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Diabetic nephropathy is one of the most dreadful diabetic complications (DCs). The polyol pathway and unified mechanism are two important pathways implicated in the progression of DCs. In this regard, targeting the key enzymes i.e., aldose reductase (ALR2) and poly (ADP-ribose) polymerase-1 (PARP-1), of these pathways can be a relevant strategy. Thus, in this study, the pharmacophoric requirements necessary for the dual inhibition of these two enzymes i.e., ALR2 and PARP-1 were identified and consequently, some hydantoin based molecules were designed. The designed molecules were subjected to structure-based molecular modelling analysis including molecular docking analysis and molecular dynamic simulations. The promising molecules were duly synthesized and examined for their ALR2 and PARP-1 dual inhibitory activities and selectivity over aldehyde reductase (ALR1) using in vitro enzymatic assays. Based on the results of in silico analysis and in vitro assays, the best three molecules were evaluated in vivo for their nephroprotective effect and antioxidant potential in the high-fat diet-streptozotocin induced diabetic rat model. The results showed that the compounds FM6B, FM7B and FM9B were having low micromolar inhibitory potential against ALR2 (IC 50 ; 1.02, 1.14 and 1.08 μM, respectively) and PARP-1 (IC 50 ; 0.95, 0.81 and 1.42 μM, respectively) with selectivity over ALR1 (selectivity index; 43.63, 37.03 and 45.14, respectively)., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

During the ongoing pandemic, there have been increasing reports of invasive fungal disease (IFD), particularly among immunocompromised populations. Candida albicans is one of the most common clinical pathogenic microorganisms which have become a serious health threat to population either infected with Covid-19 or on treatment with immunosuppressant's/broad-range antibiotics. Currently, benzothiazole is a well explored scaffold for anti-fungal activity, especially mercapto substituted benzothiazoles. It is reported that exploring the 2 nd position of benzothiazoles yield improved anti-fungal molecules. Therefore, in the current study, lead optimization approach using bioisosteric replacement protocol was followed to improve the anti-fungal activity of an already reported benzothiazole derivative, N -(1,3-benzothiazole-2-yl)-2-(pyridine-3-ylformohydrazido) acetamide. To rationally identify the putative anti-candida targets of this derivative, network analysis was carried out. Complexes of designed compounds and identified putative targets were further analyzed for the docking interactions and their consequent retention after the completion of exhaustive MD simulations. Top seven designed compounds were synthesized and evaluated for in-vitro anti-fungal property against Candida, which indicated that compounds 1.2c and 1.2f possess improved and comparable anti-fungal activity to N -(1,3-benzothiazole-2-yl)-2-(pyridine-3-ylformohydrazido) acetamide and Nystatin, respectively., Competing Interests: NOne, (© 2022 Published by Elsevier B.V.)

COVID-19 is an ongoing public health emergency that has affected millions of people worldwide and is still a threat to many more. One of the pathophysiological features of COVID-19 is associated with the activation of vascular endothelial cells (ECs) leading to the disruption of vascular integrity, coagulation and inflammation. An interlink mechanism between coagulation and inflammatory pathways has been reported in COVID-19. Multiple components are involved in these pathological pathways. Out of all, Von Willebrand Factor (VWF) is one of the primary components of coagulation pathway and also a mediator of vascular inflammation that plays an important role in thrombo-inflammation that further leads to acute respiratory distress syndrome (ARDS). The thrombo-inflammatory co-morbidities such as hyper-coagulation, thrombosis, ARDS etc. have become the major cause of mortality in the patients of COVID-19 admitted to the ICU. Thus, VWF can be explored as a potential target to manage COVID-19 associated co-morbidities. Supporting this hypothesis, there are literature reports which disclose previous attempts to target VWF for the management of thrombo-inflammation in other pathological conditions. The current report summarizes emerging insights into the pathophysiology, mechanism(s), diagnosis, management and foundations for research on this less explored clinically relevant glycoprotein as coagulation biomarker in COVID-19., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Herein, a quantum mechanics/molecular mechanics (QM/MM) based biotransformation study was performed on synthetically feasible mutual-prodrugs of epalrestat which have been identified from an in-house database developed by us. These prodrugs were submitted to quantum polarized ligand docking (QPLD) with the CES1 enzyme followed by MM-GBSA calculation. Electronic aspects of transition state of these prodrugs were also considered to study the catalytic process through density functional theory (DFT). ADMET analysis of prodrugs was then carried out to assess the drug-likeness. On the basis of in-silico results, the best five prodrugs were synthesized and further evaluated for their neuroprotective and nephroprotective potential in high-fat diet-streptozotocin (HFD-STZ) induced diabetes in rat model. Clinically relevant molecular manifestations of diabetic complications (DC) including aldose reductase (ALR2) activity and oxidative stress markers such as reduced glutathione (GSH), catalase (CAT), and thiobarbituric acid reactive substances (TBARS) were determined in blood plasma as well as tissues of the brain and kidneys. The histopathological examination of these organs was also carried out to see the improvement in structural deformities caused due to neuropathy and nephropathy. Finally, in-vivo pharmacokinetic study was performed for the best two prodrugs to assess the improvement in biopharmaceutical attributes of parent drugs. Overall, EP-G-MFA and EP-MFA have significantly reduced the hyperglycemia-induced ALR2 activity, levels of oxidative stress markers, and manifested about a two-fold increase in the biological half-life (T 1/2 ) of parent drugs. The overall findings of this study suggest that methyl ferulate conjugated prodrugs of epalrestat may be considered as potential protective agents in diabetic neuropathy and nephropathy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Initially, the selective COX-2 inhibitors were developed as safer alternatives to the conventional NSAIDs, but later on, most of them were withdrawn from the market due to the risk of heart attack and stroke. Celecoxib, the first selective COX-2 inhibitor, was approved by the Food and Drug Administration (FDA) in December 1998 and was taken back from the market in 2004. Since then, many coxibs have been discontinued one by one due to adverse cardiovascular events. United States (US), Australian and European authorities related to Therapeutic Goods Administration (TGA) implemented the requirements to carry the "Black box" warning on the labels of COX-2 drugs highlighting the risks of serious cardiovascular events. These facts encouraged the researchers to explore them well and find out the biochemical basis behind the cardiotoxicity. From the last few decades, the molecular mechanisms behind the coxibs have regained the attention, especially the specific structural features of the selective COX-2 inhibitors that are associated with cardiotoxicity. This review discusses the key structural features of the selective COX-2 inhibitors and underlying mechanisms that are responsible for the cardiotoxicity. This report also unfolds different strategies that have been reported in the last 10 years to combat the problem of selective COX-2 inhibitors mediated cardiotoxicity., Competing Interests: Declaration of competing interest There is no potential conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Diabetic complications (DC) follow multiple pathophysiological pathways and one of the key pathways is the polyol pathway which involves the metabolism of glucose via aldose reductase (ALR2) and sorbitol dehydrogenase (SDH). ALR2 inhibitors such as epalrestat has already been established as promising candidates for the management of DC. On the basis of pathophysiological understanding of polyol pathway, simultaneous inhibition of ALR2 and SDH may be expected to provide synergistic outcomes in the treatment strategies for DC. Thus, in this study, dual inhibitors of ALR2 and SDH were identified using pharmacophore-based virtual screening. For this purpose, the pharmacophore model for SDH (model ID: AAADH.343) was generated and validated. For screening against ALR2, the pharmacophore model (model ID: AADRR.1109) which was previously reported by our group was applied. Initially, flavones reported by our research group were screened by those two pharmacophore models to obtain hits with an optimum affinity for the catalytic domain of both ALR2 and SDH. Inhibitory potential of identified hits for ALR2 and SDH were then experimentally determined using enzymatic assays reported in the literature. Additional focus was laid on the selectivity of the designed molecules towards ALR2 over ALR1, thus evaluation against ALR1 was also performed. Overall, four molecules FLV-2, FLV-11, FLV-12, and FLV-15 were found to possess significant dual inhibitory activity against ALR2 and SDH, with selectivity over ALR1. Among them, FLV-2 displayed significant dual inhibitory potential with an IC 50 value of 0.689 ± 0.018 µM and 0.174 ± 0.003 µM against ALR2 and SDH respectively with a selectivity index of 52.902 to ALR2 over ALR1., Competing Interests: Declaration of Competing Interest The authors declared that there is no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The triazolopyrimidine scaffold represents one of the privileged structure in chemistry, and there has been an increase in number of studies utilizing this scaffold and its derivatives. Optimization of synthetic protocols such as aza-Wittig reaction, [3 + 2] cycloaddition reaction along with previous methods including condensation with 1,3-dicarbonyl substrates and oxidation of aminopyrimidine Schiff bases have been performed to obtain desired triazolopyrimidines. The triazolopyrimidine ring has been extensively used as a template in medicinal chemistry for its diverse pharmacological properties. Several medicinally active molecules possessing triazolopyrimidine scaffold, either fused or coupled with other heterocycles, have been reported in the literature, highlighting the significance of this nucleus. Interestingly, the unique triazolopyrimidine scaffold also exhibits an impressive potential as a ligand for the synthesis of several metal complexes with significant biological potential. Literature provides enough evidence of exhaustive exploration of this scaffold as a ligand for the chelates of platinum, ruthenium and other metals. This review aims to be a comprehensive and general summary of the different triazolopyrimidine syntheses, their use as ligands for the synthesis and development of metal complexes as medicinal agents and their main biological activities., (Copyright © 2019 Elsevier Inc. All rights reserved.)