Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations.

Herein, we report a pair of regioselective - and alkylations of a versatile indazole, methyl 5-bromo-1-indazole-3-carboxylate () and the use of density functional theory (DFT) to evaluate their mechanisms. Over thirty - and -alkylated products were isolated in over 90% yield regardless of the conditions. DFT calculations suggest a chelation mechanism produces the -substituted products when cesium is present and other non-covalent interactions (NCIs) drive the -product formation.

Synthesis of novel azasugar-containing 2'β-C-Me 9-deaza nucleosides as potential anti-hepatitis C virus agents.

As a part of our ongoing discovery efforts exploring azasugar as agents for treating various unmet medical needs, we prepared analogs of azasugar as potential anti-hepatitis C virus (HCV) agents. Herein we describe the synthesis of novel 2'β-C-Me 9-deazanucleoside azasugar analogs.

Scaffold hopping via ring opening enables identification of acyclic compounds as new complement Factor D inhibitors.

The three complement pathways comprising the early phase of the complement system (the classical, lectin, and alternative pathways) act together with the innate and adaptive immune systems to protect against foreign entities and maintain tissue homeostasis. While these systems are normally under tight regulatory control, several diseases have been reported to correlate with uncontrolled activation and amplification of the alternative pathway, including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, C3 glomerulopathy, and age-related macular degeneration. Complement FactorD (CFD), a serine protease, is the rate-limiting enzyme for the activity of alternative pathway.

Discovery and optimization of orally bioavailable and potent plasma Kallikrein inhibitors bearing a quaternary carbon.

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50,000 individuals worldwide. Berotralstat (BCX7353) is the only small molecule approved by the US Food and Drug Administration (FDA) for the prophylactic treatment of HAE attacks in patients 12 years and older. During the discovery of BCX7353, we also identified a novel series of small molecules containing a quaternary carbon as potent and orally bioavailable Plasma Kallikrein (PKal) inhibitors.

Berotralstat (BCX7353): Structure-Guided Design of a Potent, Selective, and Oral Plasma Kallikrein Inhibitor to Prevent Attacks of Hereditary Angioedema (HAE).

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50 000 individuals worldwide. Until recently, prophylactic HAE treatment options were limited to injectables, a burdensome administration route that has driven the need for an oral treatment. A substantial body of evidence has shown that potent and selective plasma kallikrein inhibitors that block the generation of bradykinin represent a promising approach for the treatment of HAE.

Impact of problematic internet use on the self-esteem of adolescents in the selected school, Kerala, India.

Background: Internet use is one of the essential tools of our present-day society whose impact is seen on adolescents such as increased use of the internet because they have free easy and daily access to the internet. Problematic internet use has become a global phenomenon that causes serious problem to the affected individual leading to impairment in psychological well-being.

Aim: The present study aims to assess the level of problematic internet use and self-esteem among adolescents in selected schools, Kochi, Kerala, India.

Effectiveness of a Nurse-Led Intervention for Adolescents With Problematic Internet Use.

The current study assessed the effect of an intervention on problematic internet use (PIU), biopsychosocial functioning, and academic performance in 100 adolescents with PIU in grades 9 and 11 in Ernakulam District, Kerala, India. Students from four comparable schools were randomly assigned to experimental and wait-list control groups after being screened for PIU. The experimental group participated in a 10-week intervention and parents of these adolescents were provided with two sessions.

Outcomes of early versus delayed cholecystectomy in patients with mild to moderate acute biliary pancreatitis: A randomized prospective study.

Background: In patients with acute biliary pancreatitis (ABP), cholecystectomy is mandatory to prevent further biliary events, but the precise timing of cholecystectomy for mild to moderate disease remain a subject of ongoing debate. The aim of this study is to assess the outcomes of early versus delayed cholecystectomy. We hypothesize that early cholecystectomy as compared to delayed cholecystectomy reduces recurrent biliary events without a higher peri-operative complication rate.

A rare case modafinil dependence.

Modafinil, a non-amphetamine psychostimulant, is indicated for narcolepsy, shift work sleep disorder and severe obstructive sleep apnea syndrome. Modafinil is prescribed at the dose of 100 mg once in a day or as two doses, 12 h apart in a day. It has also been found that it reduces cocaine dependence and withdrawal phenomenon.

ADad 4: the symptomatology and clinical presentation of Anxiety Disorders among adolescents in a rural community population in India.

Objectives: Anxiety Disorders (AD) in children and adolescents present with unique clinical features and exhibit phenotypic diversity. The symptom presentation varies with regard to age of onset, developmental factors and gender. This study documents the clinical presentation of AD among adolescents in India, and explores the symptom clusters among the different age groups as well as gender.

ADad 3: the epidemiology of Anxiety Disorders among adolescents in a rural community population in India.

Objectives: Despite being the most common mental health concern, there is paucity of literature on the epidemiology of anxiety disorders among the adolescent population in India. This study aimed to estimate the period prevalence of Anxiety Disorders (AD) among 11 to 19 y old adolescents in India.

Methods: A representative sample of adolescents (N = 500) from a rural community in Southern India was assessed for the period prevalence of all and specific Anxiety Disorders using Screen for Child Anxiety Related Emotional Disorders (SCARED), and confirmed in a subsequent interview with Schedule for Affective Disorders and Schizophrenia for School-Age Children/Present and Lifetime Version (K-SADS-PL).

Neuroendocrine tumor in choledochal cyst--case report and review of literature.

The report presents a rare case of carcinoid tumor in a 17 year female who presented with epigastric pain of one week duration. She was diagnosed to have type I choledochal cyst on abdominal ultrasound and MRI. She underwent total excision of choledochal cyst with roux-en-Y hepaticojejunostomy.

Design, parallel synthesis, and crystal structures of biphenyl antithrombotics as selective inhibitors of tissue factor FVIIa complex. Part 1: Exploration of S2 pocket pharmacophores.

Factor VIIa (FVIIa), a serine protease enzyme, coupled with tissue factor (TF) plays an important role in a number of thrombosis-related disorders. Inhibition of TF x FVIIa occurs early in the coagulation cascade and might provide some safety advantages over other related enzymes. We report here a novel series of substituted biphenyl derivatives that are highly potent and selective TF x FVIIa inhibitors.

Crystal structure of vaccinia virus uracil-DNA glycosylase reveals dimeric assembly.

Background: Uracil-DNA glycosylases (UDGs) catalyze excision of uracil from DNA. Vaccinia virus, which is the prototype of poxviruses, encodes a UDG (vvUDG) that is significantly different from the UDGs of other organisms in primary, secondary and tertiary structure and characteristic motifs. It adopted a novel catalysis-independent role in DNA replication that involves interaction with a viral protein, A20, to form the processivity factor.

Probing the S2 site of factor VIIa to generate potent and selective inhibitors: the structure of BCX-3607 in complex with tissue factor-factor VIIa.

Factor VIIa (FVIIa) is a trypsin-like serine protease in the coagulation cascade. Its complex with tissue factor (TF) triggers the extrinsic pathway of the coagulation cascade, generating a blood clot. Research programs at several centers now recognize the important roles played by TF and FVIIa in both the thrombotic and inflammatory processes associated with cardiovascular diseases.

Mechanisms of Arg-Pro-Pro-Gly-Phe inhibition of thrombin.

Investigations determined the mechanism(s) by which Arg-Pro-Pro-Gly-Phe (RPPGF) inhibits thrombin-induced platelet activation. High concentrations of RPPGF inhibit thrombin-induced coagulant activity. RPPGF binds to the active site of thrombin by forming a parallel beta-strand with Ser214-Gly216 and interacts with His57, Asp189, and Ser195 of the catalytic triad.