Gopal L. Khatik

Reversal of selectivity in acetate aldol reactions of N-acetyl-(S)-4-isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one.

Synergistic effects of the exo- and endocyclic chiral centers of an imidazolidinone-based auxiliary were investigated in the perspective of acetate aldol reactions. The reversal in diastereoselectivity was accomplished by lithium and titanium enolate reactions, which proceed through proposed open and closed transitions states, respectively. The aldol adducts were used in the stereoselective synthesis of fluoxetine.

Highly Efficient One-Pot Synthesis of 2-Aminobenzoxazoles Using Triflic Acid as a Cyclodesulfurizing Reagent

Abstract An efficient one-pot synthetic strategy for 2-aminobenzoxazoles was developed from isothiocyanates and 2-aminophenol using triflic acid as a cyclodesulfurizing reagent.

p53-Mdm2 interaction inhibitors as novel nongenotoxic anticancer agents

BACKGROUND Cancer is a major global health problem with high mortality rate. Most of the clinically used anticancer agents induce apoptosis through genotoxic stress at various stages of cell cycle and activation of p53. Acting as a tumor suppressor, p53 plays a vital role in preventing tumor development. Tumor suppressor function of p53 is effectively antagonized by its direct interaction with murine double minute 2 (Mdm2) proteins via multiple mechanisms. Thus, p53-Mdm2 interaction has been found to be an important target for the development of novel anticancer agents. Currently, nutlin, spirooxindole, isoquilinone and piperidinone analogues inhibiting p53-Mdm2 interaction are found to be promising in the treatment of cancer. OBJECTIVE The current review focused to scrutinize the structural aspects of p53-Mdm2 interaction inhibitors. METHODS The present study provides a detailed collection of published information on different classes of inhibitors of p53-Mdm2 interaction as potential anticancer agents. The review highlighted the structural aspects of various reported p53-Mdm2 inhibitors for optimization. RESULTS In the last few years, different classes of inhibitors of p53-Mdm2 have been designed and developed, and seven such compounds are being evaluated in clinical trials as new anticancer drugs. Further, to explore the role of p53 protein as a potential target for anticancer drug development, in this review, the mechanism of Mdm2 mediated inactivation of p53 and recent developments on p53- Mdm2 interactions inhibitors are discussed. CONCLUSION Agents designed to block the p53-Mdm2 interaction may have a therapeutic potential for the treatment of a subset of human cancers retaining wild-type p53. We review herein the recent advances in the design and development of potent small molecules as p53-Mdm2 inhibitors.

Design and synthesis of optically pure 3-aryl-6-methyl-2-thioxotetrahydropyrimidin-4(1H)-ones as anti-prostate cancer agents

3-Aryl-6-methyl-2-thioxotetrahydropyrimidin-4(1H)-ones were proposed as a new class of anti-prostate cancer agents on the basis of molecular modeling studies. Stereoselective synthesis of 3-aryl-6-methyl-2-thioxotetrahydropyrimidin-4(1H)-one derivatives was achieved by chiral induction employing (R)/(S)-α-methyl benzylamine and subsequent debenzylation with HBr in AcOH afforded the desired enantiomers in good yields. The compounds were screened in vitro against prostate cancer cell lines, PC-3 and LNCaP and the most potent derivatives were identified.

Advancements in Non-steroidal Antiandrogens as Potential Therapeutic Agents for the Treatment of Prostate Cancer.

Prostate cancer (PCa) is a leading cause of death in men worldwide. The main reason for the progression of prostate cancer is identified as over activation of androgen receptor (AR) through androgens. Its development can be diagnosed by monitoring the prostate specific antigen (PSA). Treatment of PCa includes prostatectomy, radiotherapy, and chemotherapy, among them chemotherapy is normally employed in early and advanced prostate cancer. Chemotherapy mainly includes two classes of drugs which are steroidal and non-steroidal antiandrogens. The non-steroidal classes of compounds are preferred over steroidal because they are relatively safe, cost effective and diverse. Non-steroidal drugs are commonly used for the treatment of PCa, however these drugs are associated with serious side effects and acquired resistance. So researchers are working in the direction to develop better analogue which can address the issue related to resistant type of prostate cancer. This review discusses the advancement in the non-steroidal antiandrogens which offers a better potential in the treatment of prostate cancer.

Design, and facile synthesis of 1,3 diaryl-3-(arylamino)propan-1-one derivatives as the potential alpha-amylase inhibitors and antioxidants

Diabetes is the most prevalent metabolic disorder causing a high rate of mortality and morbidity. Recently alpha-amylase is reported to be good drug design target for the treatment of diabetes mellitus. We have designed 116 molecules based on aza-Michael adduct of trans-chalcone as 1,3 diaryl-3-(arylamino)propan-1-ones which were studied by molecular docking and among them best six derivatives were synthesized easily via aza-Michael addition on trans-chalcone using KOH as a catalyst and evaluated for alpha-amylase inhibition along with antioxidant activity. It was observed that all compounds have alpha-amylase inhibitory activity but at different extents. The molecule 3e is the most potent alpha-amylase inhibitor of this series. 3a is the second most potent compound, whereas only one molecule 3d has shown antioxidant activity.

Synthesis and pharmacological evaluation of pyridinyl-1,3,4-oxadiazolyl-ethanone derivatives as antimicrobial, antifungal and antitubercular agents

Nicotinic acid was converted into different substituted acetylated nicotinic acid derivatives by sequential transformation involving formation of hydrazide, Schiff’s base and finally acylated oxadiazole derivatives. The synthesized compounds were characterized by spectroscopic techniques and evaluated in vitro for the antimicrobial, antifungal, as well as antitubercular activity. Among all the synthesized derivatives, compounds 6b, 6d, 6e, 6g, and 6j demonstrated excellent antimicrobial activity on Bacillus subtilis. The compounds 6d, 6j and compounds 6b, 6f, 6h, and 6i exhibited maximum zone of inhibition against fungi Candida albicans as well as Aspergillus niger, respectively at the concentration of 500 µg/mL. The antitubercular activity exhibited by 6f, 6g, and 6d with minimum inhibitory concentration (MIC) values of 1.2, 3.1, and 7.8 µg/mL, respectively. The synthesized compounds were studied by molecular docking through Autodock Vina to evaluate their interaction at respective proteins. Further the effect of synthesized derivatives on surface morphology of human erythrocytes as well as hemolysis was also evaluated. The results demonstrated lesser extent of hemolytic toxicity.Graphical abstract

Current Strategies and Drug Targets in the Management of Type 2 Diabetes Mellitus

BACKGROUND Diabetes is one of the major concerns worldwide which leads to increased level of blood glucose due to deficiency of insulin and the development of insulin resistance in diabetic individuals. Basically, its impact arises due to rapid urbanization, improper diet intake, and increasingly inactive lifestyle. Diabetic patients develop serious complications with the development of disease at later stages, such as obesity, the risk of stroke and heart failure. Globally, an estimated 422 million adults are living with type 2 diabetes mellitus. METHODS We searched the scientific database using relevant keywords. Among the searched literature, only peer-reviewed papers were collected which addresses our questions. The retrieved quality papers were screened and analyzed critically. The key findings of these studies are included along with the importance. RESULTS The quality research paper included in the review, particularly the antidiabetic drugs which account for the second largest market by sales in the pharmaceutical industry after cancer. So the research came up with several novel therapeutic targets for the management of type 2 diabetes, to produce newer generation antidiabetic drug by offering a new concept for developing new drug candidates. CONCLUSION This review discusses the strategies and future perspectives in the management of type 2 diabetes mellitus particularly antidiabetic agents which are helpful for the betterment of diabetic patients.

A Retrospect Study on Thiazole Derivatives as the Potential Antidiabetic Agents in Drug Discovery and Developments

BACKGROUND Heterocycles containing thiazole, a moiety with sulfur and nitrogen is a core structure which is found in a number of biologically active compounds. The thiazole ring is notable as a component of the certain natural products, such as vitamin B1 (thiamine) and penicillins. Thiazole is also known as wonder nucleus and has uses in different biological fields. A number of new compounds contain heterocycle thiazole moieties, thus it is one of the important areas of research. METHODS We searched the scientific database using relevant keywords. Among the searched literature only peer-reviewed papers were collected which addresses our questions. The retrieved quality research articles were screened and analyzed critically. The key findings of these studies were included along with their importance. RESULTS The quality research articles included in this review were selected for the lifethreatening diseases i.e. diabetes, which is one of the serious issues all over the globe with an estimated worldwide prevalence in 2016 of 422 million people, which is expected to rise double to by 2030. Since 1995, there has been an explosion of the introduction of new classes of pharmacological agents having thiazole moieties. However, most of the drugs can cause noncompliance, hypoglycemia, and obesity. Thus, new antidiabetic drugs with thiazole moieties came up with improved compliance and reduced side effects such as pioglitazone (Actos), rosiglitazone (Avandia), netoglitazone, DRF-2189, PHT46, PMT13, DRF-2519. With such a great importance, research in thiazole is part of many academic and industrial laboratories worldwide. CONCLUSION The present review describes the importance of thiazole nucleus and its derivatives as antidiabetic agents with an emphasis on the past as well as recent developments.

In-silico Molecular Docking Study to Search New SGLT2 Inhibitor based on Dioxabicyclo[3.2.1] octane Scaffold

BACKGROUND Diabetes is a leading cause of high mortality rate in the world. Recently SGLT2 inhibitors showed the promising result to treat diabetes and therefore several molecules are approved by US FDA Objective: SGLT2 inhibitors were designed based on the dioxabicyclo[3.2.1] octane with the aim to search new lead molecule. METHODS The molecular structures were drawn in ChemBiodraw ultra and molecular docking study was performed by AutoDock Vina 1.5.6 software. The LogP and toxicity were predicted online using AlogP and Lazar in-silico respectively. RESULTS Among all the designed molecules, SK306 showed the maximum binding affinity against the 3dh4 SGLT2 protein of Vibrio parahaemolyticus. LogP values were also calculated in order to determine the lipophilic property of the best binding molecules which showing LogP 2.82-3.79 in the range for good absorption and elimination, also predicted to be non-toxic. CONCLUSION SGLT2 inhibitors were designed based on the dioxabicyclo [3.2.1] octane resulting to a new lead molecule with high binding affinity; also these molecules were predicted non-carcinogenic with low LogP.