One of the most lethal and frequent infectious diseases worldwide is tuberculosis. Multi and extensively tuberculosis drug-resistant constitutes a serious problem and emphasizes the need for novel anti-tubercular agents. Accordingly, various pyrazine-2-carboxamides were synthesized and evaluated as potential anti-tuberculosis agents. The synthesis involved reaction of pyrazinoic acids with thionyl chloride to yield acyl chlorides which on treatment with various anilines gave various pyrazine-2-carboxamides. Based on structure-activity relationships extracted from previously published, this paper reported the synthesis and molecular docking study of 6-chloropyrazine-2-carboxamides. Synthesis involved reaction of 6-chloropyrazinoic acid with 2,4,6-trichlorobenzoyl chloride instead of thionyl chloride which listed under the Chemical Weapons Convention as it may use for the production of chemical weapons. Structure identification of 6-chloropyrazine-2-carboxamides was carried out by 1H NMR, 13C NMR, FTIR, and high-resolution mass spectroscopy. It is predicted that 6-chloro-N-octylpyrazine-2-carboxamide has better bioactivity against Mycobacterium tuberculosis, based on molecular docking study.
4-Methoxyphenethyl (E)-3-(o-tolyl)acrylate (1) was obtained in a good yield by the reaction of 2-methylcinnamic acid, 4-methoxyphenethyl alcohol, 2-methyl-6-nitrobenzoic anhydride, 4-dimethylaminopyridine, and triethylamine at room temperature for 40 min. The structure of 4-methoxyphenethyl (E)-3-(o-tolyl)acrylate (1) was established by FTIR, NMR, and the high resolution of mass spectroscopies. 4-Methoxyphenethyl (E)-3-(o-tolyl)acrylate (1) showed higher α-glucosidase inhibition activity than standard drug acarbose. The molecular docking study exhibited that the title compound 1 had a good affinity for α-glucosidase (PDB ID: 3W37) and formed some interactions with the α-glucosidase active site residue.
Suitably substituted cinnnamamides were successfully synthesized in 11-92% yield. Majority of the cinnnamamides displayed IC50 greater than acarbose. Their α-glucosidase inhibitory activity greatly depended on their structure with electron-withdrawing groups on the cinnamoyl aromatic ring causing increased inhibition activity. The synthesized cinnnamamides showed acceptable physicochemical and pharmacokinetics characteristics with little toxicity indicating their potential use as lead drug candidates. Molecular docking studies of these compounds were also conducted to elucidate their mechanism of action. Overall, these cinnnamamides show potential as lead structures for further optimization as α-glucosidase inhibitors.
The synthesized 3,3-di(indoloyl)indolin-2-ones 1a - p showed desired higher α-glucosidase inhibitory activities and lower α-amylase inhibitory activities than standard drug acarbose. Particularly, compound 1i showed favourable higher α-glucosidase % inhibition of 67±13 and lower α-amylase % inhibition of 51±4 in comparison to acarbose with % inhibition activities of 19±5 and 90±2, respectively. Docking studies of selected 3,3-di(indoloyl)indolin-2-ones revealed key interactions with the active sites of both α-glucosidase and α-amylase, further supporting the observed % inhibitory activities. Furthermore, the binding energies are consistent with the % inhibition values. The results suggest that 3,3-di(indoloyl)indolin-2-ones may be developed as suitable Alpha Glucosidase Inhibitors (AGIs) and the lower a-amylase activities should be advantageous to reduce the side effects exhibited by commercial AGIS.
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