Recent Developments in 1,2,3-Triazole based α-Glucosidase Inhibitors: Design Strategies, Structure-activity Relationship and Mechanistic Insights.

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.

Coumarin as an Elite Scaffold in Anti-Breast Cancer Drug Development: Design Strategies, Mechanistic Insights, and Structure-Activity Relationships.

Breast cancer is the most common cancer among women. Currently, it poses a significant threat to the healthcare system due to the emerging resistance and toxicity of available drug candidates in clinical practice, thus generating an urgent need for the development of new potent and safer anti-breast cancer drug candidates. Coumarin (chromone-2-one) is an elite ring system widely distributed among natural products and possesses a broad range of pharmacological properties. The unique distribution and pharmacological efficacy of coumarins attract natural product hunters, resulting in the identification of numerous natural coumarins from different natural sources in the last three decades, especially those with anti-breast cancer properties. Inspired by this, numerous synthetic derivatives based on coumarins have been developed by medicinal chemists all around the globe, showing promising anti-breast cancer efficacy. This review is primarily focused on the development of coumarin-inspired anti-breast cancer agents in the last three decades, especially highlighting design strategies, mechanistic insights, and their structure-activity relationship. Natural coumarins having anti-breast cancer efficacy are also briefly highlighted. This review will act as a guideline for researchers and medicinal chemists in designing optimum coumarin-based potent and safer anti-breast cancer agents.

Triazole derivatives as potential xanthine oxidase inhibitors: Design, enzyme inhibition potential, and docking studies.

Considerable ingenuity has been shown in the recent years in the discovery of novel xanthine oxidase (XO) inhibitors that fall outside the purine scaffold. The triazole nucleus has been the cornerstone for the development of many enzyme inhibitors for the clinical management of several diseases, where hyperuricemia is one of them. Here, we give a critical overview of significant research on triazole-based XO inhibitors, with respect to their design, synthesis, inhibition potential, toxicity, and docking studies, done till now. Based on these literature findings, we can expect a burst of modifications on triazole-based scaffolds in the near future by targeting XO, which will treat hyperuricemics, that is, painful conditions like gout that at present are hard to deal with.

The development of thymol-isatin hybrids as broad-spectrum antibacterial agents with potent anti-MRSA activity.

Bacterial resistance toward available therapeutic agents has become a nightmare for the healthcare system, causing significant mortality as well as prolonged hospitalization, thereby needing the urgent attention of research groups working on antimicrobial drug development worldwide. Molecular hybridization is a well-established tool for developing multifunctional compounds to tackle drug resistance. Inspired by the antibacterial profiles of isatin and thymol, along with the efficiency of a triazole linker in molecular hybridization, herein, we report the design, synthesis and antibacterial activity of a novel series of triazole tethered thymol-isatin hybrids. Most of the hybrids exhibited a broad-spectrum antibacterial efficacy against standard human pathogenic as well as clinically isolated multidrug-resistant bacterial strains listed in the WHO's 'priority pathogen' list and also in the ESKAPE group. Among them, hybrid compound AS8 was the most effective against methicillin-resistant Staphylococcus aureus (MIC = 1.9 µM and MBC = 3.9 µM), exhibiting biofilm inhibitory potential. AS8 exhibited dehydrosqualene synthase (CrtM) inhibitory potential in MRSA and decreased the production of virulence factor staphyloxanthin, which is one of the key mechanisms of its anti-MRSA efficacy, which was further supported by molecular docking and simulation studies. Moreover, AS8 was found to be non-toxic and showed a potent in vivo antibacterial efficacy (90% survival at 10 mg kg-1) as well as a modulated immune response in the larva-based (Galleria mellonella) model of systemic infections. Overall findings confirmed that AS8 can be a promising candidate or take the lead in the treatment and further drug development against drug-resistant infectious diseases, especially against MRSA infections.

Antidiabetic potential of thiazolidinedione derivatives with efficient design, molecular docking, structural activity relationship, and biological activity: an update review (2021-2023).

Thiazolidinedione has been used successfully by medicinal chemists all over the world in the development of potent antidiabetic derivatives. The few compounds with excellent antidiabetic potency that we have identified in this review could be used as a lead for further research into additional antidiabetic mechanisms. The information provided in this review regarding the design, biological activity, structure-activity relationships, and docking studies may be useful for scientists who wish to further explore this scaffold in order to fully utilize its biological potential and develop antidiabetic agents that would overcome the limitations of currently available medications for the treatment of diabetes. This review outlines the antidiabetic potential of Thiazolidinedione-based derivatives that have been published in the year 2021- till date.

Pathology, target discovery, and the evolution of XO inhibitors from the first discovery to recent advances (2020-2023).

Hyperuricemia, a disease characterized by elevation of serum uric acid level beyond 6 mg/dL. This elevation led to appearance of symptoms from joint pain to gout and from gout to difficulty in mobility of the patient. So, in this review, we have summarized the pathology of hyperuricemia, discovery of target and discovery of first XO inhibitor. At last, this review provides in-sights about the recently discovered as natural XO inhibitors, followed by design, structure activity relationship and biological activity of synthetic compounds as XO inhibitors discovered between 2020 and 2023 years. At last, the pharmacophores generated in this study will guide new researchers to design and modify the structure of novel XO inhibitors.

Past, present and future of xanthine oxidase inhibitors: design strategies, structural and pharmacological insights, patents and clinical trials.

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.

Molecular modeling, dynamic simulation, and metabolic reactivity studies of quinazoline derivatives to investigate their anti-angiogenic potential by targeting wild EGFRwt and mutant EGFRT790M receptor tyrosine kinases.

Non-small cell lung cancer, head and neck cancer, glioblastoma, and various other cancer types often demonstrate persistent elevation in EGFR tyrosine kinase activity due to acquired mutations in its kinase domain. Any alteration in the EGFR is responsible for triggering the upregulation of tumor angiogenic pathways, such as the PI3k-AKT-mTOR pathway, MAPK-ERK pathway and PLC-Ƴ pathway, which are critically involved in promoting tumor angiogenesis in cancer cells. The emergence of frequently occurring EGFR kinase domain mutations (L858R/T790M/C797S) that confer resistance to approved therapeutic agents has presented a significant challenge for researchers aiming to develop effective and well-tolerated treatments against tumor angiogenesis. In this study, we directed our efforts towards the rational design and development of novel quinazoline derivatives with the potential to act as antagonists against both wild-type and mutant EGFR. Our approach encompasing the application of advanced drug design strategies, including structure-based virtual screening, molecular docking, molecular dynamics, metabolic reactivity and cardiotoxicity prediction studies led to the identification of two prominent lead compounds: QU648, for EGFRwt inhibition and QU351, for EGFRmt antagonism. The computed binding energies of selected leads and their molecular dynamics simulations exhibited enhanced conformational stability of QU648 and QU351 when compared to standard drugs Erlotinib and Afatinib. Notably, the lead compounds also demonstrated promising pharmacokinetic properties, metabolic reactivity, and cardiotoxicity profiles. Collectively, the outcomes of our study provide compelling evidence supporting the potential of QU648 and QU351 as prominent anti-angiogenic agents, effectively inhibiting EGFR activity across various cancer types harboring diverse EGFR mutations.Communicated by Ramaswamy H. Sarma.

Pathogenesis of Alzheimer's Disease and Diversity of 1,2,3-Triazole Scaffold in Drug Development: Design Strategies, Structural Insights, and Therapeutic Potential.

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.

Anticonvulsant potential of Grewia tiliaefolia in pentylenetetrazole induced epilepsy: insights from in vivo and in silico studies.

Epilepsy, a chronic neurological condition, impacts millions of individuals globally and remains a significant contributor to both illness and mortality. Available antiepileptic drugs have serious side effects which warrants to explore different medicinal plants used for the management of epilepsy reported in Traditional Indian Medicinal System (TIMS). Therefore, we explored the antiepileptic potential of the Grewia tiliaefolia (Tiliaeceae) which is known for its neuroprotective properties. Aerial parts of G. tiliaefolia were subjected to extraction with increasing order of polarity viz. hexane, chloroform and methanol. Antioxidant potential of hexane, chloroform and methanol extracts of G. tiliaefolia was evaluated by 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) assay, total antioxidant capacity (TAC) assay, reducing power assay (RPA) and DNA nicking assay. Additionally, quantitative antioxidant assays were also conducted to quantify total phenolic (TPC) and total flavonoid content (TFC). As revealed by in vitro assays, methanol extract was found to contain more phenolic content. Hence, the methanol extract was further explored for its anticonvulsant potential in pentylenetetrazole (PTZ) induced acute seizures in mice. The methanol extract (400 mg/kg) significantly increased the latency to occurrence of myoclonic jerks and generalized tonic clonic seizures (GTCS). Additionally, it also reduced duration and seizure severity score associated with GTCS. The Grewia tiliaefolia methanol extract was further screened by Ultra High-Performance Liquid Chromatography (UHPLC) for presence of polyphenolic compounds, among which gallic acid and kaempferol were present in higher amount and were further analysed by in silico study to predict their possible binding sites and type of interactions these compounds show with gamma amino butyric acid (GABA) receptor and glutamate α amino-3- hydroxyl-5-methyl-4-isoxazolepropionic acid (Glu-AMPA) receptor. It was revealed that gallic acid and kaempferol had shown agonistic interaction for GABA receptor and antagonistic interaction for Glu-AMPA receptor. We concluded that G. tiliaefolia showed anticonvulsant potential possibly because of gallic acid and kaempferol possibly mediated through GABA and Glu-AMPA receptor.

Mechanistic insight and structure activity relationship of isatin-based derivatives in development of anti-breast cancer agents.

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.

Recent advances in antifungal drug development targeting lanosterol 14α-demethylase (CYP51): A comprehensive review with structural and molecular insights.

Fungal infections are posing serious threat to healthcare system due to emerging resistance among available antifungal agents. Among available antifungal agents in clinical practice, azoles (diazole, 1,2,4-triazole and tetrazole) remained most effective and widely prescribed antifungal agents. Now their associated side effects and emerging resistance pattern raised a need of new and potent antifungal agents. Lanosterol 14α-demethylase (CYP51) is responsible for the oxidative removal of 14α-methyl group of sterol precursors lanosterol and 24(28)-methylene-24,25-dihydrolanosterol in ergosterol biosynthesis hence an essential component of fungal life cycle and prominent target for antifungal drug development. This review will shed light on various azole- as well as non-azoles-based derivatives as potential antifungal agents that target fungal CYP51. Review will provide deep insight about structure activity relationship, pharmacological outcomes, and interactions of derivatives with CYP51 at molecular level. It will help medicinal chemists working on antifungal development in designing more rational, potent, and safer antifungal agents by targeting fungal CYP51 for tackling emerging antifungal drug resistance.

1,2,3-Triazole Derivatives as an Emerging Scaffold for Antifungal Drug Development against Candida albicans: A Comprehensive Review.

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.

Shikonin derivatives as potent xanthine oxidase inhibitors: in-vitro study.

Induction of hypersensitivity reactions (may be fatal too) by specific XO inhibitors has led to development of new molecules that are efficacious and have safer ADME profile. Among natural compounds, biologically active Alkannin/Shikonin (A/S) derivatives have unexplored XO inhibition potential. Therefore, their iso-hexenylnaphthazarin nucleus was studied and found that the nucleus is similar to that of allopurinol, signifying the XO inhibitory potential of these derivatives. For confirmation of their potential, ß,ß-dimethylacrylshikonin and deoxyshikonin were successfully isolated and characterised from Arnebia euchroma (Royle.) Johnst. (Boraginaceae) and were evaluated for in vitro XO inhibitory potential. ß,ß-dimethylacrylshikonin and deoxyshikonin showed a good XO inhibition potential with IC50 values of 7.475 ± 1.46 µg/mL and 4.487 ± 0.88 µg/mL, respectively. Results also validated the pharmacophore hypothesis, and it was concluded that nucleus iso-hexenylnaphthazarin can be remodelled for optimising the efficacy.

Quinoline derivatives volunteering against antimicrobial resistance: rational approaches, design strategies, structure activity relationship and mechanistic insights.

Emergence of antimicrobial resistance has become a great threat to human species as there is shortage of development of new antimicrobial agents. So, its mandatary to combat AMR by initiating research and developing new novel antimicrobial agents. Among phytoconstituents, Quinoline (nitrogen containing heterocyclic) have played a wide role in providing new bioactive molecules. So, this review provides rational approaches, design strategies, structure activity relationship and mechanistic insights of newly developed quinoline derivatives as antimicrobial agents.

Dihydrofolate reductase inhibitors: patent landscape and phases of clinical development (2001-2021).

INTRODUCTION: Dihydrofolate reductase (DHFR) plays an important role in the biosynthesis of amino acid and folic acid. It participates by reducing dihydrofolate to tetrahydrofolate, in the presence of nicotinamide dinucleotide phosphate cofactor, and has been verified by various clinical studies to use DHFR as a target for the treatment of cancer and various bacterial infections. AREA COVERED: In this review, we have disclosed patents of synthetics and natural DHFR inhibitors with diaminopyrimidine and quinazoline nucleus from 2001. Additionally, this review highlights the clinical progression of numerous DHFR inhibitors received from the last five years. EXPERT OPINION: From 2001 to 2021, numerous active chemical scaffolds have been introduced and are exposed as lead candidates that have entered clinical trials as potent DHFR inhibitors. Moreover, researchers have paid considerable attention to the development of a new class of DHFR inhibitors with higher selectivity and potency. This development includes synthesis of synthetic as well as natural compounds that are potent DHFR inhibitors. On the basis of literature review, we can anticipate that there are a huge number of novel active molecules available for the future that could possess superior abilities to target this enzyme with a profound pharmacological profile.

Evaluation of HPV E6/E7 mRNA Detection in Clinically Suspected Cases of Cervical Cancer with Abnormal Cytology: Time to Upgrade the Screening Protocols.

Background Human papillomavirus (HPV) E6/E7 mRNA tests determine the oncogenic activity of the virus and represent a good clinical biomarker for predicting the risk of cervical cancer. So, the present study was conducted to know the role of HPV E6/E7 mRNA as a predictive biomarker for cervical carcinoma. Methodology The present study was conducted on 55 clinical samples of cervical scrapings and biopsy from the clinically suspected cases (based on signs and symptoms) of cervical cancer having abnormal PAP smear. The samples were processed in three steps-(1) HPV DNA detection, (2) HPV E6/E7 mRNA detection, and (3) histopathological analysis. Results Out of a total of 55 patients, 16 (29.09%) were positive for both HPV E6/E7 mRNA and HPV DNA and six were positive for only HPV DNA. So, a total of 22 (40%) patients were positive for HPV DNA. Out of these 22 samples, 10 (45.5%) were of HPV-16, six (27.3%) were of HPV-18, four (18.2%) were of HPV-31, and two (9.1%) were of HPV-45. Out of total 16 patients positive for HPV E6/E7 mRNA, 10 (62.5%) were of genotype 16 and six (37.5%) were of genotype 18. The patients who were found positive for HPV 31 and 45 genotypes did not have E6/E7 mRNA expression. On colposcopic-guided biopsy, among these 16 samples, eight (50%) were diagnosed with invasive squamous cell carcinoma, six (37.5%) with cervical intraepithelial neoplasia grade 3 (CIN3), and two (12.5%) with CIN2. Out of those six patients in whom only HPV DNA was positive, five had normal biopsy findings and one had CIN1. Conclusion The present study suggests that HPV E6/E7 mRNA detection could be more reliable than DNA testing for predicting the risk of progression of HPV-induced cervical lesions to cervical carcinoma and it can be used as a non-invasive tool for triage and patient follow-up.

Protective effect of Grewia asiatica leaves extract in animal models of epilepsy and anxiety.

Grewia asiatica Linn. is a well-known plant for its nutritional and therapeutic attributes. It has been mentioned in ancient Indian literature as Rasayana due to its stimulant and tonic effects. Thus, present investigation was carried out to evaluate the antiepileptic and anxiolytic action of G. asiatica Linn. leaves using animal models. Methanol extract at dose levels of 100 and 200 mg/kg was capable of providing protection against both pentylenetetrazole and maximal electroshock induced seizures in mice. Extract also showed significant anxiolytic activity in elevated plus maze, light/dark box and mirror chamber mice models at same dose levels. Results of this study indicated that the methanol extract of leaves of G. asiatica plant possess significant antiepileptic and anxiolytic effect.

Synthetic heterocyclic derivatives as promising xanthine oxidase inhibitors: An overview.

Inhibition of xanthine oxidase (XO) is an effective and most prominent therapeutic approach for the management of gout. Discovery of its association in the pathophysiology of diabetes, cardiovascular disorders, etc., widened its therapeutic horizons. Limited drug candidates in clinical practice along with side effects forced researchers to develop more efficacious and safer XO inhibitors for the management of gout and other disorders associated with XO hyperactivity. In this regard, this review focus on (a) various drug candidates in clinical practice and under clinical trials, (b) Development of various heterocyclic motifs as XO inhibitors in last two decades and (c) various patented synthetic XO inhibitors.

Design, synthesis, and biological evaluation of isatin-indole-3-carboxaldehyde hybrids as a new class of xanthine oxidase inhibitors.

A novel series of triazole-linked isatin-indole-3-carboxaldehyde hybrids based on the febuxostat skeleton and its binding site interactions were rationally designed and synthesized as potential xanthine oxidase inhibitors. Among the synthesized hybrids, A19 showed the most potent xanthine oxidase inhibition (IC50 = 0.37 µM) with the mixed-type inhibitory scenario. Structure-activity relationship studies revealed that methoxy (OCH3 ) substitution on position 5 of the isatin nucleus and a two-carbon distance between isatin and the triazole moiety is most tolerable for the inhibitory potential. Various binding interactions of A19 with the binding site of xanthine oxidase are also streamlined by molecular docking studies, which showcase the favorable binding pattern for xanthine oxidase inhibition by the hybrid. Furthermore, molecular dynamic studies were performed that suggest the stability of the enzyme-hybrid complex. Overall, the study suggests that hybrid A19 can act as an effective hit lead for further development of potent xanthine oxidase inhibitors.