Reaction Optimization of Strontium Perchlorate Catalyzed Novel Protocol for Stereoselective Synthesis of Dihydropyrimidinones.

BACKGROUND: Hydrated strontium perchlorate [Sr(ClO4)2.3H2O] acts as a very strong oxidizing and dehydrating agent. Until now, it could not be reported as a catalyst in dehydration mechanism-based organic synthetic reactions. Therefore, it is important to find whether it could be an effective catalyst for one-pot multicomponent reactions (MCRs). OBJECTIVE: The main objective of the present work is the development of a novel process for the synthesis of 1,4-dihydropyrimidinones through the one-pot multicomponent strategy using hydrated Sr(ClO4)2 as a catalyst. Furthermore, it includes process optimization, stereoselectivity, and spectroscopic characterization of the synthesized compounds. METHODS: Conventional and microwave-supported synthesis of 1,4-dihydropyrimidinones using 20 mol % of hydrated Sr(ClO4)2 catalyst via the one-pot solvent-free reaction was discovered as a new catalytic MCR methodology. The box-Behnken design approach and advanced analytical techniques were used for process optimization and reaction analysis. RESULTS: The results confirmed that hydrated Sr(ClO4)2; works as an efficient catalyst for one-pot multicomponent organic synthesis under both conventional and microwave heating. It is an effective catalyst for laboratory synthesis of 1,4-dihydropyrimidinones stereoselectively with moderate to excellent yield without any undesirable effect. Microwave heating provided the desired product within 1-4 minutes. Moreover, this method provides easy isolation of the pure products simply by recrystallization, and without the use of a chromatographic purification method. CONCLUSION: The simplicity and neutrality of reaction conditions, easy post-reaction workup, higher satisfactory to excellent yield, effectiveness, the diversity of substrates, etc. render the hydrated Sr(ClO4)2 catalyst-based protocol for the stereoselective synthesis of 1,4-dihydropyrimidinones as a highly efficient method. Furthermore, it has been found to be safe un-der laboratory reaction conditions and no undesirable issues have been faced during the process.

A Review on Anticancer Profile of Flavonoids: Sources, Chemistry, Mechanisms, Structure-activity Relationship and Anticancer Activity.

BACKGROUND: Epidemiological studies have suggested that a regular intake of flavonoids is beneficial for cellular homeostasis and in the prevention of the transformation of normal cells into cancerous cells. Because of their multiple biological targets, flavonoids have been studied and investigated as phytoconstituents with potential anticancer properties. Flavonoids interfere in the development of cancerous cells by inhibition of topoisomerases, protein kinases, angiogenesis, induction of apoptosis, cell cycle arrest, modulation of multidrug resistance, and improvement in anti-oxidative activities. The current review summarizes the anticancer properties of flavonoids along with the key structural features and their mechanisms. The present study provides a detailed analysis of anticancer activities with previously published data on different flavonoids. The review highlighted the structural aspects and mechanism of action of flavonoids with their potential target sites. Flavonoids induce anticancer activity by protein kinases inhibition, P-gp modulation, antiangiogenesis, topoisomerases inhibition, etc. Open ring C, the double bond between C2-C3, the oxo group at C4, and the position of ring B are crucial determinants for their anticancer activity. Flavonoids act by multiple mechanisms but further studies on target selectivity and specificity of flavonoids are necessary to establish them as anticancer therapeutics. The presence of a C2-C3 double bond and oxo group at C4 (also known as an enone moiety) or -OH in the neighbour of a double bond that can transform easily into an enone are common features present in flavonoids. Thus, it can be concluded that enone moiety or its precursor groups are mainly responsible for the anticancer activities of flavonoids via different mechanisms of action.

Alpha-amylase as molecular target for treatment of diabetes mellitus: A comprehensive review.

The alpha (α)-amylase is a calcium metalloenzyme that aids digestion by breaking down polysaccharide molecules into smaller ones such as glucose and maltose. In addition, the enzyme causes postprandial hyperglycaemia and blood glucose levels to rise. α-Amylase is a well-known therapeutic target for the treatment and maintenance of postprandial blood glucose elevations. Various enzymatic inhibitors, such as acarbose, miglitol and voglibose, have been found to be effective in targeting this enzyme, prompting researchers to express an interest in developing potent alpha-amylase inhibitor molecules. The review mainly focused on designing different derivatives of drug molecules such as benzofuran hydrazone, indole hydrazone, spiroindolone, benzotriazoles, 1,3-diaryl-3-(arylamino) propan-1-one, oxadiazole and flavonoids along with their target-receptor interactions, IC50 values and other biological activities.

Inhibition of S-protein RBD and hACE2 Interaction for Control of SARSCoV- 2 Infection (COVID-19).

BACKGROUND: COVID-19 has become a pandemic with higher morbidity and mortality rates after its start from Wuhan city of China. The infection by RNA virus, also known as SARS-CoV-2 or 2019-nCoV, from the beta class of coronaviruses, has been found to be responsible for COVID-19. Structural analysis and evidences have been indicated that interaction between a segment of receptor binding domain (RBD) from S protein of the virus and human angiotensin-converting enzyme 2 (hACE2) is essential for cellular entry of the virus. OBJECTIVE: The current review sheds light on structural aspects for the inhibition of RBD-hACE2 interaction mediated cellular entry of SARS-CoV-2. METHODS: The present study provides a critical review of recently published information on RBDhACE2 interaction and its inhibitors to control SARS-CoV-2 infection. The review highlighted the structural aspects of the interaction between RBD-hACE2 and involved amino acid residues. RESULTS: Recently, several studies are being conducted for the inhibition of the SARS-CoV-2 attachment and entry to the human cellular system. One of the important targets for viral invasion is its binding with cell surface receptor, hACE2, through RBD on S-protein. Mimicking of three residues on ACE2 (Lys31, Glu35 and Lys353 on B chain) provided a hot target directed strategy for the inhibition of early attachment of the virus to the cell. Early screening of peptidic or non-peptidic molecules for the inhibition of RBD-hACE2 interaction has raised the hope for potential therapeutics against COVID-19. The higher affinity of molecules toward RBD than ACE2 is an important factor for selectivity and minimization of ACE2 related adverse events on the cardiovascular system, brain, kidney, and foetus development during pregnancy. CONCLUSION: Inhibition of RBD-hACE2 interaction by different molecular scaffolds can be used as a preferred strategy for control of SARS-CoV-2 infection. Recently, published reports pointed out Lys31, Glu35 and Lys353 on the B chain of ACE2 as crucial residues for mimicking and design of novel molecules as inhibitors SARS-CoV-2 attachment to human cells. Moreover, some recently identified RBD-hACE2 interaction inhibitors have also been described with their protein binding pattern and potencies (IC50 values), which will help for further improvement in the selectivity.

An Insight of Alpha-amylase Inhibitors as a Valuable Tool in the Management of Type 2 Diabetes Mellitus.

BACKGROUND: Among the millions of people around the world, the most prevalent metabolic disorder is diabetes mellitus. Due to the drawbacks which are associated with commercially available antidiabetic agents, new therapeutic approaches are needed to be considered. Alpha-amylase is a membrane- bound enzyme which is responsible for the breakdown of polysaccharides such as starch to monosaccharides which can be absorbed. METHODS: We searched the scientific database using alpha-amylase, diabetes, antidiabetic agents as the keywords. Here in, only peer-reviewed research articles were collected which were useful to our current work. RESULTS: To overcome the research gap, the alpha-amylase enzyme is regarded as a good target for antidiabetic agents to design the drug and provide an alternate approach for the treatment of type 2 diabetes mellitus. Basically, alpha-amylase inhibitors are classified into two groups: proteinaceous inhibitors, and non-proteinaceous inhibitors. Recently, non-proteinaceous inhibitors are being explored which includes chalcones, flavones, benzothiazoles, etc. as the potential antidiabetic agents. CONCLUSION: Herein, we discuss various potential antidiabetic agents which are strategically targeted alpha-amylase enzyme. These are having lesser side effects as compared to other antidiabetic agents, and are proposed to prevent the digestion and absorption of glucose leading to a decrease in the blood glucose level.

Recent advancements in mechanistic studies and structure activity relationship of FoF1 ATP synthase inhibitor as antimicrobial agent.

The emergence of drug resistance in infectious microbial strains can be overcome by development of novel drug molecules against unexploited microbial target. The success of Bedaquiline in recent years, as FoF1 ATP synthase inhibitor against XDR and MDR mycobacterium strains, has resulted in further exploration to identify more potent and safe drug molecules against resistant strains. FoF1 ATP synthase is the main energy production enzyme in almost all eukaryotes and prokaryotes. Development of bacterial ATP synthase inhibitors is a safe approach, without causing harm to mammalian cells due to structural difference between bacterial and mammalian ATP synthase target sites. This review emphasizes on providing the structural insights for FoF1 ATP synthase of different prokaryotes and will help in the design of new potent antimicrobial agents with better efficacy. Further, applications of synthetic and natural active antimicrobial ATP synthase inhibitors, reported by different research groups are summarized. Their SAR and mode of actions are also analysed.

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.

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.

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.

p53-Induced apoptosis and inhibitors of p53.

Protein p53 is a key player in mitochondrial mediated apoptotic cell death and excess p53 activity has been implicated in many disease states such athrosclerosis, diabetes, osteoarthritis, Alzheimer's disease, Parkinson's disease, Huntington's disease, AIDS, P. falciparum and S. typhimurium infections. Thus, chemical inhibitors of p53 activation might prove effective in suppressing diseases associated with excess p53 activity. Diverse chemical compounds are being synthesized and evaluated as potent inhibitors of p53 in many cell types. In this review, we have focused on the effects of apoptosis, which is involved in p53 protein and inhibition of p53 induced apoptosis. Peculiar features of p53 protein and its roles in various diseases are summarized along with important inhibitors developed in recent years.