Synthesis of benzothiazole-appended bis-triazole-based structural isomers with promising antifungal activity against Rhizoctonia solani

Abstract

In order to explore new antifungal agrochemicals, we reported the synthesis of two series 5a-f, 6 and 7a-f, 8 of benzothiazole-appended bis-triazole derivative-based structural isomers using a molecular hybridization approach. The synthesized compounds were tested for fungal growth inhibition against the plant pathogen Rhizoctonia solani. All the synthesized compounds showed excellent antifungal activity in their minimum concentrations (10-0.62 μM). Among all the synthetics, compounds 5b (ED₅₀: 2.33 μM), 5f (ED₅₀: 0.96 μM), and 7f (ED₅₀: 1.48 μM) exerted a superior inhibitory effect in comparison to the commercially available fungicide, hexaconazole (ED₅₀: 2.44 μM). The binding interactions of the active compounds 5f, 7f, 6, and 8 within the active site of the sterol 14α-demethylase enzyme were studied with the help of molecular docking studies. The studies revealed that these hybrid pharmacophores could be used as an important intermediate to demonstrate new structural isomer-based fungicides.

Fig. 1. Structures of some antifungal drugs (I–VII).

Fig. 2. Design protocol of the target compounds.

Scheme 1. Synthesis of bis-propargylated 2-aminobenzothiazoles.

Scheme 2. A possible mechanism for the synthesis of compounds 1 and 2.

Scheme 3. Synthesis of benzothiazole-appended bis-triazole derivatives 5a–e and 6.

Scheme 4. Synthesis of benzothiazole-appended bis-triazole derivatives 7a–e and 8.

Scheme 5. Synthesis of benzothiazole-appended bis-triazole derivatives containing 3-pyrrolylisatin 5f and 7f from 5e and 7e, respectively.

Fig. 3. In vitro studies of the synthesized compounds at various concentrations using PDA culture media.

Fig. 4. Antifungal evaluation against plant pathogen Rhizoctonia solani using 5a–f, 6 and 7a–f, 8 from 10 μM to 0.62 μM.

Fig. 5. 2D and 3D images of the standard drug (hexaconazole) with target protein CYP51.

Fig. 6. 2D and 3D images of compound 5f with target protein CYP51.

Fig. 7. 2D and 3D images of compound 7f with target protein CYP51.

Fig. 8. 2D and 3D images of compound 6 with target protein CYP51.

Fig. 9. 2D and 3D images of compound 8 with target protein CYP51.