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The inter-individual differences in cancer susceptibility are somehow correlated with the genetic differences that are caused by the polymorphisms. These genetic variations in drug-metabolizing enzymes/drug-inactivating enzymes may negatively or positively affect the pharmacokinetic profile of chemotherapeutic agents that eventually lead to pharmacokinetic resistance and toxicity against anti-cancer drugs. For instance, the CYP1B1*3 allele is associated with CYP1B1 overexpression and consequent resistance to a variety of taxanes and platins, while 496T>G is associated with lower levels of dihydropyrimidine dehydrogenase, which results in severe toxicities related to 5-fluorouracil. In this context, a pharmacogenomics approach can be applied to ascertain the role of the genetic make-up in a person's response to any drug. This approach collectively utilizes pharmacology and genomics to develop effective and safe medications that are devoid of resistance problems. In addition, recently reported genomics studies revealed the impact of many single nucleotide polymorphisms in tumors. These studies emphasized the importance of single nucleotide polymorphisms in drug-metabolizing enzymes on the effect of anti-tumor drugs. In this review, we discuss the pharmacogenomics aspect of polymorphisms in detail to provide an insight into the genetic manipulations in drug-metabolizing enzymes that are responsible for pharmacokinetic resistance or toxicity against well-known anti-cancer drugs. Special emphasis is placed on different deleterious single nucleotide polymorphisms and their effect on pharmacokinetic resistance. The information provided in this report may be beneficial to researchers, especially those who are working in the field of biotechnology and human genetics, in rationally manipulating the genetic information of patients with cancer who are undergoing chemotherapy to avoid the problem of pharmacokinetic resistance/toxicity associated with drug-metabolizing enzymes. [ABSTRACT FROM AUTHOR]

Scientific pieces of evidence indicate that the polymorphism in the ALR2 regulatory gene favors the susceptibility to diabetic complications (DCs). Previous studies have uncovered several single nucleotide polymorphisms (SNPs) in the ALR2 regulatory sites that negatively modulate the activity of this enzyme and eventually increase the risks of DCs. In view of this, the current study aimed at investigating whether the mutation as a resultant of missense SNPs in the regulatory site of ALR2 enzyme can also hamper the interactions of ALR2 inhibitors with the key amino acid residues in the ALR2 binding site. Around 202 SNPs in the ALR2 gene were reported in the dbSNP database. Out of these, eighteen SNPs that are responsible for point mutations in the regulatory sites of ALR2 enzyme were identified and considered for the study. Identified SNPs were then categorized as stabilizing or destabilizing using various in silico tools and webservers. The resulting mutational constructs of ALR2 were further probed for their influence on the binding affinities and binding modes with well-known ALR2 inhibitors using structure-based analyses. This study identified three destabilizing SNPs, i.e., rs779176563 (C298S), rs1392886142 (G16A), and rs1407261115 (A245T), that lead to the compromised response to most of the ALR2 inhibitors which are in clinical trials. On the other hand, treatment with these ALR2 inhibitors may benefit the population which carries missense SNPs rs748119899, rs1402962430, and rs1467939858 that code for W219S, Q183V, and S214A, respectively. Overall findings of the study suggest that one SNP in the inhibitor site and two SNPs in the co-factor site of ALR2 may be responsible for the low efficacy and unsuccessful journey of ALR2 inhibitors in the clinical trials. [ABSTRACT FROM AUTHOR]

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]

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]

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]

Over activated molecular target ALR2 of polyol pathway and oxidative stress are two well established pathological indicators in diabetic complications. In present study, mutual prodrugs of Epalrestat and natural product based antioxidants were designed, synthesized and evaluated. In silico techniques such as molecular dynamic simulations and quantum mechanical approaches, considering human esterase enzyme (hCE1) as the site of hydrolytic cleavage were employed in designing of these mutual prodrugs. Geometrical parameters (distance and Burgi-Dunitz angle favorable for nucleophilic attack) and quantum mechanical parameters (HOMO-LUMO energy gap), which govern the hydrolytic cleavage of ester prodrugs by esterase enzyme were calculated. Further, on the basis of in silico analysis, mutual prodrugs were synthesized and considering the values of in silico parameters, EPL-GUA ( 3g ) was evaluated for its in vivo antioxidant activity. Results suggested that 3g possess significant antioxidant activity intermediary to control and Epalrestat. Thus, this study has concluded that these mutual prodrugs could be optimized to develop molecules for the management of diabetic complications. [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]

• Psoriasis is an autoimmune disease of the skin with chronic inflammatory conditions. • Various signaling pathways are involved in its pathophysiology. • The basis of molecular modulation of psoriasis has been addressed. • Various strategies to counter this complex disease have been discussed in detail. • Recent development in the anti-psoriatic therapy has been discussed. Psoriasis is a hyperproliferative skin disorder which is associated with dysregulation of the immune system. In this genetically transmitted disease, the immune system is activated by various triggers such as genetic predisposition, stress, and pathogenic microbes which in turn stimulate various immunocytes such as keratinocytes, macrophages, monocytes, dendritic cells and T-cells to secrete various pro-inflammatory cytokines that ultimately accelerate inflammation and cause psoriatic plaques. These cytokines are also responsible for T-cell differentiation, keratinocyte hyperproliferation, and accumulation of neutrophils and lymphocytes in the skin. At the molecular level, several pathways have been proposed underlying the pathophysiology of psoriasis that directly or indirectly kindle various psoriatic factors. The most common pathways include PDE-4, ICAM-1, LFA-1 and JAK/STAT pathways. In order to target these pathways, various strategies have been developed that counter moderate to severe psoriasis. The most effective therapies include interleukin inhibitors, TNF-α inhibitors, JAK inhibitors, PDE-4 inhibitors and immunosuppressants such as methotrexate, cyclosporin, tazarotene, and acitretin. Apart from these inhibitors, phototherapy (UV-A and PUVA) and topical therapies (corticosteroids, vitamin D analogs, retinoids, emollients, and keratolytic agents) have also been employed for the treatment of mild to moderate psoriasis. This review provides the retrospective analysis of psoriasis and current therapeutic options which are under development for the amelioration of psoriatic diseases. The information provided in this report may be helpful for the research community engaged in the development of effective novel therapies against psoriasis. [Display omitted] [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]

• Synthetic analogues of curcumin may open up a new horizon for the research • Curcumin knocks multiple targets involved in cancer • Substitution with heterocyclic moiety at the central methylene position enhances anti-cancer activity Cancer represents one of the leading health-care issues around the globe. The overall life expectancy of cancer patients remains dismal regardless of enduring investigations and advances in the management of a disease. Thus the focus is always on the discovery of potential and less toxic alternatives of anticancer agents. Natural compounds from plant and animal kingdoms are grabbing eyeballs around the world owing to their relatively safer and huge unexplored therapeutic potential. One such natural compound is curcumin, which is a yellow polyphenolic compound procured from the plant "Curcuma longa Linn" and used widely as a spice in Indian households. Curcumin has proved its worth in various pathological conditions at preclinical stages. Despite the enormous therapeutic potential, low bioavailability and rapid metabolism are the roadblocks in the journey of curcumin to be a successful clinical candidate. This review is an earnest attempt to provide a summarized account of all the strategies to overcome obstacles of limited bioavailability and improving the therapeutic efficacy of curcumin.Special emphasis is laid on the structural insights into the development of novel curcumin based synthetic analogues endowed with anticancer potential and their docking analysis. Important aspects related to a possible mechanism of action and future prospects in designing of novel curcumin based anticancer analogues are also roofed in this article. Image, graphical abstract [ABSTRACT FROM AUTHOR]

• QM/MM based biotransformation study of epalrestat based mutual-prodrugs. • Synthesis and biological evaluation against diabetic neuropathy and nephropathy. • Histopathological examination of brain and kideny sections. • EP-G-MFA and EP-MFA came out as better protective agents than epalrestat. • In-vivo pharmacokinetic study of best prodrugs in rats. 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. [ABSTRACT FROM AUTHOR]

COVID-19, caused by SARS-CoV-2, emerged as the deadliest outbreak that has now become a serious health issue to mankind. Activation of inflammatory signaling pathways and cytokine storm are crucial factors that lead to acute respiratory distress syndrome (ARDS) in COVID-19 patients. Excessive secretion of pro-inflammatory cytokines and chemokines leads to the dysregulation of the innate immune system. The cytokine storm attracts many inflammatory cells that infiltrate into the lung tissues and ultimately cause immune damage. In addition to the dysregulation of the immune system, dysfunction of the renin-angiotensin system (RAS) due to the downregulation of ACE2 is also associated with the mortality of COVID-19 patients. Both the mechanisms are directly or indirectly associated with cytokine storm that promotes vascular hyperpermeability, vascular edema leading to hypercoagulation and hence multiorgan damage. As of now, there is no specific treatment available for COVID-19, but scientists have purposed several treatment options including cytokine inhibitors, JAK inhibitors, immunomodulators, plasma therapy, etc. In this article, we have provided the detailed mechanism of occurrence of SARS-CoV-2 induced inflammatory storm and its connection with the pre-existing inflammatory conditions. Possible treatment options to cope up with the severe clinical manifestations of COVID-19 are also discussed. Image 1 • COVID-19, caused by SARS-CoV-2, is an ongoing pandemic. • Various inflammatory pathways are activated in COVID-19. • Patients with pre-existing inflammatory conditions are more prone to infection. • Various strategies to counter these conditions have been discussed in detail. [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]

EZH2 is a classic histone methyltransferase that causes the trimethylation of H3K27 and consequently suppresses the cancer preventive genes. The role of elevated levels of EZH2 expression in breast cancer aggressiveness and poor prognosis is very well established. The present study focusses on the insight of the clinically important SNPs of EZH2 gene in determining the structure–function relationship towards breast cancer susceptibility. For this purpose the EZH2 SNPs (rs41277434A>C and rs201135441C>T (A490T)) were computationally explored and further the prediction outcomes were validated by performing population-based association and pharmacogenetic study in north Indian region of Punjab. The results of the present analysis provided the novel insight of rs201135441C>T (A490T) mutation, that A>T change i.e. nonpolar amino acid to polar amino acid stabilizes the enzyme-substrate (EZH2-Histone) complex which in turn promotes trimethylation over histone 3 (H3) at lysine residue 27 (H3K27me3) and this might be leading to the methylation of the promoter region of various cancer preventive genes, hence may increase the risk of breast cancer susceptibility. Further the association based study of SNP rs201135441C>T (A490T) support the in silico outcomes by revealing that the T mutant allele of rs201135441 has significantly increased the risk of breast cancer susceptibility and also reduce the overall survival and progression free survival of ER+/tamoxifen treated breast cancer patients and triple negative breast cancer (TNBC) patients, respectively. To the best of our knowledge, this is the first study on EZH2 polymorphism with breast cancer. In conclusion, these findings suggest that these variations in the EZH2 gene may have strong clinical significance as they can be targeted for prognosis, prevention and in drug development. [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]

[Display omitted] • Ten hydantoin derivatives were designed as dual inhibitors of ALR2 and PARP-1. • They were synthesized, characterized and evaluated using in vitro as well as in vivo methods. • Three molecules FM6B, FM7B and FM9B were found to be the best dual inhibitors. • These three also have nephroprotective and antioxidant potential. 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). [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 2nd position of benzothiazoles yield improved anti-fungal molecules. Therefore, in the current study, a lead optimization approach using a 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 six 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. [Display omitted] [ABSTRACT FROM AUTHOR]

• Design and synthesis of quinazolin-4(3H)-one based derivatives as an optimized structure to Zenarestat. • Implimenting Scaffold hopping approach as a suggestion for bioisosteres • Subjecting to Molecular docking and Dynamics approach to understand the interaction pattern. • Screening the designed derivatives for in-silico ADMET predictions. • Evaluationof In-vitro ALR2 inhibitory activity Zenarestat withdrawal from the clinical trials owing to severe renal toxicity was a major setback in developing ALR2-targeted agents to manage diabetic complications. Addressing the toxicity issue by making some structural modifications in a well-known ALR2 inhibitor Zenarestat via a bioisosteric replacement/scaffold hopping approach can be very fruitful. This approach helps in obtaining a library of optimized analogues that can be potential ALR2 inhibitors with minimal side effect. Herein, using scaffold hoping, quinazolin-4(3H)-one was obtained as one of the top bioisostere with good BIF, shape and field scores. The designed in-house library of quinazolin-4(3H)-one was studied for their SAR profile based on the developed qualitative model via Activity atlas option. Important field points i.e., positive and negative electrostatics along with shape properties were analyzed that are crucial for ALR2 inhibitory activity. Some structure-based approaches including molecular docking and dynamics also suggested that the designed quinazolin-4(3H)-one based derivatives can be putative ALR2 inhibitors. These molecules were synthesized and evaluated for in-vitro ALR2 inhibitory activity. It was observed that compound Q2, Q3 and Q10 are most potent inhibitors with IC 50 values of 2.56 ± 0.03, 1.72 ± 0.02 and 1.47 ± 0.03 µM, respectively. Additionally, the predicted ADMET properties were also found to be favorable in comparison to Zenarestat. [ABSTRACT FROM AUTHOR]