Dipeptidyl peptidase IV inhibitors: a new paradigm in type 2 diabetes treatment

Dipeptidyl peptidase IV (DPP4) is a promising target for the treatment of chronic metabolic type 2 diabetes mellitus (T2D). DPP4 is a highly specific serine protease involved in the regulation and cleavage of two incretin hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These incretin hormones are released by the gastrointestinal tract in response to ingestion of food and stimulate insulin secretion and thereby regulate glucose homeostasis with a low risk of hypoglycemia and glucagon secretion. Currently different chemical classes of DPP4 inhibitors are in last-stage of clinical trials and few of them such as sitagliptin, vildagliptin, saxagliptin alogliptin and linagliptin have already been successfully released into market. These drugs have been approved as either monotherapy or combination therapy with other oral hypoglycemic agents such as metformin, pioglitazone, sulfonylurea, glyburide and glibenclamide for the treatment of T2D. Though several clinical trial compounds were discontinued because of severe adverse toxic effects that are associated with other prolyldipeptidases include DPP8 and DPP9. The current review provides an overview of DPP4 and its inhibitors with emphasis on the structure, expression, activity, selectivity and pharmacokinetics information. This review further dwells upon the issues relating to the rational design and development of selective DPP4 inhibitors for the treatment of T2D

Modeling the permeability of drug-like molecules through the cell wall of Mycobacterium tuberculosis: an analogue based approach

The emergence of drug resistant strains of Mycobacterium Tuberculosis (Mtb) accentuates the urgent need for the development of novel antitubercular drugs. The major causes of drug resistance are genetic mutations, the influx–efflux transporter system, and the complex cell wall system of Mtb, which can function as permeability barriers. The driving force for permeability of small molecules through a biological system depends on various physicochemical factors. To understand the permeability of small molecules and subsequent cell inhibition, we have developed predictive QSAR models based on reported enzyme-based (IC50) and cell-based (MIC) Mtb inhibitory data. The compounds that are highly active in enzyme-based assays and have significant variation in cell-based assays are assumed to possess the required permeability through the Mtb cell wall. The obtained models suggest the importance of molecular connectivity, lipophilicity (log P, size, shape), electrotopology (relative atomic mass, polarizability, electronegativity, ionization potential, atomic charges, van der Waals volume, hybridization, hydrogen bond acceptors/donors, number of fused rings) and functional groups (hydroxyl groups, primary and secondary amines) of a molecule in determining both its inhibitory potency and Mtb cell permeability. The models were validated with known Mtb inhibitors (9804) collected from the ChEMBL database, Mtb drugs (27) and clinical candidates (5). Further, these validated models were used to screen and prioritize a large database of compounds, including Zinc (152 128), Asinex (435 215), DrugBank (6531) and antimicrobial compounds (1324). The results obtained from 2D-QSAR analysis could improve our understanding towards Mtb cell permeability, which may aid in the rational design of novel potent molecules for tuberculosis (TB)

Pyrazole derivatives as potent inhibitors of c-Jun N-terminal kinase: synthesis and SAR studies

Mitogen activated protein kinases including c-Jun N-terminal kinase play an indispensable role in inflammatory diseases. Investigation of reported JNK-1 inhibitors indicated that diverse heterocyclic compounds bearing an amide group rendered potent JNK-1 inhibitory activity which prompted us to synthesize new JNK-1 inhibitors containing a pyrazole heterocyclic group. A DABCO mediated 1,3-dipolar cycloaddition reaction in neat resulted in pyrazole carboxylic acid which was converted to desired amides. Upon confirmation of the structures, all the compounds were screened for JNK-1 inhibitory activity and in vivo anti-inflammatory activity. Several synthesized analogues have exhibited JNK-1 inhibitory activity less than 10 μM, in particular compounds 9c, 10a and 10d were found to be potent among all the compounds

Design and synthesis of 3-(3-((9H-carbazol-4-yl)oxy)-2-hydroxypropyl)-2-phenylquinazolin-4(3H)-one derivatives to induce ACE inhibitory activity

In an attempt to develop a new class of cardiovascular drugs, a series of novel carbazolyloxy phenylquinazoline derivatives 9a–g have been synthesized and evaluated as angiotensin converting enzyme (ACE) inhibitors. Most of these compounds exhibited activity as significant ACE inhibitors and three compounds (9b, 9c & 9e) showed maximum inhibitory potency in enzyme based assays. To render support to the experimental results, a series of quinazolinone derivatives were docked into active site of ACE and identified the probable binding modes compared to Lisinopril. Also we have identified common pharmacophore hypothesis (AAADDRR) among the best docked conformers of most potent compounds in a series of compounds. The most potent 9b, 9c, 9e compounds shared common active site with the Lisinopril binding site and retained the key active site residue interactions. The obtained results from pharmacological and molecular modeling studies can be utilized for further optimization of identified hits for selective inhibition of ACE

Design, synthesis and biological activity evaluation of novel pefloxacin derivatives as potential antibacterial agents

A facile and efficient method for the synthesis of novel derivatives of pefloxacin hydrazone via condensation of various aldehydes and pefloxacin acid hydrazide using conventional as well as solvent-free microwave irradiation methods was reported. The biological activity of these compounds was screened using array of techniques and found to exhibit promising broad spectrum of antibacterial activity against Gram-positive and Gram-negative bacteria, moderate antimycobacterial activity against Mycobacterium smegmatis and moderate antifungal activity opposed to Aspergillus clavatus and Candida albicans. Cytotoxic assay of the title compounds was evaluated against human Pc-3 cancer cell lines, and interestingly, very good anticancer properties were shown by the compounds. To explore the binding mode of the compounds and understand the key active site residues with Staphylococcusaureus DNA gyrase, a molecular docking study has been performed. The results of the docking studies of the reported derivatives were quite promising and manifested strong non-bonded interactions with DNA Gyrase

Luotonin-a based quinazolinones cause apoptosis and senescence via HDAC inhibition and activation of tumor suppressor proteins in HeLa cells

A series of novel quinazolinone hybrids were synthesized by employing click chemistry and evaluated for anti-proliferative activities against MCF-7, HeLa and K562 cell lines. Among these cell lines, HeLa cells were found to respond effectively to these quinazolinone hybrids with IC<SUB>50</SUB> values ranging from 5.94 to 16.45 &#x03BC;M. Some of the hybrids (4q, 4r, 4e, 4k, 4t, 4w) with promising anti-cancer activity were further investigated for their effects on the cell cycle distribution. FACS analysis revealed the G1 cell cycle arrest nature of these hybrids. Further to assess the senescence inducing ability of these compounds, a senescence associated β-gal assay was performed. The senescence inducing nature of these compounds was supported by the effect of hybrid (4q) on p16 promoter activity, the marker for senescence. Moreover, cells treated with most effective compound (4q) show up-regulation of p53, p21 and down-regulation of HDAC-1, HDAC-2, HDAC-5 and EZH2 mRNA levels. Docking results suggest that, the triazole nitrogen showed Zn<SUP>+2</SUP> mediated interactions with the histidine residue of HDACs