Design, synthesis of novel furan appended benzothiazepine derivatives and in vitro biological evaluation as potent VRV-PL-8a and H+/K+ ATPase inhibitors.

A series of new of furan derivatised [1,4] benzothiazepine analogues were synthesized starting from 1-(furan-2-yl)ethanone. 1-(Furan-2-yl)ethanone was converted into chalcones by its reaction with various aromatic aldehydes, then were reacted with 2-aminobenzenethiol in acidic conditions to obtain the title compounds in good yields. The synthesized new compounds were characterized by 1H NMR, 13C NMR, Mass spectral studies and elemental analyses. All the new compounds were evaluated for their in vitro VRV-PL-8a and H+/K+ ATPase inhibitor properties. Preliminary studies revealed that, some molecules amongst the designed series showed promising VRV-PL-8a and H+/K+ ATPase inhibitor properties. Further, rigid body docking studies were performed to understand possible docking sites of the molecules on the target proteins and the mode of binding. This finding presents a promising series of lead molecules that can serve as prototypes for the treatment of inflammatory related disorder that can mitigate the ulcer inducing side effect shown by other NSAIDs.

Design, synthesis and docking studies of novel 4-aminophenol-1,2,4-oxadiazole hybrids as apoptosis inducers against triple negative breast cancer cells targeting MAP kinase.

In our study, a series of novel 4-aminophenol benzamide-1,2,4-oxadiazole hybrid analogues have been designed and synthesized by condensing 4-hydroxyphenyl arylamides (3a-c) and 5-chloromethyl-3-aryl-1,2,4-oxadiazoles (6a-d). The structure of the synthesised compounds was verified by various spectroscopic techniques (1H NMR, 13C NMR, IR and LC-MS). All the prepared compounds were subjected to in silico and in vitro antiproliferative study against TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that compound 7k significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC50 values of 22.31 µM and 26.27 µM, respectively. Compound 7k interacted with crucial active sites of MAPK and exhibited the highest docking score of -7.06 kcal/mol. Docking was validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Consequently, 7k forms stable H-Bonds and π-π stacking with amino acid residues along with π-cation. Our investigations reveal that the in vitro antiproliferative study of 7k was in good correlation with the in silico studies. Hence, 7k serves as a potential novel lead for the inhibition of TNBCs by downregulating MAPK P38.Communicated by Ramaswamy H. Sarma.

Novel 4-aminophenol benzamide-1,2,4 oxadiazole library of small molecules displayed potent antiproliferative activity.Compound 7k induces apoptosis significantly against triple-negative breast cancer cells.Compound 7k potentiates apoptosis by targeting MAPK P38 and altering mitochondrial membrane potential.Molecular docking and molecular dynamic simulations confirm the efficient binding of compound 7k with MAPK (Docking score of ­7.06 kcal/mol).

Design and synthesis of 4-aminophenol-1,3,4-oxadiazole derivative potentiates apoptosis by targeting MAP kinase in triple negative breast cancer cells.

Women below 40 years greatly suffer from triple negative breast cancers (TNBCs). Compared to other breast cancer cases, the poor prognosis and lower survival rate of TNBC patients make it an alarming task to save the human era from this dreadful disease. Therefore, identifying potential novel leads is urgently required to combat the TNBC. To discover a novel anticancer agent, we synthesized a series of novel 4-aminophenolbenzamide-1,3,4 oxadiazole hybrid analogues (7a-l). The structure of the compounds was confirmed by spectral methods (1H & 13C NMR, IR and MS). All the compounds were subjected to their in-silico and in-vitro antiproliferative studies against the TNBC cell lines MDA-MB-468 and MDA-MB-231. The investigations revealed that 7i has significantly promoted apoptosis against MDA-MB-468 and MDA-MB-231 cells with IC50 values of 16.89 and 19.43 µM, respectively. Molecular docking of 7i, with MAPK has exhibited the highest binding score of -7.10 kcal/mol by interacting with crucial amino acids present at the active sites. Molecular docking is further validated with molecular dynamic studies with simulation for 100 ns, depicting various stable interactions with MAPK. Compound 7i, forms stable H-bonds and π-π stacking with amino acid residues. Molecular dynamic simulation (MDS) reveals that hydrophobic and water bridges were very prominent for 7i to bind, with the amino acid residues in close proximity to the active site of p38 MAPK. The investigations show that the In-vitro antiproliferative study of 7i agreed with the in-silico studies. Collectively, our investigations depict 7i as a potent novel lead for the inhibition of TNBCs by targeting p38 MAPK.Communicated by Ramaswamy H. Sarma.

A novel 4-aminophenolbenzamide-1,3,4 oxadiazole library of small molecules displayed potent antiproliferative activity.Compound 7i induces apoptosis significantly against triple-negative breast cancer cells.Compound 7i potentiates apoptosis by targeting p38 MAPK and altering mitochondrial membrane potential.Molecular docking and molecular dynamic simulation (MDSs) confirm the efficient binding of compound 7i with MAPK (Docking score of −7.10 kcal/mol).

Design, synthesis, characterization, and antioxidant activity studies of novel thienyl-pyrazoles.

In a sustained search for novel and effective antioxidants, a potential therapeutic leads against renal, and neurological disorders. Amongst the heterocycles, pyrazole and their derivatives have been extensively studied for their biological potencies, particularly to a larger extent for their antioxidant properties. Although many of pyrazole derivatives displayed antioxidant activities, still there is a need of developing efficient protocol for their synthesis, involving ecofriendly conditions, molecules of greater antioxidant efficacy and lesser toxicity, etc. In this context, the current study presents an amberlyst-15 catalysed efficient synthesis of 2-pyrazoline derivatives, 5(a-g) via (3 + 2) annulation of chalcones with phenylhydrazines. Structure proofs of new pyrazoles offered by spectral studies, and the molecular structure of compound 5d of the series by crystallographic studies, which revealed an intra molecular hydrogen bond interactions (C-H⋯N type), and stabilization by C-H...π and π---π molecular interactions. Of the series, compounds 5g and 5h show excellent DPPH (IC50 = 0.245 ± 0.01, and 0.284 ± 0.02 µM); and hydroxyl (IC50 = 0.905 ± 0.01, and 0.892 ± 0.01µM) radical scavenging activities comparable with respective controls, ascorbic acid (IC50 = 0.483 ± 0.01µM) and BHA (IC50 = 1.739 ± 0.01µM). The molecular docking and ADME/Tox studies indicate that, these compounds have good antioxidant activity through π-π stacking with Catalase via Try337 and Phe140, and therefore, might be lead antioxidants for further study.

Active-site directed peptide l-Phe-d-His-l-Leu inhibits angiotensin converting enzyme activity and dexamethasone-induced hypertension in rats.

Hypertension is the fundamental cause of cardiovascular and cerebrovascular disorders. Several natural and synthetic peptides are being used as antihypertensive agents, which target angiotensin converting enzyme (ACE), the master regulator of angiotensin (Ang) II production. In this study, we have evaluated ACE-inhibitory potential of the tripeptide l-Phenylalanyl-d-Histidyl-l-Leucine (l-Phe-d-His-l-Leu) in vitro and its antihypertensive effect in rat model of dexamethasone-induced hypertension. l-Phe-d-His-l-Leu was custom-designed by changing the configuration of penultimate amino acid residue (histidine) from C-terminal of Ang I, the site at which ACE acts upon and generates Ang II. l-Phe-d-His-l-Leu effectively inhibited ACE activity in a dose-dependent and competitive manner with an IC50 of 53.32 ± 0.13 nmol/L. Both fluorescence spectra and circular dichroism data revealed the direct interaction between l-Phe-d-His-l-Leu and ACE. In addition, molecular docking studies revealed the strong interaction of l-Phe-d-His-l-Leu with the critical active site amino acid residues of ACE. Further, the administration of l-Phe-d-His-l-Leu resulted in decrease in blood pressure (142 ± 3 mmHg) compared to dexamethasone alone group (167 ± 2 mmHg). Besides, l-Phe-d-His-l-Leu decreased the levels of circulating Ang II, and reduced fibrosis in heart and kidney, as evidenced by decreases in collagen deposition. Thus, the strategy of incorporation of d-amino acids in ACE-inhibitory peptides could be valuable in the development of antihypertensive drugs.