Synthesis and Anti-Proliferative Activity of 5-Benzoyl and 5-Benzylhydroxy Derivatives of 3-Amino-2-Arylcarboxamido-Thieno[2-3-b]Pyridines.

3-Amino-2-arylcarboxamido-thieno[2-3-b]pyridines have been previously described as having potent anti-proliferative activity against MDA-MB-231 and HCT116 cancer cell lines. The mechanism by which these molecules prevent cancer cell growth is proposed to be through interfering with phospholipid metabolism via inhibition of PI-PLC, along with other cellular processes. Previously, 5-cinnamyl derivatives of these thieno[2-3-b]pyridines have been shown to have enhanced anti-proliferative activity compared to compounds lacking this moiety, indicating a tethered aromatic ring is important for this western region of the pharmacophore. Herein, we report the synthesis and biological evaluation of a library of 40 novel thieno[2-3-b]pyridine analogues containing shorter benzoyl or secondary benzyl alcohol tethers at the 5-position, in addition to various substituents on the two phenyl rings present on the molecule. Compounds bearing alcohol functionality had improved efficacy compared to their benzoyl counterparts, in addition to a 2-methyl-3-halogen substitution on the 2-arylcarboxamide ring being important for maximising anti-proliferative activity. The most potent molecules 7h and 7i demonstrated IC50 concentrations of 25-50 nM against HCT116 and MDA-MB-231 cells, a similar level of activity as previous thienopyridine compounds bearing cinnamyl moieties, suggesting that these novel derivatives with shorter tethers were able to maintain potent anti-proliferative activity, while allowing for a more concise synthesis.

Synthesis, characterization, antimicrobial, antioxidant and computational evaluation of N-acyl-morpholine-4-carbothioamides.

The present research paper reports the convenient synthesis, successful characterization, in vitro antibacterial, antifungal, antioxidant potency and biocompatibility of N-acyl-morpholine-4-carbothioamides (5a-5j). The biocompatible derivatives were found to be highly active against the tested bacterial and fungal strains. Moreover, some of the screened N-acyl-morpholine-4-carbothioamides exhibited excellent antioxidant potential. Docking simulation provided additional information about possibilities of their inhibitory potential against RNA. It has been predicted by in silico investigation of the binding pattern that compounds 5a and 5j can serve as the potential surrogate for design of novel and potent antibacterial agents. The results for the in vitro bioassays were promising with the identification of compounds 5a and 5j as the lead and selective candidate for RNA inhibition. Results of the docking computations further ascertained the inhibitory potential of compound 5a. Based on the in silico studies, it can be suggested that compounds 5a and 5j can serve as a structural model for the design of antibacterial agents with better inhibitory potential. Binding mode of compound 5j inside the active site of RNA in 3D space. 5j displayed highest antibacterial potential than the reference drug ampicillin with ZOI 10.50 mm against Staphylococcus aureus. 5j also displayed highest antifungal potential than the reference drug amphotericin B with ZOI 18.20 mm against Fusarium solani.

Synthesis, characterization, alkaline phosphatase inhibition assay and molecular modeling studies of 1-benzylidene-2-(4-tert- butylthiazol-2-yl) hydrazines.

Alkaline phosphatases are homodimeric protein enzymes which removes phosphates from several types of molecules. These catalyze the hydrolysis of monoesters in phosphoric acid which in turn catalyze a transphosphorylation reaction. Thiazoles are a privileged class of heterocyclic compounds which may potentially serve as effective phosphatase inhibitors. In this regard, the present research paper reports the facile synthesis and characterization of substituted 1-benzylidene-2-(4-tert-butylthiazol-2-yl) hydrazines with excellent yields. The synthesized compounds were tested for inhibitory potential against alkaline phosphatases. The compound 1-(4-Hydroxy, 3-methoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine (5e) was found to be the most potent inhibitor of human tissue non-alkaline phosphatase in this group of molecules with an IC50 value of 1.09 ± 0.18 µM. The compound 1-(3,4-dimethoxybenzylidene)-2-(4-tert-butylthiazol-2-yl) hydrazine (5d) exhibited selectivity and potency for human intestinal alkaline phosphatase with an IC50 value of 0.71 ± 0.02 µM. In addition, structure activity relationship and molecular docking studies were performed to evaluate their binding modes with the target site of alkaline phosphatase. The docking analysis revealed that the most active inhibitors showed the important interactions within the binding pockets of human intestinal alkaline phosphatase and human tissue non-alkaline phosphatase and may be responsible for the inhibitory activity of the compound towards the enzymes. Therefore, the screened thiazole derivatives provided an outstanding platform for further development of alkaline phosphatase inhibitors.

Synthesis, characterization, in vitro tissue-nonspecific alkaline phosphatase (TNAP) and intestinal alkaline phosphatase (IAP) inhibition studies and computational evaluation of novel thiazole derivatives.

Alkaline phosphatases (APs) are a class of homodimeric enzymes which physiologically possess the dephosphorylation ability. APs catalyzes the hydrolysis of monoesters into phosphoric acid which in turn catalyze a transphosphorylation reaction. Thiazoles are nitrogen and sulfur containing aromatic heterocycles considered as effective APs inhibitors. In this context, the current research paper presents the successful synthesis, spectroscopic characterization and in vitro alkaline phosphatase inhibitory potential of new thiazole derivatives. The structure activity relationship and molecular docking studies were performed to find out the binding modes of the screened compounds with the target site of tissue non-specific alkaline phosphatase (h-TNAP) as well as intestinal alkaline phosphatase (h-IAP). Compound 5e was found to be potent inhibitor of h-TNAP with IC50 value of 0.17 ± 0.01 µM. Additionally, compounds 5a and 5i were found to be highly selective toward h-TNAP with IC50 values of 0.25 ± 0.01 µM and 0.21 ± 0.02 µM, respectively. In case of h-IAP compound 5f was the most potent inhibitor with IC50 value of 1.33 ± 0.10 µM. The most active compounds were resort to molecular docking studies on h-TNAP and h-IAP to explore the possible binding interactions of enzyme-ligand complexes. Molecular dynamic simulations were carried out to investigate the overall stability of protein in apo and holo state.

Novel N-Acyl-1H-imidazole-1-carbothioamides: Design, Synthesis, Biological and Computational Studies.

The present study reports the convenient synthesis, spectroscopic characterization, bio-assays and computational evaluation of a novel series of N-acyl-1H-imidazole-1-carbothioamides. The screened derivatives displayed excellent antioxidant activity, moderate antibacterial and antifungal potential. The screened derivatives were found to be highly biocompatible against hRBCs. Molecular docking ascertained the mechanism and mode of action towards the molecular target delineating that ligands and complexes were stabilized at the active site by electrostatic and hydrophobic forces in accordance to the corresponding experimental results. Docking simulation provided additional information about the possibilities of inhibitory potential of the compounds against RNA. Computational evaluation predicted that N-acyl-1H-imidazole-1-carbothioamides 5c and 5g can serve as potential surrogates for hit to lead generation and design of novel antioxidant and antibacterial agents.

Synthesis, single crystal analysis, biological and docking evaluation of tetrazole derivatives.

Tetrazoles are conjugated nitrogen-rich heterocycles considered as bio-isosteres of carboxylic acids. Tetrazoles owing to their conjugated structures serve as biologically relevant potent scaffolds. The present research paper reports the successful synthesis and single crystal analysis of three different tetrazole derivatives (2, 4, 6). The synthesized tetrazole derivatives were evaluated for their possible cytotoxicity LD50 (52.89, 49.33, 17.28 µg/ml) and antileishmanial activities IC50 (0.166, 10, 5.0 µg/ml). Moreover, molecular docking studies were performed to determine the possible interaction sites of the tetrazole derivatives (2, 4, 6) with TryR, an enzyme involved in the redox metabolism of the Leishmania parasite. Docking computations demonstrates that the tetrazole derivatives (2, 4, 6) established prominent binding interactions with the key residues of the TryR and possess the potential to effectively inhibit the catalytic activities of the enzyme. The results suggested that the synthesized tetrazole derivative (2, 4, 6) can be possible hit candidates which can be tested further against amastigote stage of parasite and then in an animal model of leishmaniasis.