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Resistance against clinically approved anticancer drugs is the main roadblock in cancer treatment. Drug metabolizing enzymes (DMEs) that are capable of metabolizing a variety of xenobiotic get overexpressed in malignant cells, therefore, catalyzing drug inactivation. As evident from the literature reports, the levels of DMEs increase in cancer cells that ultimately lead to drug inactivation followed by drug resistance. To puzzle out this issue, several strategies inclusive of analog designing, prodrug designing, and inhibitor designing have been forged. On that front, the implementation of computational tools can be considered a fascinating approach to address the problem of chemoresistance. Various research groups have adopted different molecular modeling tools for the investigation of DMEs mediated toxicity problems. However, the utilization of these in-silico tools in maneuvering the DME mediated chemoresistance is least considered and yet to be explored. These tools can be employed in the designing of such chemotherapeutic agents that are devoid of the resistance problem. The current review canvasses various molecular modeling approaches that can be implemented to address this issue. Special focus was laid on the development of specific inhibitors of DMEs. Additionally, the strategies to bypass the DMEs mediated drug metabolism were also contemplated in this report that includes analogs and pro-drugs designing. Different strategies discussed in the review will be beneficial in designing novel chemotherapeutic agents that depreciate the resistance problem. [ABSTRACT FROM AUTHOR]

Different resistant strains of M. tuberculosis (Mtb) highlight the urgent need of novel anti-tubercular drugs. In mycobacteria, decaprenyl-phosphoryl-β-D-ribose 2'-oxidase (DprE1) is an appealing enzyme to target as it is involved in the biosynthesis of cell wall component arabinogalactan.1, 3-benzothiazin-4-ones (BTZs) based drugs are promising irreversible inhibitors of DprE1. However, a single point mutation of Cys387Ser in DprE1 results in the development of resistance to these drugs. Herein, we made an effort to decode the molecular mechanism of Cys387Ser DprE1 mutation associated resistance in Mtb against BTZs using different in silico techniques. Since the 3D crystal structure of mutant Cys387Ser protein is not yet been solved, thus the homology model was also developed using 4P8N as a template protein with 99.8% homology with the target protein. The computational results suggested that the factors like HOMO–LUMO energy gap, Burgi-Dunitz angle and distance support the covalent inhibition of wild DprE1 by 1, 3-benzothiazin-4-ones class of drugs, using BTZ043 as a reference drug and the same factors support the cause of resistance in case of Cys387Ser mutation. On the basis of these results, it was concluded that BTZ043 can efficiently inhibit the wild type DprE1 than mutant DprE1. [ABSTRACT FROM AUTHOR]

Regardless of continuous research to develop effective chemotherapies and improve patient's prognosis, cancer still remains one of the most deadly diseases worldwide. The reduction in the pace of successfully developing an effective anti-cancer drug is due to the rapid emergence of drug resistance exhibited by tumor cells. One of the resistance mechanisms which is least considered and somewhat overlooked is chemoresistance via drug metabolizing enzymes (DMEs). Therefore, this review emphasizes on pharmacokinetic resistance specifically the DMEs associated chemoresistance, in which drug molecule is rapidly metabolized by DMEs resulting in diminished potential of anti-cancer drugs. The current review will be covering DMEs that are associated with chemoresistance such as ALDH1A1, GST-π, DPD, CYP1B1 and so forth. Although several strategies have been developed to solve this problem such as prodrug designing, analog designing, DMEs inhibitors designing and development of specific pharmaceutical formulations but the inhibition of DMEs is still not considered significantly. Considering the significance of DMEs in chemoresistance, this review shed light on the mechanism of DMEs associated resistance at molecular level, their reported inhibitors that can be used as an adjuvant therapy and strategies (like prodrug designing, analog designing etc.) used so far to combat this problem. [ABSTRACT FROM AUTHOR]

Diabetic complications follow multiple pathophysiological pathways involving aldose reductase (ALR2)‐mediated polyol pathway, advanced glycation end products (AGEs) and reactive oxygen species formation. Literature suggests ALR2 inhibitors such as epalrestat to possess significant potential in retinopathy and neuropathy. Thus, in this study, multiple pathophysiology directed molecules targeting ALR2, AGEs and free radicals formation were designed using in silico techniques. Initially, database was screened via in silico tools to obtain hits with affinity for the catalytic domain of ALR2. Additional focus was laid on the presence of structural attributes responsible for AGE's inhibitory and anti‐oxidant potential. Out of obtained hits, 2‐benzoxazolinone scaffold was selected and ten derivatives were synthesized accordingly. Finally, the synthesized molecules were evaluated for their ALR2 and AGEs inhibitory activities along with free radical scavenging potency. Ten 2‐benzoxazolinone‐based derivatives were synthesized on the basis of in silico analysis and further evaluated in vitro for their aldose reductase (ALR2) inhibitory, advanced glycation end products (AGEs) inhibitory and free radical scavenging activities. Among all synthesized molecules, compound BV‐4 displayed best activity for all mentioned targets. [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]

• Pharmacophore based virtual screening of previously reported flavones. • Best 15 flavones were identified using in silico methods. • Evaluated in-vitro against ALR1, ALR2, and SDH enzymes. • Four molecules were found significant dual inhibitors with selectivity over ALR1. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.)

Background: Lawsonia inermis Linn popularly known as Henna, plays an important role in ayurvedic or natural herbal medicines. The presence of phytoconstituents in henna, that may affect the animal or human health adversely, needs to be elucidated for L. inermis Linn species grown in India., Introduction: The aim of this research was to perform phytochemical screening, and study cytotoxicity and anti-inflammatory activities to understand the potential of leaves of Lawsonia inermis of Indian origin to provide a way forward for therapeutic use in medicine., Methods: We assessed the phytochemical profile for the presence of phytoconstituents (alkaloids, carbohydrates, glycosides, steroids, flavonoids, saponins, tannins, proteins/amino acids and gums/mucilage) in various extracts of the plant leaves. The extracts were further purified by column chromatography for the isolation of plant constituents and monitored by TLC, analyzed by Fourier transform infrared FT-IR spectroscopy, H1NMR, and GC-MS analysis. Fractions were assessed for cytotoxicity and anti-inflammatory properties at various concentrations. We assessed the anti-inflammatory activity by nitric oxide production in various leaf extracts determined by Griess assay., Results: All the spectral results suggest that the compounds from the extract contain an aromatic nucleus and OH group along with the methoxy group, allyl as well as vinyl group. Fractions of chloroform/methanolic (7:3) leaf extract of Lawsonia inermis confirmed the presence of the two constituents i.e. fraxetin and 1(3H)-isobenzofuranone. We observed a significant difference in cytotoxicity at higher concentrations in methanol and chloroform: methanol (8:2) leaf extracts (p>0.05), we could not find any significant differences amongst other leaf extracts at different concentrations. Some leaf extracts have potential cytotoxic activity on Vero cells. Reducing the chloroform concentration during extraction decreases the cytotoxic effect on cells. Nitric oxide levels decreased from 1000 μg/ml concentration to lower concentrations with varying degrees. Overall the highest nitric oxide production by CHCl 3 (70%)/ MeOH (30%) was observed amongst various fractions at different concentrations., Conclusion: Phytochemical screening and the study of cytotoxicity and anti-inflammatory activities highlight the potential of leaves of the plant to provide a way further for their use in medicine. Fraxetin 1(3H) and isobenzofuranone structures were confirmed in fractions of CHCl 3 (70%)/ MeOH (30%) extract as potent constituents. Some leaf extracts have potential cytotoxic activity on Vero cells. Reducing the chloroform concentration during extraction, it decreases the cytotoxic effect on cells. The cytotoxicity studies indicate the presence of cytotoxic compounds in some of these extracts, warranting research for the fabrication of suitable formulations comprising these constituents to reduce dose/toxicity for beneficial effects of the plant components., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Bio-molecules are the most important target to be considered while designing any drug delivery system. The logic lies in using such bio-sensing or bio-mimicking systems in their formulations that can mimic the active site of those receptors to which the drug is going to bind. Polymers mimicking the active site of target enzymes are regarded as bio-inspired polymers and can be used to ameliorate many diseased conditions. Nowadays, this strategy is also being adopted against diabetes and its complications. Under hyperglycemic conditions, many pathways get activated which are responsible for the progression of diabetes-associated secondary complications viz. retinopathy, neuropathy, and nephropathy. The enzymes involved in the progression of these complications can be mimicked for their effective management. For an instance, Aldose Reductase (ALR2), a rate-limiting enzyme of the polyol pathway (downstream pathway) which gets over-activated under hyperglycemic condition is reported to be mimicked by using polymers which are having same functionalities in their structure. This review aims at critically appraising reports in which target mimicking bio-inspired formulations have been envisaged against diabetes and its complications. The information summarized in this review will provide an idea about the bio-sensing approaches utilized to manage blood glucose level and the utility of bio-inspired polymers for the management of diabetic complications (DC). Such type of information may be beneficial to pharmaceutical companies and academia for better development of targeted drug delivery systems with sustained-release property against these diseased conditions., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Nitrogen and sulphur based heterocyclic molecules have gained significant attention owing to their broad spectrum pharmacological profiles. Thiazine is one of such promising scaffolds which has been widely utilized in the synthesis of compounds that possess interesting biological profile including anti-proliferative, anti-bacterial, antipsychotic, analgesic, anti-inflammatory, antifungal and antiviral activities. The current review focuses on the chemistry of thiazine and its derivatives along with potential pharmacological activities reported for these in scientific literature. Multifaceted pharmacological profile of thiazine derivatives provides new aspects for the design of superior medicinally active agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Trypanosoma evansi, the causative agent of surra, is pathogenic to a wide variety of wild and domestic animals, including equines, camels, goats, sheep, cattle, buffaloes, pigs, dogs, tigers, elephants etc. The infection is mainly restricted to animals but ability to infect human beings has also been reported due to the lack of efficient apolipoprotein L 1. The parasite is mechanically transmitted by blood-sucking flies such as Tabanus and Stomoxys species. The disease has a major economic impact in tropical countries. The control of trypanosomosis may be aimed either at the fly or against the parasite. Due to difficulties in large scale fly control, trypanocides have been widely used to control the disease. However, current chemotherapeutic agents are limited in number and usually associated with severe side effects. Moreover, current therapeutic agents are far from ideal. The emergence of drug resistant trypanosomes results in failure of prophylaxis and treatment of the disease. Retrospective and prospective studies on drug and delivery against T. evansi will provide an overview of the chemotherapeutic and prophylactic measures in vogue and suggest future strategies for combating this neglected disease. In this perspective, we have reviewed the currently used drugs available for prophylaxis and therapy, their mechanism of action and associated limitations. The options available for prophylaxis and therapy along with potential new molecules/therapeutic agents and novel approaches for delivery of the drugs to enhance their therapeutic value are presented in this review.