Synthesis and biological evaluation of some N-(3-(1H-tetrazol-5-yl) phenyl)acetamide derivatives as novel non-carboxylic PTP1B inhibitors designed through bioisosteric modulation.

Described herein is the synthesis and biological evaluation of a series of non-carboxylic inhibitors of Protein Tyrosine Phosphatase 1B designed using bioisosteric replacement strategy. Six N-(3-(1H-tetrazol-5-yl)phenyl)acetamide derivatives designed employing the aforementioned strategy were synthesized and screened for PTP1B inhibitory activity. Among the synthesized compounds, compound NM-03 exhibited the most potent inhibitory activity with IC50 value of 4.48 µM. Docking studies with NM-03 revealed the key interactions with desired amino acids in the binding site of PTP1B. Furthermore, compound NM-03 also elicited good in vivo activity. Taken together, the results of this study establish N-(3-(1H-tetrazole-5-yl)phenyl)-2-(benzo[d]oxazol-2-ylthio)acetamide (NM-03) as a valuable lead molecule with great potential for PTP1B inhibitor development targeting diabetes.

A new approach for PEGylation of dendrimers.

Dendrimers have emerged as one of the most interesting themes for researchers as a result of unique functional architecture and macromolecular characteristics. The reported methods of PEGylation are very time consuming and required multisteps for synthesis. In present work we have synthesized PEGylated polyamidoamine (PAMAM) dendrimers using epichlorohydrin as a linker. The PEGylated dendrimers were evaluated for color reaction UV, IR and NMR studies and compared with standard data.

Novel 3-((2-chloroquinolin-3-yl)methylene)indolin-2-one derivatives produce anticancer efficacy in ovarian cancer in vitro.

A novel series of 3-((2-chloroquinolin-3-yl)methylene)indolin-2-ones were synthesized, using the 'molecular hybridization approach' and evaluated for anticancer efficacy. Eleven 3-((2-chloroquinolin-3-yl)methylene)indolin-2-ones (LM01 to LM11) were synthesized and evaluated for in vitro cytotoxic efficacy in cancer (ovarian, prostate and colon) and two non-cancerous cell lines. Among the 3-((2-chloroquinolin-3-yl)methylene)indolin-2-one derivatives, LM08, with a 6-Cl substitution in the 3-quinolinyl moiety, had selective and potent cytotoxic efficacy in the ovarian cancer cell line A2780. Further mechanistic investigations indicated that LM08 significantly inhibited the clonogenic survival of A2780 cancer cells, which was mediated by inducing apoptosis.

Synthesis, cytotoxic evaluation and in silico pharmacokinetic prediction of some benzo[a]phenazine-5-sulfonic acid derivatives.

Cancer is one of the life threatening diseases and the development of novel anticancer molecules is limited by many reasons. In the present investigation, some novel benzo[a]phenazine-5-sulfonic acid derivatives as DNA intercalator was designed with optimized pharmacokinetic features for cancer treatment. The compounds with desired pharmacokinetic profile were synthesized and structurally characterized. Cytotoxic activity study against HL-60 tumor cell lines shows that 10-dimethyl carboxamido derivative of benzo[a]phenazine-5-sulfonic acid is found to be the most active in the series with cytotoxic activity (IC(50) = 19 microM) comparable to cisplatin (IC(50) = 7 microM). The study concluded that the novel benzo[a]phenazine-5-sulfonic acid derivatives were found to have enhanced DNA binding affinity and exhibited significant activity in vitro against HL-60 cell lines. This work will also guide for further development of effective DNA intercalators for cancer treatment.

QSAR analysis of some 5-amino-2-mercapto-1,3,4-thiadiazole based inhibitors of matrix metalloproteinases and bacterial collagenase.

A quantitative structure-activity relationship (QSAR) study has been performed on 5-amino-2-mercapto-1,3,4-thiadiazole based inhibitors of matrix metalloproteinases (MMPs) and a bacterial collagenase known as Clostridium histolyticum collagenase (ChC) to understand the structural features influencing the affinity of these inhibitors towards the enzyme. The compounds in the selected series were characterized by topological and fragmental descriptors calculated using QuaSAR module of molecular operating environment (MOE). An indicator variable was also assigned to account for the presence of amide function in vicinity of sulfonamide group in the parent structure. Correlations between different inhibitory activities and calculated predictor variables were established through stepwise multiple regression employing the method of least squares. The results of the study indicates that MMP inhibitory activity of 5-amino-2-mercapto-1,3,4-thiadiazoles can be successfully explained in terms of topology of the molecule. The obtained correlations also suggest that increase in the number of fluorine atoms in the aromatic ring will augment inhibitory activity of these molecules against all the MMPs probably by virtue of hydrogen bond interaction with some complementary groups in the active site of the enzymes. One prime requirement for better inhibition of MMPs (except for MMP-1) and ChC identified from the present study is the presence of amide function in vicinity of sulfonamide group in the parent structure as suggested by the presence of indicator variable in almost all correlations. While MMP-1 and ChC inhibitory activity of the compounds studied is shown to be dependent on Kier's first order carbon valence molecular connectivity index indicating that increase in branching and presence of heteroatoms in the molecule will improve the MMP-1 and ChC inhibitory potency of 5-amino-2-mercapto-1,3,4-thiadiazoles, correlations derived for other enzymes (MMP-2, MMP-8, MMP-9) are quite similar. In addition to the number of fluorine atoms and presence of indicator variable, MMP-2, MMP-8 and MMP-9 inhibitory activity of 5-amino-2-mercapto-1,3,4-thiadiazoles is found to be dependent on Kier's alpha modified index of third order in such a way that infer, terminally branched functions will increase the affinity of these molecules to the MMPs.