Effectiveness of estrogen and its derivatives over dexamethasone in the treatment of COVID-19.

Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus and dexamethasone is a glucocorticoid widely used for its treatment. Dexamethasone is not used in non-severe cases due to its immunosuppressant action. So, considering this, Estrogen and Estetrol were tested for the treatment of COVID-19 as they all possess a common steroid ring and dislike dexamethasone, they are immunoenhancer. Virtual screening of test ligands was performed through molecular docking, MM-GBSA, simulations, in silico ADMET and drug-likeness prediction to identify their potential to inhibit the effects of SARS-CoV-2. Results showed that test ligands possess drug-like properties and they are safe as drug candidates. The protein-ligand interaction study revealed that they bind with the amino acid residues at the active site of the target proteins and the test ligands possess better binding potential than Dexamethasone. With protein Mpro, Estetrol and Estrogen showed docking score of -7.240 and -5.491 kcal/mol, and with protein ACE2, Estetrol and Estrogen showed docking score of -5.269 and -4.732 kcal/mol, respectively. Further, MD Simulation was carried out and most of the interactions of molecular docking are preserved during simulation. The prominent interactions that our test ligands showed during MD Simulation are similar to drugs that possess in vitro anticovid activity as shown in recent studies. Hence, our test ligands possessed potential for anticovid activity and they should be further tested through in vitro and in vivo studies for their activity against COVID-19.Communicated by Ramaswamy H. Sarma.

Synthesis, in-Silico studies and biological evaluation of pyrimidine based thiazolidinedione derivatives as potential anti-diabetic agent.

Despite the advancements in the management of Diabetes mellitus, the design and synthesis of drug molecule which ameliorates the hyperglycemia and associated secondary complications in diabetic patients, still remains a challenge. Herein, we report the synthesis, characterization and anti-diabetic evaluation of pyrimidine-thiazolidinedione derivatives. The synthesized compounds were characterized by 1H NMR, 13C NMR, FTIR and Mass Spectroscopic analytical techniques. The in-silico ADME studies depicted that the compounds were within the permissible limits of the Lipinski's rule of five. The compounds 6e and 6m showing the best results in OGTT were evaluated for in-vivo anti-diabetic evaluation in STZ induced diabetic rats. Administration of 6e and 6m for four weeks decreased the blood glucose levels significantly. Compound 6e (4.5 mg/kg p.o.) was the most potent compound of the series. It reduced the level of blood glucose to 145.2 ± 1.35 compared to the standard Pioglitazone (150.2 ± 1.06). Moreover, the 6e and 6m treated group did not show increase in bodyweight. The biochemical estimations showed that the levels of ALT, ASP, ALP, urea, creatinine, blood urea nitrogen, total protein and LDH restored to normal in 6e and 6m treated groups as compared to STZ control group. The histopathological studies supported the results obtained in biochemical estimations. Both the compounds did not show any toxicity. Moreover, the histopathological studies of pancreas, liver, heart and kidney revealed that the structural integrity of these tissues restored to almost normal in 6e and 6m treated groups as compared to STZ control group. Based upon these findings it can be concluded that the pyrimidine-based thiazolidinedione derivatives represent novel anti-diabetic agents with least side effects.

Primary obstructive megaureter in children; 10 years' experience from a tertiary care center.

Introduction: Primary obstructive megaureter (POM) is a congenital dilatation of the ureter due to an adynamic segment of vesicoureteric junction obstruction. Surgical intervention is needed if nuclear scan shows obstructive curve. We analyzed our data and outcome of conservative and surgical treatment in such cases at our tertiary care hospital. Materials and Methods: We evaluated all cases of POMs during the study period. Investigations included ultrasonography (USG), voiding cystourethrogram, diethylene pentacetic acid (DTPA) scan, and dimercaptosuccinyle acid scan. In antenatal cases, any pelvic dilatation ≥12 mm after 6 weeks were subjected to reonography. Patients with anterior-posterior pelvic diameter (APPD) ≥12 mm had to undergo DTPA scan to look for DRF and drainage. Follow-up USG was done in all cases of mild-to-moderate hydroureteronephrosis, with APPD <12 at 3 months interval. Results: A total of 270 megaureters were registered and treated during the study period (2008-2019). The total number of patients included was 50 (64 ureters). The mean age of presentation in these 30 children was 21.78 ± 18.1 months (range 1-72 months) and the mean weeks of gestation in antenatal cases at presentation as megaureter was 24 ± 7 weeks (range 13-37 weeks). The mean weight of babies was 2.72 ± 0.7 g. The duration of follow-up ranged from 16 to 1W12 months. The mean APPD on the affected side was 19.99 ± 10.3 mm (range 11-43 mm). The mean ureteric diameter was 1.67 ± 0.33 mm (range 0.78-2.66 cm). The mean split function of patients with POM was 34.88% ± 11.5% on the affected side. Twenty patients (40%) had spontaneous resolution over a mean time period of 24.1 ± 11.1 months. Thirty patients underwent surgical procedures. In three children, HTN was observed over a mean follow-up period of 3 years. Conclusion: The babies with POM need a close follow-up. Surgery is indicated in prolonged t½/Tmax on renal scan, function <40% at the initial scan, or >5% split function deterioration in the subsequent renal scan.

Synthesis, biological evaluation and docking studies of methylene bearing cyanopyrimidine derivatives possessing a hydrazone moiety as potent Lysine specific demethylase-1 (LSD1) inhibitors: A promising anticancer agents.

A series of novel cyanopyrimidine-hydrazone hybrids were synthesized and characterized with various spectroscopic techniques. The synthesized compounds were tested at NCI, USA, on a 60-cell line panel and most of the compounds showed remarkable cytotoxic activity against different cancer cell lines. Compound 5a was found to be the most potent compound of the series and it was further selected for five dose assays wherein it exhibited GI50 value of 0.414 µM and 0.417 µM against HOP-62 and OVCAR-4 cell lines respectively. The in-silico mechanistic studies indicated that these compounds are acting through inhibition of lysine specific demethylase 1 (LSD1) as evident from in to vitro LSD1 inhibition activity of compounds. Among various synthesized derivatives, compound 5a was found to have IC50-value of 0.956 µM. In addition, absorption, distribution, metabolism, excretion and toxicity profile (ADMET) was assessed for these novel derivatives to get an insight on their pharmacokinetic/dynamic attributes which revealed that synthesized compounds showed acceptable metabolic stability in human liver microsomes with minimal inhibition of cytochrome P450s (CYPs). The results indicated that compound 5a could be a promising lead compound for further development as a therapeutic agent for anticancer activity.