Coumarin-Based Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Pre-ADME Analysis, Toxicity Profile, Computational Analysis, and In Vitro Enzyme Assay.

Recent research on dipeptidyl peptidase-IV (DPP-IV) inhibitors has made it feasible to treat type 2 diabetes mellitus (T2DM) with minimal side effects. Therefore, in the present investigation, we aimed to discover and develop some coumarin-based sulphonamides as potential DPP-IV inhibitors in light of the fact that molecular hybridization of many bioactive pharmacophores frequently results in synergistic activity. Each of the proposed derivatives was subjected to an in silico virtual screening, and those that met all of the criteria and had a higher binding affinity with the DPP-IV enzyme were then subjected to wet lab synthesis, followed by an in vitro biological evaluation. The results of the pre-ADME and pre-tox predictions indicated that compounds 6e, 6f, 6h, and 6m to 6q were inferior and violated the most drug-like criteria. It was observed that 6a, 6b, 6c, 6d, 6i, 6j, 6r, 6s, and 6t displayed less binding free energy (PDB ID: 5Y7H) than the reference inhibitor and demonstrated drug-likeness properties, hence being selected for wet lab synthesis and the structures being confirmed by spectral analysis. In the in vitro enzyme assay, the standard drug Sitagliptin had an IC50 of 0.018 µM in the experiment which is the most potent. All the tested compounds also displayed significant inhibition of the DPP-IV enzyme, but 6i and 6j demonstrated 10.98 and 10.14 µM IC50 values, respectively, i.e., the most potent among the synthesized compounds. Based on our findings, we concluded that coumarin-based sulphonamide derivatives have significant DPP-IV binding ability and exhibit optimal enzyme inhibition in an in vitro enzyme assay.

Virtual Screening, Synthesis, and Biological Evaluation of Some Carbohydrazide Derivatives as Potential DPP-IV Inhibitors.

Dipeptidyl peptidase-4 (DPP-IV) inhibitors are known as safe and well-tolerated antidiabetic medicine. Therefore, the aim of the present work was to synthesize some carbohydrazide derivatives (1a-5d) as DPP-IV inhibitors. In addition, this work involves simulations using molecular docking, ADMET analysis, and Lipinski and Veber's guidelines. Wet-lab synthesis was used to make derivatives that met all requirements, and then FTIR, NMR, and mass spectrometry were used to confirm the structures and perform biological assays. In this context, in vitro enzymatic and in vivo antidiabetic activity evaluations were carried out. None of the molecules had broken the majority of the drug-likeness rules. Furthermore, these molecules were put through additional screening using molecular docking. In molecular docking experiments (PDB ID: 2P8S), many molecules displayed more potent interactions than native ligands, exhibiting more hydrogen bonds, especially those with chloro- or fluoro substitutions. Our findings indicated that compounds 5b and 4c have IC50 values of 28.13 and 34.94 µM, respectively, under in vitro enzymatic assays. On the 21st day of administration to animals, compound 5b exhibited a significant reduction in serum blood glucose level (157.33 ± 5.75 mg/dL) compared with the diabetic control (Sitagliptin), which showed 280.00 ± 13.29 mg/dL. The antihyperglycemic activity showed that the synthesized compounds have good hypoglycemic potential in fasting blood glucose in the type 2 diabetes animal model (T2DM). Taken all together, our findings indicate that the synthesized compounds exhibit excellent hypoglycemic potential and could be used as leads in developing novel antidiabetic agents.

Synthesis and computational insights of flavone derivatives as potential estrogen receptor alpha (ER-α) antagonist.

Hormone-related breast cancer is mostly caused by interactions with estrogen receptor alpha (ER-α), which functions as a transcription factor to control the transcription of numerous genes. Flavones are considered a good substrate for the estrogen receptor. Substitution of the N-heterocyclic ring on the flavon structure may potentiate its anticancer effect. A series of flavon derivatives with an N-heteroaryl ring at the 4' position of the B ring of flavon were designed, prepared and evaluated for in vitro breast cancer activity. Binding interactions of the PzFL, PzF, PiFL, PiF and IFL compounds with ER-α were studied by molecular docking. Molecular dynamics simulation studies were carried out in order to determine the stability and convergence of protein-ligand complexes. The compounds were produced by cyclizing chalcones and chalcones were produced by Claisen-Schmidt condensation of substituted aldehydes and 2-hydroxy acetophenone. Breast cancer activity was evaluated by the MTT assay on MCF-7 cell lines. Also, compounds were studied for their estrogen receptor binding potential on the same cell lines. Molecular docking of compounds showed a good docking score. The molecular dynamics of these compounds expressed stable root mean square deviation, stable radius of gyration and low binding energy, suggesting that ligand bound to protein is quite stable in the complex. MTT assay on MCF-7 cell lines reported PzF and IFL were the most active compounds with lower IC50 values. ER-α binding assay of these compounds revealed the presence of binding interactions with receptors. This study offers a viable reference point for the design of flavon-incorporated N-heterocyclic ring derivatives as breast cancer compounds.Communicated by Ramaswamy H. Sarma.

Clinical correlates of regional gray matter volumes in schizophrenia: A structural magnetic resonance imaging study.

Objectives: The objective of this study is to investigate the correlation between the regional gray matter volumes and length of Para Cingulate Sulcus (PCS) with the clinical profile of patients with schizophrenia. Materials and Methods: In this hospital-based, cross-sectional study, thirty consecutive in-patients diagnosed with schizophrenia and equal number of healthy volunteers matched for age- and sex- were recruited as controls. Detailed clinical assessment and magnetic resonance imaging (MRI) of the brain were carried out within 2 days for controls and within 2 weeks of hospitalization for patients. The Positive and Negative Syndrome Scale and Montreal Cognitive Assessment were applied to schizophrenia patients to assess symptoms and cognitive function, respectively. Results: Schizophrenia patients had significant volume deficit in bilateral amygdalae, bilateral superior temporal gyri, anterior cingulate cortex and bilateral hippocampi, along with a highly significant reduction in the length of right PCS. Schizophrenia patients with the duration of untreated psychosis (DUP) of 6-12 months showed a significantly greater volume of the right superior temporal gyrus (STG). First-episode schizophrenia patients had a significant reduction in the length of the left PCS. The volume of bilateral superior temporal gyri in schizophrenia patients showed a significant direct correlation with positive symptoms and an inverse correlation with negative symptoms. Conclusion: Schizophrenia patients have significant volume deficit in some brain regions. DUP of 6-12 months is associated with significantly greater volume of the right STG. First-episode schizophrenia patients have a significant reduction in the length of the left PCS. In schizophrenia patients, the volume of bilateral superior temporal gyri showed a significant direct correlation with the positive symptoms and an inverse correlation with the negative symptoms.

Recognizing novel drugs against Keap1 in Alzheimer's disease using machine learning grounded computational studies.

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the world, affecting an estimated 50 million individuals. The nerve cells become impaired and die due to the formation of amyloid-beta (Aß) plaques and neurofibrillary tangles (NFTs). Dementia is one of the most common symptoms seen in people with AD. Genes, lifestyle, mitochondrial dysfunction, oxidative stress, obesity, infections, and head injuries are some of the factors that can contribute to the development and progression of AD. There are just a few FDA-approved treatments without side effects in the market, and their efficacy is restricted due to their narrow target in the etiology of AD. Therefore, our aim is to identify a safe and potent treatment for Alzheimer's disease. We chose the ursolic acid (UA) and its similar compounds as a compounds' library. And the ChEMBL database was adopted to obtain the active and inactive chemicals against Keap1. The best Quantitative structure-activity relationship (QSAR) model was created by evaluating standard machine learning techniques, and the best model has the lowest RMSE and greatest R2 (Random Forest Regressor). We chose pIC50 of 6.5 as threshold, where the top five potent medicines (DB06841, DB04310, DB11784, DB12730, and DB12677) with the highest predicted pIC50 (7.091184, 6.900866, 6.800155, 6.768965, and 6.756439) based on QSAR analysis. Furthermore, the top five medicines utilize as ligand molecules were docked in Keap1's binding region. The structural stability of the nominated medications was then evaluated using molecular dynamics simulations, RMSD, RMSF, Rg, and hydrogen bonding. All models are stable at 20 ns during simulation, with no major fluctuations observed. Finally, the top five medications are shown as prospective inhibitors of Keap1 and are the most promising to battle AD.

Weaved around COVID-19: Case series of coronavirus thematic delusions.

Stressful situations such as the COVID-19 pandemic can serve as a niche for developing pathological mental state or influence the symptomatology of patients with psychiatric disorders. Here, we present four such cases. Three cases highlight the onset of psychosis precipitated by the immense stress posed by the pandemic. In the last case, psychopathology of a patient with preexisting mental illness getting influenced by the pandemic is highlighted. In all the four cases, it is interesting to note that delusional work is weaved around the COVID-19.

Impact of COVID-19 pandemic on mental health of health-care workers in a tertiary care teaching and dedicated COVID-19 hospital.

AIM: We aimed to assess the consequences of dealing with patients during the COVID-19 pandemic lockdown period on the mental state of health-care workers. MATERIALS AND METHODS: An anonymous online survey was conducted with 353 participants using a self-made questionnaire comparing the prevalence of low mood, apprehension, tension, and coping skills used and the Depression, Anxiety, and Stress Scale-21. The data were analyzed to compare the mental health of male and female doctors. To identify predictors of mental health outcomes, a multivariate logistic regression was carried out. RESULTS: Both men and women were almost equally affected in terms of developing features of low mood, with easy physical and mental exhaustion. While the feeling of being isolated and irritability was slightly higher in females, both sexes were equally affected by the media. It was observed that the prevalence of smoking (tobacco/marijuana, etc.) had increased in both with slightly higher percentage in males as compared to females while there was a considerable increase in caffeine and alcohol consumption in males. The sleeping pattern and appetite were equally affected in both sexes. The sexual drive was also altered in both male and female residents, but the change was considerably more in males. The significant predictors of anxiety were age, depression, mental exhaustion, burden of increased quantity of work, and feeling of having no choice but to work due to obligation. CONCLUSION: Both male and female doctors working during the COVID-19 pandemic developed anxiety and depression. While substance use and altered sexual drive were more in males, exhaustion and stress were more in females.

Prevalence of smartphone addiction and its relation with sleep disturbance and low self- esteem among medical college students.

BACKGROUND: Use of smartphone is on the increase worldwide. They have revolutionized our lives to an extent that was unimaginable before the pandemic. Excessive use of smartphones reaching the levels of potential addiction among medical students and its relation to individual's sleep quality and self-esteem led us to study this prevalence. AIM: This stuay aimed to study the prevalence of smartphone addiction and its relation with self-esteem and sleep disturbance in medical college students. MATERIALS AND METHODS: A cross sectional analytical study was carried out and the prevalence of smartphone addiction, self- esteem, and sleep disturbance was measured using standardized questionnaires smartphone addiction scale short form, Rosenberg self esteem scale, Pittsburgh sleep quality index assessment respectively. RESULTS: Prevalence of smartphone addiction among medical college students was 52%. Smartphone addiction was seen more in boys than girls. There was a significant association between the smartphone addiction and sleep disturbance. However, there was no significant association between smartphone addiction and low self-esteem. CONCLUSION: The prevalence of smartphone addiction among medical students is found to be high and is associated with poor sleep.

Induced delusional disorder: A case series.

Phenomenon of induced delusional disorder has a relatively long, controversial history of conceptualization. It is a rare entity and goes undiagnosed mostly as only the primary partner is brought to clinical attention. We present a case series of induced delusional disorder with different presentations. For effective management, understanding the dynamics of relationship shared by the partners and addressing the biopsychosocial factors are crucial. Failure to adhere to treatment poses additional challenge in these cases.

Isatin Hybrids and Their Pharmacological Investigations.

Hybridization is an important strategy to design molecules that can be effectively used to treat fatal diseases known to mankind. Molecular hybrids and their pharmacological investigations aided in discovering several potent isatin (Indole 2, 3 dione) derivatives with anti-HIV, antimalarial, antitubercular, antibacterial, and anticancer activities. Indole-2,3-dione and their derivatives have diverse pharmacological properties and have a prominent role in the discovery of new drugs. To understand the various approaches for designing new molecules based on isatin nucleus analysis of various pharmacophore hybrids, spacers/linkers between pharmacophores and isatin for hybridization and their biological activities are important. This review discusses the progress in developing isatin hybrids as biologically effective agents and their crucial aspects of design and structure-activity relationships.

Exploring cyberchondria and its associations in dental students amid COVID-19 infodemic.

BACKGROUND: Adverse psychological effect of pandemic includes not only increased levels of stress, anxiety, and depression but also cyberchondria - the problematic online health research behavior. It is thought that the distress and uncertainty of pandemic clubbed with information overload and its ambiguity have paved the way for cyberchondria. Students being the vulnerable population, the present study was an effort at understanding cyberchondria in students. AIM: The aim of the study is to assess cyberchondria and its association with depression, anxiety, stress, and quality of life (QOL) in dental students during the pandemic. MATERIALS AND METHODS: An online questionnaire-based survey was carried out on dental students. The survey tool comprised a semi-structured pro forma, General Health Questionnaire-12, Depression Anxiety and Stress Scale 21, Cyberchondria Severity Scale 15, and European Health Interview Survey QOL 8. RESULTS: The study revealed that 98.7% of the students were affected by one of the constructs of cyberchondria, viz., "excessiveness" (93.7%), followed by "distress" (84.3%) and "reassurance"-seeking behavior (83.7%). Cyberchondria affected girls more than boys and shared robust positive correlation with depression, anxiety, and stress but not QOL. Factors such as stress, anxiety, QOL, and changes in appetite were associated with higher severity of depression. Family financial losses, preexisting psychiatric illness, and media adverse effect shared robust positive associations with severity of depression, anxiety, and stress and an inverse association with QOL. 76.0% of the students expressed excessive worries regarding missing out on clinical exposure, and nearly half of the students were dissatisfied with eLearning. 78.3% of the students experienced changes in sleep; 68.7% had changes in appetite; and 89.0% reported reduction in the level of physical activity. CONCLUSION: Cyberchondria is affecting the large majority of students. Educational institutions must put efforts to sensitize students about cyberchondria.

COVID-19 pandemic and its aftermath: Knowledge, attitude, behavior, and mental health-care needs of medical undergraduates.

BACKGROUND: The undeniable impact of the COVID-19 pandemic on the educational sector has left the students perplexed and uncertain. Infection-related fears, inevitable loneliness, disturbed routine making way for adverse lifestyle habits, stressors such as financial crisis faced by their families, and many more further accentuate their vulnerability to mental health issues. AIM: The aim was to assess the knowledge, attitude, and behavior of medical undergraduate students about the COVID-19 outbreak, and to assess their stress, anxiety, depression, and quality of life (QOL). The study also explored the correlation between the knowledge, attitude, and behavior of the medical undergraduate students about the pandemic and their mental health issues. MATERIALS AND METHODS: An online questionnaire-based survey was carried out on medical undergraduate students. The survey tool comprised a semi-structured proforma; General Health Questionnaire-12 items; Depression, Anxiety, and Stress scale-21 items; and European Health Interview Survey-Quality of Life-8 items. RESULTS: Nearly 61.8% of the students seemed well read and had good knowledge about the medical aspects of the pressing issue of COVID-19, and majority of the students had adaptive attitudes and behaviors toward the pandemic. Almost 23.2% of the students had depression, 20.7% had anxiety, and 13.0% had stress ranging from mild to extremely severe. Nearly 75.1% of the students experienced changes in appetite and 53.6% had changes in appetite. Nearly half of the students expressed excessive worries regarding studies. The mean score of QOL of students was 3.9 ± 0.6. Students with adaptive attitudes and behavior experienced relatively less severe depression, anxiety, and stress compared to their counterparts. CONCLUSION: A significant portion of the medical undergraduates are experiencing mental health issues and study related concerns due to the adversity brought by the pandemic. The concerned educational bodies and institutes must take up necessary steps to mitigate the adverse effects of the pandemic on students.

The association between diabetic retinopathy and periodontal disease.

PURPOSE: The purpose of the study was to study the association between diabetic retinopathy (DR) and periodontal disease (PD) in a South Indian cohort. METHODS: This was a cross-sectional, observational, interdisciplinary hospital-based study wherein patients with diabetes mellitus visiting the ophthalmology department of a university teaching hospital in coastal Karnataka, south India, during the study period, were screened independently for retinopathy by an ophthalmologist and PD by a periodontal surgeon. All the patients were above 18 years of age and did not have juvenile or gestational diabetes. A total of 213 patients consented to participate in the study. The data were analyzed for association using the Chi-square test. RESULTS: There was a statistically significant association between the presence of DR and PD (P = 0.02). The increasing severity of DR was associated with an increase in the components of PD including plaque index (P < 0.001) and gingival index (P < 0.001). CONCLUSION: There is a significant association between DR and PD. The awareness of this association can aid in the screening of potentially sight-threatening retinopathy in diabetics presenting to the dental clinic with PD.

Calcium activated neutral protease in blood cells from patients & carriers of Duchenne muscular dystrophy.

As blood cells such as platelets, lymphocytes and erythrocytes from patients with Duchenne muscular dystrophy show evidence of membrane alterations and elevation of intra-cellular calcium, one of the calcium related changes i.e., the activity of calcium activated neutral protease (CANP) was monitored and found to be elevated in erythrocytes, lymphocytes and platelets. As similar changes were observed in platelets of carriers of this disease, CANP in platelets may serve as a useful index for carrier detection.

Importance of monitoring calcium & calcium related properties in carrier detection for Duchenne muscular dystrophy.

Calcium and calcium dependent enzymes viz., calcium ATPase, protein kinase C and calcium activated neutral protease (milli CANP mCANP) were studied in the erythrocytes, platelets and lymphocytes of obligate carriers, in order to assess the usefulness of these indices for detection of carriers for Duchenne muscular dystrophy (DMD). With the exception of mCANP and lymphocyte calcium ATPase, other calcium dependent enzyme activities showed considerable overlap between carriers and control. Since the increase in the level of platelet mCANP was found in all affected boys (no false negatives) and obligate carriers, and patients with other myopathic conditions and some neurogenic causes did not show high platelet mCANP activity, this parameter could be considered as a good phenotypic index. Unlike SCK, the platelet mCANP of carriers did not overlap that of controls, hence tests are to be carried out to verify its usefulness as an index of carrier state in mutations other than DNA deletion since testing of non-deletion is both costly and has practical limitations.

Assessment of proarrhythmic activity of chloroquine in in vivo and ex vivo rabbit models.

OBJECTIVES: To evaluate the prolongation of ventricular repolarization and proarrhythmic activity of antimalarial drug chloroquine in two rabbit proarrhythmia models viz., in vivo α1 adrenoceptor-stimulated anesthetized rabbit and ex vivo isolated Langendorff rabbit heart using clofilium as standard proarrhythmic agent. MATERIALS AND METHODS: In the in vivo model, three groups of rabbits, anesthetized by pentobarbitone sodium and α-chloralose, sensitized with α1 agonist methoxamine followed by either continuous infusion of saline (control) or clofilium (3 mg/kg) or chloroquine (21 mg/kg) for 30 min. In ex vivo model, rabbit hearts were perfused with clofilium (10 µM) or chloroquine (300 µM) continuously after priming along with methoxamine, acetylcholine chloride and propranolol hydrochloride. RESULTS: In these models, prolongation of repolarization during α1-adrenoceptor stimulation produced early after depolarization (EAD) and Torsade de pointes (TdP). Saline infusion did not induce any abnormality in the animals. Clofilium caused expected changes in the electrocardiogram in both the models including TdP (50.0% in in vivo and 66.67% in ex vivo). Chloroquine caused decrease in heart rate and increase in the corrected QT (QTc) interval in both the models. Further, apart from different stages of arrhythmia, TdP was evident in 33.33% in ex vivo model, whereas no TdP was observed in in vivo model. CONCLUSIONS: The results indicated that proarrhythmic potential of chloroquine and clofilium was well evaluated in both the models; moreover, both the models can be used to assess the proarrhythmic potential of the new drug candidates.