Novel hybrids of quinoline with pyrazolylchalcones as potential antimalarial agents: Synthesis, biological evaluation, molecular docking and ADME prediction.

A novel series of pyrazolyl chalcones containing quinoline scaffold, 5 a-v has been synthesized by Claisen Schimdt condensation of aromatic acetophenone with 1-(4-methylquinolin-2-yl)-3-aryl-1H-pyrazole-4-carbaldehyde in quantitative yield. The compounds were characterized using IR, NMR, MS and elemental analysis. An E-configuration about CC ethylenic bond was determined using 1H NMR spectroscopy. These compounds exhibited significant antimalarial potential against CQ-sensitive and CQ-resistant strain of Plasmodium falciparum. Structure activity relationship has also been established based on outcomes of in vitro schizont inhibition assay. Compound 5u, (Z)-3-(1-(4-methylquinolin-2-yl)-3-p-tolyl-1H-pyrazol-4-yl)-1-p-tolylprop-2-en-1-one, was found to be the most potent among the series of synthetic analogues. In vivo, it demonstrated significant parasitemia suppression of 78.01% at a dose of 200 mg/kg against P. berghei in infected mice without any mortality in 7 days. In silico molecular docking study revealed that this compound 5u bound to the active site of cysteine protease falcipain-2 enzyme. Furthermore, in silico ADME studies, were also performed and physicochemical qualifications of the title compounds were determined. The biological outcomes of newer heterocyclic compounds may pave the new paths for researchers in development of potential antimalarial agents.

Pancreatic lipase inhibitors: The road voyaged and successes.

Human pancreatic lipase (triacylglycerol acyl hydrolase EC3.1.1.3) is the most widely studied member of the human lipase superfamily related to carboxyl esterase. It is secreted from the acinar cell of pancreas and has strong preference for triacylglycerides over cholesterol esters, phospholipids, and galactolipids. Apart from the hydrolysis of triacylglycerides, pancreatic lipase may cause the hydrolysis of retinyl esters in vivo. So, it is very much evidenced that pancreatic lipase with its cofactor colipase has prominent role in efficient digestion of dietary fat. Hence, the modulation of human pancreatic lipase may represent a new insight in the discovery of a number of therapeutics that can inhibit the absorption of fat in body and can be used in obesity and other related metabolic disorders. Even, the only Food and drug administration (FDA) approved antiobesity drug, orlistat, is also an inhibitor of pancreatic lipase. This review summarizes studies about structure, mechanistic approach of pancreatic lipase enzyme while emphasizing on the various synthetic pancreatic lipase inhibitors with their structure activity relationship (SAR).

Use of Simplified Molecular Input Line Entry System and molecular graph based descriptors in prediction and design of pancreatic lipase inhibitors.

AIM: The inhibition of pancreatic lipase (PL) enzyme is the most explored strategy for the treatment of obesity. The present study describes the development of quantitative structure-activity relationship (QSAR) models for a diverse set of 293 PL inhibitors by means of the Monte Carlo optimization technique. Methodology & results: The hybrid optimal descriptors were used to build QSAR models with three subsets of three splits. The developed QSAR models were further validated with corresponding external sets. The best QSAR model has the following statistical particulars: R2 = 0.752, Q LOO 2 = 0 . 736 for the test set and R2 = 0.768, Q F 1 2 = 0 . 628 , Q F 2 2 = 0 . 621 for the validation set. CONCLUSION: The developed QSAR models were robust, stable and predictive and led to the design of novel PL inhibitors.

QSAR Differential Model for Prediction of SIRT1 Modulation using Monte Carlo Method.

Silent information regulator 2 homologue one (SIRT1) modulators have therapeutic potential for a number of diseases like cardiovascular, metabolic, inflammatory and age related disorders. Here, we have studied both activators and inhibitors of SIRT1 and constructed differential quantitative structure activity relationship (QSAR) models using CORAL software by Monte Carlo optimization method and SMILES notation. 3 splits divided into 3 subsets: sub-training, calibration and test sets, were examined and validated with a prediction set. All the described models were statistically significant models. The values of sensitivity, specificity, accuracy and Matthews' correlation coefficient for the validation set of best model were 1.0000, 0.8889, 0.9524 and 0.9058, respectively. In mechanistic interpretation, structural features important for SIRT1 activation and inhibition have been defined.

Use of the Monte Carlo Method for OECD Principles-Guided QSAR Modeling of SIRT1 Inhibitors.

SIRT1 inhibitors offer therapeutic potential for the treatment of a number of diseases including cancer and human immunodeficiency virus infection. A diverse series of 45 compounds with reported SIRT1 inhibitory activity has been employed for the development of quantitative structure-activity relationship (QSAR) models using the Monte Carlo optimization method. This method makes use of simplified molecular input line entry system notation of the molecular structure. The QSAR models were built up according to OECD principles. Three subsets of three splits were examined and validated by respective external sets. All the three described models have good statistical quality. The best model has the following statistical characteristics: R2 = 0.8350, Q2test = 0.7491 for the test set and R2 = 0.9655, Q2ext = 0.9261 for the validation set. In the mechanistic interpretation, structural attributes responsible for the endpoint increase and decrease are defined. Further, the design of some prospective SIRT1 inhibitors is also presented on the basis of these structural attributes.

How much successful are the medicinal chemists in modulation of SIRT1: A critical review.

Silent information regulator two homologue one (SIRT1) is the most widely studied member of the sirtuin family related to histone deacetylases class III super-family using nicotinamide adenine dinucleotide (NAD(+)) as its cofactor. It is located in the nucleus but also modulates the targets in cytoplasm and mainly acts as transacetylase rather than deacetylase. SIRT1 specifically cleaves the nicotinamide ribosyl bond of NAD(+) and transfers the acetyl group from proteins to their co-substrate through an ADP- ribose-peptidyl imidate intermediate. It has been indicated that SIRT1 and its histone as well as non histone targets are involved in a wide range of biological courses including metabolic diseases, age related diseases, viral infection, inflammation, tumor-cell growth and metastasis. Modulation of SIRT1 expression may present a new insight in the discovery of a number of therapeutics. This review summarizes studies about SIRT1 and mainly focuses on the various modulators of SIRT1 evolved by natural as well as synthetic means.

Ectopic tubal choriocarcinoma: a rarity.

Herein, we present a case of tubal choriocarcinoma which was diagnosed initially as chronic ectopic pregnancy. During laparotomy we noticed a haemorrhagic friable mass in the left flank, adherent to the bowel. Left-sided salpingoopherectomy was performed. Serum ß HCG (human chorionic gonadotropin) levels performed in the postoperative period were elevated. Histopathology demonstrated choriocarcinoma. She was given six cycles of chemotherapy (etoposide, methotrexate, actinomycin D-cyclophosphamide, vincristine/oncovine (EMA-CO) regime) and monitored by serial ß HCG estimation. This case highlights the importance of undertaking histopathological examination of the tubal tissue in every patient who presents with ectopic pregnancy. This important diagnostic test prevents the potential of missing this rare and highly malignant disease which is otherwise curable in most instances.

Molar pregnancy in postmenopausal women: a rare phenomenon.

Benign gestational trophoblastic disease generally occurs in women of the reproductive age group and is extremely rare in postmenopausal women. We describe a case of complete hydatidiform mole in a 60-year-old postmenopausal woman who was referred with diagnosis of suspected malignancy/myoma resulting in delay in management. This case highlights the fact that gestational trophoblastic disease can occur in menopausal woman and this should be included in the differential diagnosis of perimenopausal and postmenopausal haemorrhage to prevent delay in diagnosis and treatment.