepared methyl-2-(4-oxobenzotriazin-3(4H)-yl)alkanoates 6a-c. Starting with hydrazides 7a,b, N-alkyl-2-(4-oxobenzotriazin-3(4H)-yl)alkanamides 9-10(a-h) and methyl-2-(2-(4-oxobenzotriazin-3(4H)-yl)alkanamido)alkanoates 11-12(a-e) were prepared via azide coupling. Hydrazones 13-15 were prepared via condensation of hydrazides 7a,b with 4-methoxybenzaldehyde, 4-dimethylaminobenzaldehyde, and/or arabinose. Molecular docking was done for synthesized compounds using MOE 2008-10 software. The compounds 9a, 12a, 12c, 13a, 13b, and 14b have the most pronounced strong binding affinities toward the target E. coli Fab-H receptor, whereas compounds 3, 11e, 12e, and 13a have the most pronounced strong binding affinities toward the target vitamin D receptor. The in vitro antibacterial activities of the highest binding affinity docked compounds were tested against E. coli, Staphylococcus aureus, and Salmonella spp. Majority of the tested compounds showed effective positive results against E. coli, while they were almost inactive against Staphylococcus aureus and Salmonella spp . The in vitro cytotoxic activities of the highest binding affinity-docked compounds were tested against the human liver carcinoma cell line (HepG2). Some compounds showed potent cytotoxic activity with low IC₅₀ values, especially for 3 (6.525 μM) and 13a (10.97 μM) than that for standard drug doxorubicin (2.06 μM).

Figure 1

Some current commercial benzotriazinone anticancer drugs.

Scheme 1. Multistep Method for Preparation of Methyl 2-(4-Oxobenzotriazin-3(4H)-yl)acetate 6a

Scheme 2. Direct Preparation of Methyl 2-(4-Oxobenzotriazin-3(4H)-yl)alkanoates 6a–c and Corresponding Hydrazides 7a,b

Scheme 3. Azide Coupling Method for the Preparation of N-alkyl-2-(4-oxobenzotriazin-3(4H)-yl)alkanamides 9–10(a–h)

Scheme 4. Azide Coupling Method for the Preparation of Methyl 2-(2-(4-Oxobenzotriazin-3(4H)-yl)alkanamido)alkanoates (Dipeptides) 11–12(a–e)

Scheme 5. Condensation of 2-(4-Oxobenzotriazin-3(4H)-yl)alkanoic Acid Hydrazides 7a and 7b with Aldehydes

Scheme 6. Condensation of 3-(4-Oxo-4H-benzo[d][1,2,3]triazin-3-yl)-propionic Acid Hydrazide7b with Arabinose

Figure 2

Two-dimensional (2D) and three-dimensional (3D) interactions of compound 12a.

Figure 3

Two-dimensional (2D) and three-dimensional (3D) interactions of compound 12c.

Figure 4

Two-dimensional (2D) and three-dimensional (3D) interactions of compound 13b.

Figure 5

Two-dimensional (2D) and three-dimensional (3D) interactions of compound 3.

Figure 6

Two-dimensional (2D) and three-dimensional (3D) interactions of compound 11e.

Figure 7

Two-dimensional (2D) and three-dimensional (3D) interactions of compound 13a.