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.

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.

Synthesis of 4-hydroxy-3,4-dialkyl-2,6-diaryl-piperidine derivatives as potent antimicrobial agent.

A series of 4-hydroxy-3,4-dialkyl-2,6-diaryl-piperidine (7-12) have been synthesised by reduction of 3-alkyl-2,6-diarylpiperidin-4-one using the Grignard reagent. Structural assignments and conformational analysis of the compounds were established based on the spectral studies. All the piperdin-4-ol derivatives (7-12) were assayed for antibacterial, antifungal and anthelmintic activities and they exhibited significant results.

DFT and experimental prediction of negative chemical shifts of methyl protons in some piperidines.

The high resolution (1)H NMR spectra of four 3-ethyl-4-hydroxy-4-phenylpiperidines 1-4 have been recorded in CDCl(3), C(6)D(6), and (CD(3))(2)CO and analysed. These compounds exist in chair conformation with axial orientation of hydroxyl group at C(4) and equatorial orientation of the remaining substituents. The chemical shifts of methyl protons of ethyl group are quiet novel and surprising and are closer to TMS in CDCl(3) and somewhat higher in C(6)D(6). Changing the solvent from CDCl(3) to (CD(3))(2)CO alters the chemical shifts of these protons and they are very closer to TMS (0.01 ppm) in 3-4 and negative in 2 i.e., less than zero. The results are interpreted in terms of the magnetic anisotropic effect of the phenyl rings at C(2) and C(4) which in turn depends on the conformations of the ethyl group at C(3) and hydroxyl group at C(4). DFT studies were also performed to predict the favoured conformations of ethyl group at C(3) and hydroxyl group at C(4). Chemical shifts were also computed theoretically in the favoured conformation and they also support negative chemical shifts of 2 in acetone-d(6).

Piperidine-mediated synthesis of thiazolyl chalcones and their derivatives as potent antimicrobial agents.

A series of new thiazolyl chalcones, 1-[2-amino-4-methyl-1,3-thiazol-5-yl]-3-aryl-prop-2-en-1-one were prepared by piperidine mediated Claisen-Schmidt condensation of thiazolyl ketone with aromatic aldehyde. These chalcones on cyclisation gave 2-amino-6-(2-amino-4-methyl-1,3-thiazol-5-yl)-4-aryl-4H-pyridine-3-carbonitrile and 2-amino-6-(2-amino-4-methyl-1,3-thiazol-5-yl)-4-aryl-4H-pyran-3-carbonitrile. The result showed that the compounds exhibited marked potency as antimicrobial agents.

Unexpected shielding of methyl group protons in some piperidines.

High resolution 1H and 13C NMR spectra of four 3-ethyl-4-hydroxy- 4-phenylpiperidines 1-4 have been recorded in CDCl3 and analysed. The conformations of phenyl and hydroxyl groups at C(4) and ethyl group at C(3) were analysed in detail. The chemical shift of the methyl protons in the ethyl group are quite surprising; they are close to TMS in CDCl(3) and even negative in DMSO-d6. These results are interpreted in terms of the magnetic anisotropy of the phenyl rings at C(2) and C(4) which, in turn, depend on the conformations of the ethyl group at C(3) and the hydroxyl group at C(4). Favoured conformations of ethyl group at C(3) and hydroxyl group at C(4) were calculated by AM1 methods.