Design, synthesis, in-vitro thymidine phosphorylase inhibition, in-vivo antiangiogenic and in-silico studies of C-6 substituted dihydropyrimidines.

Thymidine phosphorylase (TP) is an angiogenic enzyme. It plays an important role in angiogenesis, tumour growth, invasion and metastasis. In current research work, we study the effect of structural modification of dihydropyrimidine-2-ones (DHPM-2-ones) on TP inhibition. A series of eighteen new derivatives of 3,4-dihydropyrimidone-2-one were designed and synthesized through the structural modification at C-6 position. All these new derivatives were then assessed for in-vitro inhibition of thymidine phosphorylase (TP) from E. coli. Oxadiazole derivatives 4a-e exhibited excellent TP-inhibition at low micromolar concentration levels better than standard drug 7-deazaxanthine (7-DX). Among all these compounds, 4b was found to be the most potent with IC50 = 1.09 ±â€¯0.004 µM. Anti-angiogenesis potential of representative compounds were also studied in a chorioallantoic membrane (CAM) assay. Here again, compound 4b was found to be the potent anti-angiogenesis compound in a CAM assay. Docking studies were also performed with Molecular Operating Environment (MOE) to further analyse the mode of inhibition of these compounds. Binding mode analysis of the most active inhibitors showed that these are well accommodated into the binding site of enzyme though stable hydrogen bonding and hydrophobic interactions.

A Prospective Study to Determine the Predictive Ability of HDP-Gestosis Score for the Development of Pre-eclampsia.

Background: HDP-gestosis score is a risk scoring system (score 1-3) for the development of pre-eclampsia. When a pregnant woman's total score is equal to or greater than 3, she is labelled as "at risk for pre-eclampsia" and is managed accordingly. Objectives: To determine the sensitivity, specificity, Positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy of HDP-gestosis score for predicting pre-eclampsia. Methods: This prospective study included 473 pregnant women who presented at the department of Obstetrics and Gynaecology, from June 2020 to December 2021. After 20 weeks of pregnancy, the patients were assessed for the development of pre-eclampsia. Details of age, gravida, obstetric history, menstrual cycle regularity, polycystic ovarian disease history, duration of marriage, parity, past medical and surgical intervention, previous/present medication, and family history were taken. Gestosis score was calculated and classified into mild (score of 1), moderate (score of 2) and high risk (score of ≥ 3) for the development of Pre-eclampsia (PE). Sensitivity, Specificity, PPV, NPV and diagnostic accuracy of HDP-gestosis score for predicting the development of PE were determined. Results: The mean age, gestational age, and BMI of the women were 28.4 ± 6.8 years, 11.5 ± 2.04 weeks, and 24.5 ± 3.7 kg/m2, respectively. The gestosis score was 2 in 43.13% of the participants, 1 in 42.28%, and ≥ 3 in 14.59% of the women. PE developed in 15.01% (n = 71) participants. The Sensitivity, Specificity, PPV, NPV, and Diagnostic accuracy of HDP-gestosis score for predicting PE were 83.1%, 97.51%, 85.51%, 97.03% and 95.35%, respectively. Conclusion: Gestosis score is a novel early marker for prediction of the development of PE allowing for a prompt management for the patients, thereby curbing the adverse consequences.

Structure based medicinal chemistry-driven strategy to design substituted dihydropyrimidines as potential antileishmanial agents.

In an attempt to explore novel and more potent antileishmanial compounds to diversify the current inhibitors, we pursued a medicinal chemistry-driven strategy to synthesize novel scaffolds with common pharmacophoric features of dihydropyrimidine and chalcone as current investigational antileishmanial compounds. Based on the reported X-ray structure of Pteridine reductase 1 (PTR1) from Leishmania major, we have designed a number of dihydropyrimidine-based derivatives to make specific interactions in PTR1 active site. Our lead compound 8i has shown potent in vitro antileishmanial activity against promastigotes of L. Major and Leishmania donovani with IC50 value of 0.47 µg/ml and 1.5 µg/ml respectively. The excellent in vitro activity conclusively revealed that our lead compound is efficient enough to eradicate both visceral and topical leishmaniasis. In addition, docking analysis and in silico ADMET predictions were also carried out. Predicted molecular properties supported our experimental analysis that these compounds have potential to eradicate both visceral and topical leishmaniasis.