Synthesis, antimycobacterial screening, molecular docking, ADMET prediction and pharmacological evaluation on novel pyran-4-one bearing hydrazone, triazole and isoxazole moieties: Potential inhibitors of SARS CoV-2

Abstract

The respiratory infection tuberculosis is caused by the bacteria Mycobacterium tuberculosis and its unrelenting spread caused millions of deaths around the world. Hence, it is needed to explore potential and less toxic anti-tubercular drugs. In the present work, we report the synthesis and antitubercular activity of four different (hydrazones 7-12, O-ethynyl oximes 19-24, triazoles 25-30, and isoxazoles 31-36) hybrids. Among these hybrids 9, 10, 33, and 34, displayed high antitubercular activity at 3.12 g/mL with >90% of inhibitions. The hybrids also showed good docking energies between -6.8 and -7.8 kcal/mol. Further, most active molecules were assayed for their DNA gyrase reduction ability towards M. tuberculosis and E.coli DNA gyrase by the DNA supercoiling and ATPase gyrase assay methods. All four hybrids showed good IC50 values comparable to that of the reference drug. In addition, the targets were also predicted as a potential binder for papain-like protease (SARS CoV-2 PLpro) by molecular docking and a good interaction result was observed. Besides, all targets were predicted for their absorption, distribution, metabolism, and excretion - toxicity (ADMET) profile and found a significant amount of ADMET and bioavailability.

Keywords: Hydrazone; Isoxazole; Pre-ADMET; Pyranone; Triazole; Tuberculosis.

Graphical abstract

Fig. 1

Tetrahydropyran containing natural products as drug.

Fig. 2

Chemical structures of INH derivatives as drug.

Scheme 1

Synthesis of target hydrazone compounds (7–12).

Scheme 2

Synthesis of compounds (19–36).

Fig. 3

Activity profile of the most active compounds against M. tuberculosis in the Nutrient starvation method.

Fig. 4

Molecular docking of compound 9 with M. tuberculosis DNA gyrase active site.

Fig. 5

Hydrogen bond interaction with Try158 and hydrophobic interactions with NAD, Gly96, Phe97, Ala157, Met155, Pro156, Ile215 and Leu218 of compound 10.

Fig. 6

Target prediction of compounds.

Fig. 7

The binding mode of compound triazole with SARS-CoV2 (3mj5).

Fig. 8

ADME properties of compounds and standard drug by graphical representation (boiled-egg) (predict gastrointestinal absorption and brain penetration).