Discovery of pyrimidine-tethered benzothiazole derivatives as novel anti-tubercular agents towards multi- and extensively drug resistant Mycobacterium tuberculosis

Abstract

In this study, new benzothiazole-pyrimidine hybrids (5a-c, 6, 7a-f, and 8-15) were designed and synthesised. Two different functionalities on the pyrimidine moiety of lead compound 4 were subjected to a variety of chemical changes with the goal of creating various functionalities and cyclisation to further elucidate the target structures. The potency of the new molecules was tested against different tuberculosis (TB) strains. The results indicated that compounds 5c, 5b, 12, and 15 (MIC = 0.24-0.98 µg/mL) are highly active against the first-line drug-sensitive strain of Mycobacterium tuberculosis (ATCC 25177). Thereafter, the anti-tubercular activity was evaluated against the two drug-resistant TB strains; ATCC 35822 and RCMB 2674, where, many compounds exhibited good activity with MIC = 0.98-62.5 3 µg/mL and 3.9-62.5 µg/mL, respectively. Compounds 5c and 15 having the highest anti-tubercular efficiency towards sensitive strain, displayed the best activity for the resistant strains by showing the MIC = 0.98 and 1.95 µg/mL for MDR TB, and showing the MIC = 3.9 and 7.81 µg/mL for XDR TB, consecutively. Finally, molecular docking studies were performed for the two most active compounds 5c and 15 to explore their enzymatic inhibitory activities.

Keywords: Benzothiazole; DprE1; anti-mycobacterial activity; molecular docking; screening.

Figure 1.

Scaffolds of some reported benzothiazole with potent anti-mycobacterial activity (I–VI).

Figure 2.

Structures of some reported pyrimidine or thiouracil-based derivatives (VII, VIII, and IXa–b) as potent anti-mycobacterial agents.

Figure 3.

Examples of some benzothiazole derivatives (X and XIa–b) incorporating pyrimidine moiety as potent anti-mycobacterial agents.

Figure 4.

Design of the lead compound 4 and the target hybrids.

Scheme 1.

Synthesis of compounds 2–4; conditions and reagents: (a) dry benzene, anhydrous K₂CO₃, reflux for 12 h; (b) absolute ethyl alcohol, anhydrous K₂CO₃, reflux for 10–12 h; (c) dry acetone, anhydrous K₂CO₃, reflux for 8–10 h.

Scheme 2.

Synthesis of 5a–c and 6; conditions and reagents: (a) dry DMF, CH₃I/C₆H₅CH₂Cl/ClCH₂COOC₂H₅, anhydrous K₂CO₃, reflux for 12 h; (b) POCl₃, reflux for 3 h.

Scheme 3.

Synthesis of compounds 7a–f and 8–13; conditions and reagents: (a) absolute ethyl alcohol, primary or secondary amine, TEA, room temperature for 24 h, then the heating under reflux for 6–12 h; (b) hydrazine hydrate, abs. ethanol, reflux, 6 h; (c) thiourea, abs. ethanol, reflux, 6 h; (d) n-butanol, glycine, reflux for 3 h; (e) reflux for 2 h with acetic anhydride; (f) fusion with the anthranilic acid in the oil bath at 190 °C, for 2 h; (g) glacial acetic acid, sodium azide, reflux for 3 h.

Scheme 4.

Synthesis of 14 and 15; conditions and reagents: (a) glacial acetic acid and acetyl acetone, reflux for 6 h. (b) Reflux with the ethyl acetoacetate in NaOC₂H₅, for 4 h.

Figure 5.

2D and 3D interactions of compound 5c with the binding position of DprE1 enzyme.

Figure 6.

2D and 3D interactions of compound 15 with the binding position of DprE1 enzyme.

Figure 7.

The 2D and 3D interactions of compound 5c with the binding position of TMPKmt enzyme.

Figure 8.

The 2D and 3D interactions for the compound 15 with the binding position of TMPKmt enzyme.