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Herein, we report four series of mutual prodrugs of epalrestat by combining it with different antioxidants using glycine, beta-alanine, and phenylalanine as a linker and by directly linking them through an ester linkage. The designed prodrugs were subjected to pharmacophore and docking-based virtual screening to determine the susceptibility of these prodrugs to be hydrolyzed by human carboxylesterases (hCES1 and hCES2). Five best prodrugs from each series were further submitted to detailed mechanistic study of hCES1 and hCES2 based hydrolytic activation using quantum mechanics and molecular dynamics approach. Additionally, Verloop'ssterimol parameters (B1-B5, L) were calculated in order to investigate the steric constraint of prodrugs to the catalytic sites of hCES1 and hCES2 enzymes. Our results indicated that, among these prodrugs, EP-D4, EP-E13, EP-F5, and EP-F14 are best substrates for hCES1 while EP-G3 and EP-G15 are potential substrates for hCES2. On the other hand, EP-D19 serves as good substrates for both enzymes. Image 1 • Epalrestat-antioxidant mutual prodrugs were designed. • Homology model was built for hCES2. • Pharmacophore models were generated for both hCES1 and hCES2. • Molecular docking and dynamics simulations were performed. • Quantum mechanical and sterimol parameters were calculated to determine the catalytic efficiency of hCES1 and hCES2. [ABSTRACT FROM AUTHOR]

Complex diseases comprises of highly complicated etiology resulting in limited applicability of conventional targeted therapies. Consequently, conventional medicinal compounds suffer major failure when used for such disease conditions. Additionally, development of multidrug resistance (MDR), adverse drug reactions and clinical specificity of single targeted drug therapy has increased thrust for novel drug therapy. In this rapidly evolving era, natural product-based discovery of hybrid molecules or multi-targeted drug therapies have shown promising results and are trending now a days. Historically, nature has blessed human with different sources viz. plant, animal, microbial, marine and ethnopharmaceutical sources which has given a wide variety of medicinally active compounds. These compounds from natural origin are always choice of interest of medicinal chemists because of their minimum side effects. Hybrid molecules synthesized by fusing or conjugating different active molecules obtained from these sources are reported to synergistically block different pathways which contribute in the pathogenesis of complex diseases. This review strives to encompass all natural product-derived hybrid molecules which act as multi-targeting agents striking various targets involved in different pathways of complex diseased conditions reported in literature. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Leading causes of mortality in patients with COVID-19 are thrombo-inflammatory co-morbidities. • VWF is a multifunctional glycoprotein that plays important roles in primary and secondary haemostasis. • VWF appears to be an important component of the "clot" in COVID-19. • Retrospective study of COVID-19 patients revealed that significantly elevated VWF levels. [ABSTRACT FROM AUTHOR]

The fused heterocyclic ring system has been recognized as a privileged structure that is used as a template in medicinal chemistry for drug discovery. Benzimidazole is one of the common scaffolds found in several natural products such as histidine, purines, and an integral part of vitamin B12. This hetero-aromatic bicyclic ring system acts as a pharmacophore in various drugs of therapeutic interest and has a broad spectrum of activity. Literature reports suggest that diversely substituted benzimidazoles possess distinct pharmacological profiles with multi-targeting potential, thereby, an indispensable anchor for the development of novel therapeutic agents against complex diseases such as cancer, malaria, inflammatory disorders, microbial diseases, hypertension, etc. Thus, lots of efforts have been diverted towards exploring the therapeutic potential of benzimidazoles. Despite great efforts made by the research community, still, some multi-factorial diseases continue to progress due to their complex pathophysiology. Under these sets of circumstances, there is a need to explore this nucleus for hybrid designing with multi-targeting potential against complex diseases. Benzimidazole-based hybrids have been reported to treat multifactorial diseases, making it a scaffold of interest for various pharmaceutical companies and research groups. In this write-up, we shed light on the recent pharmacological profiles, various designing strategies, and structure-activity relationships (SAR) of different benzimidazole-based hybrids. • Complex diseases involve multiple pathways. • Strategies adopted for designing of benzimidazole-based hybrids have been reported. • Benzimidazole-based hybrids have been summarized against various complex diseases. • SAR profile of benzimidazole-based hybrid molecules has been discussed. [ABSTRACT FROM AUTHOR]

• Novel analogues of arbidol (Umifenovir) were designed by scaffold morphing approach. • Top hits subjected to docking based virtual screening against SARS-CoV-2 targets. • Fifteen analoges demonstrated good results in-silico with optimum ADME properties. • A_BR18 and A_BR28 displayed multi-targeting potential in COVID-19. The rapid emergence of novel coronavirus, SARS-coronavirus 2 (SARS-CoV-2), originated from Wuhan, China, imposed a global health emergency. Angiotensin-converting enzyme 2 (ACE2) receptor serves as an entry point for this deadly virus while the proteases like furin, transmembrane protease serine 2 (TMPRSS2) and 3 chymotrypsin-like protease (3CLpro) are involved in the further processing and replication of SARS-CoV-2. The interaction of SP with ACE2 and these proteases results in the SARS-CoV-2 invasion and fast epidemic spread. The small molecular inhibitors are reported to limit the interaction of SP with ACE2 and other proteases. Arbidol, a membrane fusion inhibitor approved for influenza virus is currently undergoing clinical trials against COVID-19. In this context, we report some analogues of arbidol designed by scaffold morphing and structure-based designing approaches with a superior therapeutic profile. The representative compounds A_BR4, A_BR9, A_BR18, A_BR22 and A_BR28 restricted the interaction of SARS-CoV-2 SP with ACE2 and host proteases furin and TMPRSS2. For 3CLPro, Compounds A_BR5, A_BR6, A_BR9 and A_BR18 exhibited high binding affinity, docking score and key residue interactions. Overall, A_BR18 and A_BR28 demonstrated multi-targeting potential against all the targets. Among these top-scoring molecules A_BR9, A_BR18, A_BR22 and A_BR28 were predicted to confer favorable ADME properties. [ABSTRACT FROM AUTHOR]

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. Unlabelled Image [ABSTRACT FROM AUTHOR]