Diabetes mellitus is a chronic and most prevalent metabolic disorder affecting 422 million the people worldwide and causing life‐threatening associated conditions including disorders of kidney, ...heart, and nervous system as well as leg amputation and retinopathy. Steadily rising cases from the last few decades suggest the failure of currently available drugs in containment of this disease. α‐Glucosidase is a potential target for effectively tackling this disease and attracting significant interest from medicinal chemists around the globe. Besides having a set of side effects, currently available α‐glucosidase inhibitors (carbohydrate mimics) offer better tolerability, safety, and synergistic pharmacological outcomes with other antidiabetic drugs therefore medicinal chemists have working extensively over last three decades for developing alternative α‐glucosidase inhibitors. The 1,2,3‐Triazole nucleus is energetically used by various research groups around the globe for the development of α‐glucosidase inhibitors posing it as an optimum scaffold in the field of antidiabetic drug development. This review is a systematic analysis of α‐glucosidase inhibitors developed by employing 1,2,3‐triazole scaffold with special focus on design strategies, structure‐activity relationships, and mechanism of inhibitory effect. This article will act as lantern for medicinal chemists in developing of potent, safer, and effective α‐glucosidase inhibitors with desired properties and improved therapeutic efficacy.
•Drug resistance pattern among available antibiotics.•Design strategies in the development of anti-MRSA candidates has been rationally analyzed.•Structural insights have been critically ...reviewed.•Pharmacological outcomes have been summarized.•Future perspectives in anti-MRSA drug development with rational utilization of 1,2,3-triazole nucleus has been discussed.
Methicillin-resistant Staphylococcus aureus (MRSA) is an important bacterial pathogen that has the capability to cause mild to life-threatening infections. It has posed a significant threat to the healthcare system across the globe since its emergence in the 1960s. Since then, it has rapidly evolved and developed resistance to various antibiotics from time to time and forced research groups to look for newer antibiotics. Currently, MRSA is resistant to the large portion of available antibiotics in clinical practice which created a global emergency to develop novel and effective antibiotics against MRSA. 1,2,3-Triazole is a diverse nucleus in the field of medicinal chemistry and bioisostere to amide, ester, carboxylic acid and other heterocyclic fragments as well as an integral part of antibacterial agents like cefatrizine and tazobactam, therefore act as an important tool for drug development targeting MRSA. This review will provide, (a) Key information about the pathogenesis and drug resistance pattern of MRSA among available antibiotics. (b) Rational design strategies utilized in the development of anti-MRSA agents using triazole nucleus and (c) Pharmacological outcomes along with a critical discussion on structure activity relationships. This review will help various research groups across the globe in designing novel, potent and effective anti-MRSA agents by rational utilization of 1,2,3-triazole nucleus to overcome drug resistance acquired by MRSA.
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Gamma-Aminobutyric Acid (GABA) inhibitory neurotransmitter departs an energetic role in brain signalling system. Levels of GABA in the brain influence human behaviour, diminishes in the degree of ...GABA can cause seizures, depression, Parkinson's. To put it plainly, it plays a basic part in the significant issues of mind. It is exceptionally important to cure the issues linked to GABA. Writing overview proposed that nipecotic acid is an intense GABA reuptake inhibitor. This scaffold is likewise present in one of the promoted anticonvulsant drugs ‘Tiagabine’. Tiagabine is only drug in the market which works through this mechanism however the medication is regulated with one more prescription for the synergistic impact. Nipecotic acid has several disadvantages such as it can't cross the blood-brain barrier because of its hydrophilic and zwitterionic nature. To avoid this problem nipecotic acid scaffold hybrids with the different aromatic groups can enhance the physical (lipophilicity) as well as biological properties of the resultant compound. So, there is a dire requirement for compounds that work through this mechanism. Several medicinal chemists and researchers are already working in this field and developed outstanding newer molecules. This review article compiles these developed new hybrids along with design strategies, structure-activity relationship, and biological activity as well as in silico studies. This review also demonstrates the synthesis of nipecotic acid and the core mechanism through which nipecotic acid acts as a GABA reuptake inhibitor.
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•Hybrids of Nipecotic acid emerged as potential drug candidates.•In recent years target selectivity is in great focus for the development of selective inhibitors.•The GABA reuptake inhibition of the synthesized potent derivatives was discussed along with their SAR.•The review focused on biological activity, SAR and in silico studies of developed GABA reuptake inhibitors.
Anorexia nervosa (AN) is an eating disorder characterized by restriction of food intake which results in a dangerously low body weight. AN affects approximately 1% of the population, and incidence ...peaks during adolescence. The most recent genome wide association study (GWAS) of AN identified 8 risk loci associated with the condition, as well as significant genetic correlations with anthropometric and metabolic traits. Gaps remain in our understanding of how genetic susceptibility to AN leads to the development of the disorder. Genetic susceptibility to AN (as measured by a polygenic risk score, PRS) is associated with lower body mass index (BMI) and with lower weight gain trajectories in the general population. Whether genetic susceptibility to AN associates with dimensions of childhood psychopathology, including how the genetic overlap with anthropometric and metabolic traits affects these associations, is unknown. We aim to address these questions in a population-based cohort of children.
We obtained GWAS summary statistics for AN (n=72,517) and BMI (n=681,275) from the Psychiatric Genomics Consortium and the GIANT data repository, respectively. To disentangle the genetic correlation between AN and BMI we ran a "GWAS-by-subtraction", resulting in a set of "conditional AN" summary statistics. We developed PRSs for children in the Canadian Healthy Infant Longitudinal Development (CHILD) study, a birth cohort of pregnant women recruited between 2008 and 2012. Genotyping data were available for 2,833 children. At age 5, parents completed the Child Behavior Checklist (CBCL) assessing internalizing (e.g. anxious, withdrawal, somatic, emotionally reactive), externalizing (e.g. attention problems, aggressive behavior), and total problems (a sum of internalizing, externalizing, sleep issues and other problems). We analyzed the associations between PRSs and CBCL scores using linear regression, adjusting for sex and the first 6 genetic principal components.
Our GWAS-by-subtraction results showed that after adjusting for the genetic correlation with BMI, the 8 risk loci for AN had reduced effect sizes, and 3 were no longer genome-wide significant. Conditional AN GWAS results remained highly correlated with psychiatric traits (rg=0.34 for major depressive disorder and rg=0.41 for obsessive compulsive disorder) but showed decreased correlations with anthropometric and metabolic traits (e.g. rg=-0.11 for waist-hip-ratio vs. unconditional rg= -0.22). We restricted initial analyses to 1453 children of European ancestry who had both genotype and CBCL data. Externalizing problem scores were higher for boys than girls on average (6.5 and 5.2 respectively), while internalizing problem scores were similar (5.7 and 5.4). Higher AN PRS was associated with lower externalizing problems (beta= -0.37, p=0.033), specifically attention problems (beta= -0.12, p=0.005). Higher conditional AN PRS was associated only with lower attention problems (beta= -0.09, p=0.044) but not with the composite problem scales.
We found weak associations between genetic susceptibility to AN and dimensions of childhood pathology in a population-based sample of 5-year-old Canadian children. Case-control studies of AN report internalizing symptoms during adolescence as risk factors for the development of eating disorders. Therefore, we will next test the replicability of our findings in the CHILD sample using CBCL data collected at the 8-year visit, and in the UK-based ALSPAC cohort.
Breast cancer is most common in women and most difficult to manage that causes highest mortality and morbidity among all diseases and posing significant threat to mankind as well as burden on ...healthcare system. In 2020, 2.3 million women were diagnosed with breast cancer and it was responsible for 685,000 deaths globally, suggesting the severity of this disease. Apart from that, relapsing of cases and resistance among available anticancer drugs along with associated side effects making the situation even worse. Therefore, it is a global emergency to develop potent and safer antibreast cancer agents. Isatin is most versatile and flying one nucleus which is an integral competent and various anticancer agent in clinical practice and widely used by various research groups around the globe for development of novel, potent, and safer antibreast cancer agents. This review will shed light on the structural insights and antiproliferative potential of various isatin-based derivatives developed for targeting breast cancer in last three decades that will help researchers in design and development of novel, potent, and safer isatin-based antibreast cancer agents.
Keeping in view the inhibitory potential of monoterpenes thymol and carvacrol as well as coumarin nucleus against α-glucosidase, novel series of thymol/carvacrol-coumarin hybrids was designed, ...synthesized and evaluated for α-glucosidase inhibitory potential. Among the series of hybrid molecules, AS14 with IC50 value of 4.32 ± 0.11 μM was selective α-glucosidase inhibitor over α-amylase (IC50 = 37.36 ± 0.84 μM). AS14 was non-toxic toward mouse normal fibroblast cells (L929: IC50 > 100 μM). Molecular docking and dynamic simulation studies confirmed desired interactions of AS14 with α-glucosidase responsible for the inhibition of its catalysis capabilities. Acute oral toxicity study confirmed AS14 as safer molecule for in vivo pharmacological investigations with LD50 value of 300 mg/kg. AS14 also showed acute hypoglycaemic effects reduction in blood glucose levels at 1 h of administration in maltose loading test (at 10 and 20 mg/kg by 62.65 % and 70.12 %) and sucrose loading test (at 10 and 20 mg/kg by 59.65 % and 60.23 %), respectively as well as long term (28 days) fasting blood glucose reduction (At day 28: 10 mg/kg = 54.69 % and 20 mg/kg = 62.23 % reduction in fasting blood glucose levels) capabilities in streptozotocin induced diabetic rats. Overall study represents, AS14 as potential α-glucosidase inhibitor with adequate efficacy and safety profile and act as an effective hit lead for the further development of potent and safer α-glucosidase inhibitors for the management of postprandial hyperglycemia in diabetic patients.
Alzheimer’s disease is a most prevalent form of dementia all around the globe and currently poses a significant challenge to the healthcare system. Currently available drugs only slow the progression ...of this disease rather than provide proper containment. Identification of multiple targets responsible for this disease in the last three decades established it as a multifactorial neurodegenerative disorder that needs novel multifunctional agents for its management and the possible reason for the failure of currently available single target clinical drugs. 1,2,3-Triazole is a miraculous nucleus in medicinal chemistry and the first choice for development of multifunctional hybrid molecules. Apart from that, it is an integral component of various drugs in clinical trials as well as in clinical practice. This review is focused on the pathogenesis of Alzheimer’s disease and 1,2,3-triazole containing derivatives developed in recent decades as potential anti-Alzheimer’s agents. The review will provide (A) precise insight of various established targets of Alzheimer’s disease including cholinergic, amyloid, tau, monoamine oxidases, glutamate, calcium, and reactive oxygen species hypothesis and (B) design hypothesis, structure–activity relationships, and pharmacological outcomes of 1,2,3-triazole containing multifunctional anti-Alzheimer’s agents. This review will provide a baseline for various research groups working on Alzheimer’s drug development in designing potent, safer, and effective multifunctional anti-Alzheimer’s candidates of the future.
Estrogen acting through estrogen receptor β (ERβ) has been shown to oppose the stimulation of cardiac myocytes and cardiac fibroblasts that results in cardiac hypertrophy and fibrosis. Previous work ...has implicated signal transduction from ERβ as being important to the function of estrogen in this regard. Here we address whether membrane ERβ is sufficient to oppose key mechanisms by which angiotensin II (AngII) stimulates cardiac cell pathology. To do this we first defined essential structural elements within ERβ that are necessary for membrane or nuclear localization in cells. We previously determined that cysteine 418 is the site of palmitoylation of ERβ that is required and sufficient for cell membrane localization in mice and is the same site in humans. Here we determined in Chinese hamster ovarian (CHO) cells, and mouse and rat myocytes and cardiac fibroblasts, the effect on multiple aspects of signal transduction by expressing wild-type (WT ) or a C418A-mutant ERβ. To test the importance of the nuclear receptor, we determined a 4-amino acid deletion in the E domain of ERβ that strongly blocked nuclear localization. Using these tools, we expressed WT and mutant ERβ constructs into cardiomyocytes and cardiac fibroblasts from ERβ-deleted mice. We determined the ability of estrogen to mitigate cell pathology stimulated by AngII and whether the membrane ERβ is necessary and sufficient.
Xanthine oxidase, a molybdo-flavoenzyme, and an isoform of xanthine dehydrogenase both exist as xanthine oxidoreductase and are responsible for purine catabolism. Xanthine oxidase is more involved in ...pathological conditions when extensively modulated. Elevation of xanthine oxidase is not only the prime cause of gout but is also responsible for various hyperuricemia associated pathological conditions like diabetes, chronic wounds, cardiovascular disorders, Alzheimer's disease,
etc.
Currently available xanthine oxidase inhibitors in clinical practice (allopurinol, febuxostat and topiroxostat) suffer from fatal side effects that pose a serious problem to the healthcare system, raising global emergency to develop novel, potent and safer xanthine oxidase inhibitors. This review will provide key and systematic information about: a. design strategies (inspired from both marketed drugs in clinical practice and natural products), structural insights and pharmacological output (xanthine oxidase inhibition and associated activities) of various pre-clinical candidates reported by various research groups across the globe in the past two decades; b. patented xanthine oxidase inhibitors published in the last three decades and c. clinical trials and their outcomes on approved drug candidates. Information generated in this review has suggested fragment-based drug design (FBDD) and molecular hybridization techniques to be most suitable for development of desired xanthine oxidase inhibitors as one provides high selectivity toward the enzyme and the other imparts multifunctional properties to the structure and both may possess capabilities to surpass the limitations of currently available clinical drugs. All in combination will exclusively update researchers working on xanthine oxidase inhibitors and allied areas and potentially help in designing rational, novel, potent and safer xanthine oxidase inhibitors that can effectively tackle xanthine oxidase related disease conditions and disorders.
Xanthine oxidase, a molybdo-flavoenzyme, and an isoform of xanthine dehydrogenase both exist as xanthine oxidoreductase and are responsible for purine catabolism.
Candida infections are most prominent among fungal infections majorly target immunocompromised and hospitalized patients and cause significant morbidity and mortality. Candida albicans is the ...notorious and most prevalent among all pathogenic Candida strains. Its emerging resistance toward available antifungal agents making it hard to tackle and emerging as global healthcare emergency. Simultaneously, 1,2,3‐triazole nucleus is a privileged scaffold that is gaining importance in antifungal drug development due to being a prominent bioactive linker and isostere of triazole based antifungal class core 1,2,4‐triazole. Numerous reports have been updated in scientific literature in last few decades related to utilization of 1,2,3‐triazole nucleus in antifungal drug development against Candida albicans. Present review will shed light on various preclinical studies focused on development of 1,2,3‐triazole derivatives targeting Candida albicans along with brief highlight on clinical trials and newly approved drugs. Structure‐activity relationship has been precisely discussed for each architect along with future perspective that will help medicinal chemists in design and development of potent antifungal agents for tackling infections derived from Candida albicans.
