2-Amino-5-(3-fluoro-4-methoxyphenyl)thiophene-3-carbonitrile have been synthesized from 1-(3-fluoro-4-methoxyphenyl)ethanone, malononitrile, a mild base and sulfur powder using Gewald synthesis technique and the intermediate was treated with 1,3-disubstituted pyrazole-4-carboxaldehyde to obtain the novel Schiff bases. 1,3-disubstituted pyrazole-4-carboxaldehyde derivatives have been synthesized by Vilsmeier-Haack reaction in the course of a multi-step reaction. The structure of novel compounds were established on the basis of their elemental analyses IR,
1
H NMR,
13
C NMR, and mass spectral data and then screened for their
in vitro
antimicrobial activity. Among them 5a, 5c, 5f and 5h showed excellent activity when compared to other derivatives. Remaining derivatives showed moderate activity.
Aim: To investigate a novel series of quinazoline monopeptide esters for the in vitro antibacterial activity. Methodology/results: The compounds were synthesized via one-pot Dimroth rearrangement of suitable formamidine intermediates with 3-aminobenzoic acid, followed by coupling the resulting acids with amino acid esters and screening for their antibacterial activity by broth dilution method. The compounds 5a, 5b, 5c, 5g, 5i and 5j showed promising activity against the Gram-positive bacteria, 5c and 5g being the most potent against Enterococcus faecalis and Staphylococcus aureus, respectively, with a minimal inhibitory concentration of 0.51 μM. The percentage hemolysis of the compounds ranged from 2.79 to 12.92 at a concentration of 100 μg/ml. The molecular docking studies revealed their GlmU inhibitory action. Conclusion: The compounds 5a and 5g emerged as antibacterial hits.
Abstract2‐amino‐5‐(3‐fluoro‐4‐methoxyphenyl)thiophene‐3‐carbonitrile derivatives have been synthesized from 1‐(3‐fluoro‐4‐methoxyphenyl)ethanone, malononitrile, mild base, and sulfur powder using the Gewald method through a multistep reaction sequence. The structures of newly synthesized compounds were established on the basis of their elemental analyses, IR, 1H NMR, 13C NMR, and mass spectral data, and then synthesized compounds were screened for their in vitro antimicrobial activity. Among them, derivatives 3b (thiphene), 3f (pyrazole), and 3d (halogen) showed good activity and remaining derivatives exhibited moderate activity.
Sirtuin's (Sirt's), are NAD þ-dependent, class-III lysine deacetylase, plays a central role in caloric dependent epigenetic modification. The modulation of sirtuin's activity is a promising approach in the recent scenario for the treatment of various aging related metabolic disorders like diabetes, neurodegeneration and cancer. Among all seven sirtuins, Sirt1, Sirt2 and Sirt3 are the most studied and are very close homolog belongs to the same sub-class. It was found that Sirt1, Sirt2 and Sirt3 not only localized in different cellular compartments but also behave differentially in various pathological conditions. Therefore, selective inhibition of Sirt1, Sirt2 or Sirt3 is a prime requirement for the development of new target-based therapies and also a potential instrument for illustrating their biological functions. However, the development of selective inhibitors for Sirt1, Sirt2 or Sirt3 appears difficult due to high sequence similarity and huge structural conservity of their catalytic pockets. Although, some selective inhibitors of Sirt2 are reported in recent past; But, most of them exhibit low micromolar to high nanomolar potency (IC 50 values), and are moderately Sirt1 selective, except for the inhibitor EX527. And, also the mechanism as to how some molecules gain selectivity for specific sirtuin isoform remains elusive to date. From the long-range molecular dynamics simulations, modeling and docking studies of apo-/holocomplexes of Sirt1, Sirt2 and Sirt3 we have identified a new selectivity pocket in Sirt1 and designed novel molecules that inhibit Sirt1 more selectively than the reported most selective inhibitor EX527. The designed potential molecules are validated by in-vitro assays for their cell viability and cell-based activity, which have shown positive results that align well with our in-silico extracts.
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