Kunal Nepali

Taipei Medical University | TMU · School of Pharmacy

Introduction: Scaffold hopping has emerged as a practical tactic to enrich the synthetic bank of small molecule antitumor agents. Specifically, it enables the chemist to refine the lead compound's pharmacodynamic, pharmacokinetic, and physiochemical properties. Scaffold hopping opens up fresh molecular territory beyond established patented chemica...

Precedential evidence ascertaining the overexpression of LSD1 and HDACs in colorectal cancer spurred us to design a series of dual LSD1-HDAC inhibitors. Capitalizing on the modular nature of the three-component HDAC inhibitory model, tranylcypromine as a surface recognition motif was appended to zinc-binding motifs via diverse linkers. A compendium...

Introduction: Spleen tyrosine kinase (SYK), a nonreceptor tyrosine kinase, has emerged as a vital component in the complex symphony of cancer cell survival and division. SYK activation (constitutive) is documented in various B-cell malignancies, and its inhibition induces programmed cell death. In some instances, it also acts as a tumor suppressor...

In infectious disease management, antibacterial agents have long been viewed as pivotal tools in the relentless battle against microorganisms. However, the escalating threat of antibacterial drug resistance has emerged as a formidable challenge to global health. Contemporary Approaches to Mitigating Antibacterial Drug Resistance delves into the hea...

The rise of modern antimicrobial drug resistance has evolved into a pressing global health crisis, challenging the very foundation of our ability to combat infectious diseases. The overuse and accessibility of antibiotics, particularly in emerging nations, have given rise to resilient "superbugs," rendering common medications ineffective. This esca...

Structural analysis of tazemetostat, an FDA-approved EZH2 inhibitor, led us to pinpoint a suitable site for appendage with a pharmacophoric fragment of second-generation HSP90 inhibitors. Resultantly, a magnificent dual EZH2/HSP90 inhibitor was pinpointed that exerted striking cell growth inhibitory efficacy against TMZ-resistant Glioblastoma (GBM)...

Proteolysis Targeting Chimeras (PROTACs) technology has emerged as a promising strategy for the treatment of undruggable therapeutic targets. Researchers have invested a great effort in developing druggable PROTACs; however, the problems associated with PROTACs, including poor solubility, metabolic stability, cell permeability, and pharmacokinetic...

Structural tailoring of the flavone framework (position 7) via organopalladium-catalyzed C–C bond formation was attempted in this study. The impact of substituents with varied electronic effects (phenyl ring, position 2 of the benzopyran scaffold) on the antitumor properties was also assessed. Resultantly, the efforts yielded a furyl arm bearing be...

Introduction: PARP inhibitors block the DNA-repairing mechanism of PARP and represent a promising class of anti-cancer therapy. The last decade has witnessed FDA approvals of several PARP inhibitors, with some undergoing advanced-stage clinical investigation. Medicinal chemists have invested much effort to expand the structure pool of PARP inhibit...

The pursuit of activating the HDAC inhibitory template towards additional mechanisms spurred us to design dual modulators (Sig-1R agonist - HDAC inhibitor) via utilization of the core structural unit of donepezil (an FDA-approved anti-Alzheimer's agent) as a surface recognition part. Literature precedents coupled with our experience rendered us wit...

Unprecedented efforts of the researchers have been witnessed in the recent past towards the development of vaccine platforms for the control of the COVID-19 pandemic. Albeit, vaccination stands as a practical strategy to prevent SARS-CoV-2 infection, supplementing the anti-COVID19 arsenal with therapeutic options such as small molecules/peptides an...

Glioblastoma (GBM) is a highly malignant brain tumor characterized by a heterogeneous population of genetically unstable and highly infiltrative cells that are resistant to chemotherapy. Although substantial efforts have been invested in the field of anti-GBM drug discovery in the past decade, success has primarily been confined to the preclinical...

A fragment recruitment process was conducted to pinpoint a suitable fragment for installation in the HDAC inhibitory template to furnish agents endowed with the potential to treat lung cancer. Resultantly, Ring C expanded deoxyvasicinone was selected as an appropriate surface recognition part that was accommodated in the HDAC three-component model....

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 e...

Introduction The tumor microenvironment is mainly flooded with immunosuppressive cells and inhibitory cytokines, resulting in the inability of effective immune cells to infiltrate and recognize tumors and even the loss of anti-cancer ability. Objectives We propose a novel HDAC6/HSP90 dual inhibitory strategy as well as a chemoimmunotherapeutic age...

Protein kinases are amongst the most focused enzymes in current century to design, synthesize and formulate drugs ought to be effective in the treatment of various disordered and diseased states involving either overexpression or deficiency situations. The ATP pocket on the kinases is the binding active site for most of the kinase inhibitors. Howev...

Epigenetic mutations like aberrant DNA methylation, histone modifications, or RNA silencing are found in a number of human diseases. This review article discusses the epigenetic mechanisms involved in neurodegenerative disorders, cardiovascular disorders, auto-immune disorder, and genomic imprinting disorders. In addition, emerging epigenetic thera...

Age-related macular degeneration (AMD) occurs due to an abnormality of retinal pigment epithelium (RPE) cells that leads to gradual degeneration of the macula. Currently, AMD drug pipelines are endowed with limited options, and anti-VEGF agents stand as the dominantly employed therapy. Despite the proven efficacy of such agents, the evidenced side...

Aberrant alteration of epigenetic information disturbs chromatin structure and gene function, thereby facilitating cancer development. Several drugs targeting histone deacetylases (HDACs), a group of epigenetic enzymes, have been approved for treating hematologic malignancies in the clinic. However, patients who suffer from solid tumors often respo...

Epigenetic drug discovery field has evidenced significant advancement in the recent times. A plethora of small molecule inhibitors have progressed to clinical stage investigations and are being explored exhaustively to ascertain conclusive benefits in diverse malignancies. Literature precedents indicates that substantial amount of efforts were dire...

Hurdled and marred by the notorious nature of glioblastomas (GBM) in terms of resistance to therapy and limited drug delivery into the brain, the anti-GBM drug pipeline is required to be loaded with mechanistically diverse agents. The consideration of HDAC inhibition as a prudent approach to circumvent the resistance issue in GBM spurred us to prag...

Aim Terpenes are natural compounds found in several organisms belonging to the animal and plant kingdom, therefore, constitute the largest class of natural products and were a rich reservoir of candidate compounds for drug discovery. The review aims to focus on that the extensive is still needed to explore the anti-cancer components from natural pr...

Background: Quinoline is considered to be a privileged heterocyclic ring owing to its presence in diverse scaffolds endowed with promising activity profiles. In particular, quinoline containing compounds have exhibited substantial antiproliferative effects through diverse mechanism of actions which indicates that the heteroaryl unit is flexible as...

The ocular drug discovery field has evidenced significant advancement in the past decade. The FDA approvals of Rhopressa, Vyzulta, and Roclatan for glaucoma, Brolucizumab for wet age-related macular degeneration (wet AMD), Luxturna for retinitis pigmentosa, Dextenza (0.4 mg dexamethasone intracanalicular insert) for ocular inflammation, ReSure seal...

This study reports the design, synthesis and evaluation of a series of histone deacetylase (HDAC) inhibitors containing purine/purine isoster as a capping group and an N-(2-aminophenyl)-benzamide unit. In vitro cytotoxicity studies reveal that benzamide 14 suppressed the growth of triple-negative breast cancer cells MDA-MB-231 (IC50 = 1.48 μM), MDA...

This study reports the synthesis of a series of 2-aroylisoindoline hydroxamic acids employing N-benzyl, long alkyl chain and acrylamide units as diverse linkers. In-vitro studies led to the identification of N-benzyl linker-bearing compound (10) and long chain linker-containing compound (17) as dual selective HDAC6/HSP90 inhibitors. Compound 17 dis...

Indoline framework is often perpended as a privileged heterocycle present in medicinally valuable compounds of natural and synthetic origin. This review article presents the rational approaches/strategies employed for the design of anticancer indolines along with the structure activity relationship and mechanistic insights revealed in the in-vitro...

A series of 10,11-dihydro-5H-dibenzo [b,f]azepine hydroxamates (4-15) were synthesized, behaving as histone deacetylase inhibitors, and examined for their influence on vascular cognitive impairment (VCI), which correlated with dementia. The results revealed that (E)-3-(4-(((3-(3-chloro-10,11-dihydro-5H-dibenzo [b,f]azepin-5-yl)propyl)amino)methyl)p...

The study is focused on the design and synthesis of amide tethered quinoline-resorcinol hybrid constructs as a new class of HSP90 inhibitor. In-vitro studies of the synthetic compounds led to the identification of compound 11, which possesses potent cell growth inhibitory effects against HCT116, Hep3B and PC-3 cell lines, exerted through HSP90 inhi...

Correction for ‘Benzoflavone derivatives as potent antihyperuricemic agents’ by Jatinder V. Singh et al. , MedChemCommun , 2019, DOI: 10.1039/c8md00512e.

Two series of benzoflavone derivatives were rationally designed, synthesized and evaluated for their xanthine oxidase (XO) inhibitory potential. Among both the series, eight compounds (NF-2, NF-4, NF-9, NF-12, NF-16, NF-25, NF-28, and NF-32) were found to exert significant XO inhibition with the IC50 values lower than 10 µM. Enzyme kinetic studies...

We report structure-activity relationships of 1-arylsulfonyl indoline based benzamides. The benzamide (9) exhibits striking tubulin inhibition with an IC50 value of 1.1 μM, better than that of combretastain A-4 (3), and substantial antiproliferative activity against a variety of cancer cells, including MDR-positive cell lines with an IC50 value of...

The nitro group is considered to be a versatile and unique functional group in medicinal chemistry. Despite a long history of use in therapeutics, the nitro group has toxicity issues and is often categorized as a structural alert or a toxicophore, and evidence related to drugs containing nitro groups is rather contradictory. In general, drugs conta...

Correction for ‘2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition’ by Kunal Nepali et al. , Org. Biomol. Chem. , 2016, 14 , 716–723.

In an effort to discover an effective and selective antitumour agent, synthesis and anti-cancer potential of 4-(pyridin-4-yl)-6-(thiophen-2-yl)pyrimidin-2(1H)-one (SK-25), which has been reported earlier by us with significant cytotoxicity towards MiaPaCa-2 malignant cells, with an IC50 value of 1.95 μM and was found to instigate apoptosis. In the...

A series of 1-aroylindoline-hydroxamic acids have been synthesized in the present study. The results of the biological evaluation led to the identification of compound 12 as dual HDAC6/HSP90 inhibitor. Compound 12 displayed striking inhibitory effects towards the HDAC6 isoform and HSP 90 protein with IC50values of 1.15 nM (HDAC6) and 46.3 nM (HSP90...

In an effort to discover an effective and selective antitumour agent, synthesis and anti-cancer potential of 4-(pyridin-4-yl)-6-(thiophen-2-yl)pyrimidin-2(1H)-one (SK-25), which has been reported earlier by us with significant cytotoxicity towards MiaPaCa-2 malignant cells, with an IC50 value of 1.95 μM and was found to instigate apoptosis. In the...

A series of bicyclic arylamino/heteroarylamino hydroxamic acids (7-31) have been examined as novel histone deacetylase 6 (HDAC6) inhibitors. One compound (13) exhibits remarkable inhibitory activity of HDAC6 with an IC50 value of 0.29 nM, which is 4000-43000 times more selective over other HDAC isoforms. Compound 13 was shown to have antiproliferat...

Hydroxamic acids are a potent class of drugs that act epigenetically to control various pharmacological functions and are currently used for the treatment of various cancers. To better understand their function and role, one must first understand the difference between genetic and epigenetics.

Pyran is a therapeutically vital oxygen containing heterocyclic moiety which exhibits an array of credible pharmacological properties. Pyran is also one of the important structural units found widely in natural products, such as coumarins, benzopyrans, sugars, flavonoids, xanthones and other natural products. The diverse anticancer capabilities of...

Pyran is an oxygen-containing heterocyclic moiety, which exhibits an array of pharmacological properties. Pyran is also one of the important structural subunits found widely in natural products, e.g. coumarins, benzopyrans, sugars, flavonoids, xanthones, etc. The diverse anticancer capabilities of pyrans have been additionally evidenced by the fact...

Pyran is an oxygen-containing heterocyclic moiety, which exhibits an array of pharmacological properties. Pyran is also one of the important structural subunits found widely in natural products, e.g. coumarins, benzopyrans, sugars, flavonoids, xanthones, etc. The diverse anticancer capabilities of pyrans have been additionally evidenced by the fact...

In an attempt to develop potent anti-tubulin agents against most dreadful disease cancer, a library of 28 novel triazole tethered isatin-coumarin hybrids were synthesized by click chemistry approach. Synthesized hybrids were characterized and evaluated against a panel of human cancer cell lines viz. THP-1, COLO-205, HCT-116 and PC-3. Biological ass...

In view of developing effective xanthine oxidase (XO) enzyme inhibitors, a series of 100 pyrano[3,2-d]pyrimidine derivatives were synthesized and evaluated for their in vitro XO enzyme inhibition. Structure activity relationship was also established. Among all the synthesized compounds, 4d, 8d and 9d were found to be the most potent enzyme inhibito...

A library of forty 7,8-Benzoflavone derivatives was synthesized and evaluated for their inhibitory potential against cholesterol esterase (CEase). Among all the synthesized compounds seven benzoflavone derivatives (A-7, A-8, A-10, A-11, A-12, A-13, A-15) exhibited significant inhibition against CEase in in vitro enzymatic assay. Compound A-12 showe...

This study is focused on modification of the indole moiety and the N1-zinc binding domain of tubastatin A, and the effects of such changes on biological activity. Fourteen N-substituted indoles (5-18) were synthesized and structure-activity relationship studies indicated that the change of the tetrahydro-γ-carboline in tubastatin A led to substitut...

Idiopathic pulmonary fibrosis (IPF), a chronic and progressive fibrosing interstitial pneumonia is a fatal lung disease with a median survival time of 3-5 years. Problems in accurate diagnosis, poor prognosis, limited clinical therapy and high mortality rate together demonstrate that the development of efficient therapeutic strategies for IPF is an...

Introduction: Xanthine oxidase (XO) is a versatile molybdoflavoprotein, widely distributed, occurring in milk, kidney, lung, heart, and vascular endothelium. Catalysis by XO to produce uric acid and reactive oxygen species leads to many diseases. Anti hyperuricemic therapy by xanthine oxidase inhibitors has been mainly employed for the treatment of...

Background: Topoisomerases are a set of nuclear enzymes that play a vital role in handling of topological consequences of DNA during various genetic activities necessary for vitality of cell. Inhibition of these enzymes consequently leads to the blockage of ligation step of the cell cycle which generates single and double strand breakage in DNA st...

Introduction: Microtubules represent one of the most logical and strategic molecular targets amongst the current targets for chemotherapy, alongside DNA. In the past decade, tubulin inhibitors as cancer therapeutics have been an area of focus due to the improved understanding and biological relevance of microtubules in cellular functions. Fueled b...

Keeping in view the confines allied with presently accessible antitumor agents and success of C5-curcuminoid based bifunctional hybrids as novel antitubulin agnets, molecular hybrids of C5-curcuminoid and coumarin tethered by triazole ring have been synthesized and investigated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and PC-3 hum...

The present study involves the design and synthesis of naphthoflavones as antiproliferative agents. The strategy presents naphthoflavones as hybrids of naphthyl based chalcones and flavones. A panel of human cancer cell lines were employed for the cytotoxicity studies. DK-13 exhibited significant cytoxicity against MiaPaCa-2 cell lines with IC50 va...

Kinases control a diverse set of cellular processes comprising of reversible phosphorylation of proteins. Protein kinases play a pivotal role in human tumor cell proliferation, migration and survival of neoplasia. In the recent past, purine based molecules have emerged as significantly potent kinase inhibitors. In view of their promising potential...

Background: Recent researches and relevant patents have been reported to prove the significant value of Caveolin-1 (Cav-1) in cancer diagnosis and treatment. Objective: Our study aimed to study the role of Cav-1 in gastric cancer progression and investigate the relationship between Cav-1/E-cadherin expression and the clinical status of gastric c...

Quinazoline scaffold has been successfully utilized for development of various inhibitors of tubulin, epidermal growth factor receptor (EGFR), Hedgehog-Gli Signaling, polo like kinase (PLKs) and protein kinase B (PKB)/Akt. Compounds based on quinazolines have shown efficacies in µM to nM range in various cancer cell lines and could be useful scaffo...

Background: Crotepoxide is a potent molecule for the development of anticancer pharmacodynamics therefore; estimation process for such novel compound is highly desired for future research work in the field of natural products. Introduction: Piper attenuatum is an important species used as a drug in Ayurvedic system of medicine. Pipoxide chlorohydri...

Protein kinases constitute one of the largest and most functionally diverse gene families that regulate key cell functions. In past several years, kinase inhibitors have developed as potential Anti-cancer drug targets. Purine, a heterocyclic aromatic organic compound, is a privileged structure for various bioactive molecules. Numerous reports on th...

A series of 4-aryl/heteroaryl-4H-fused pyrans was synthesized via multicomponent reaction in a microwave synthesizer. All the pyrans were evaluated for in vitro xanthine oxidase inhibition. Structure–activity relationship was also established. Among the series of 108 compounds, Compound 5n was the most potent displaying remarkable inhibition agains...

4,6-diarylpyrimidones as constrained chalcone analogues have been synthesised in the present study. The synthesised compounds were evaluated agaisnt a panel of human cancer cell lines. Striking selectivity was displayed by the compounds against MiaPaca-2 (Breast) cell lines while PC-3 (prostate) and A-549 (lung) cell lines were almost resistant to...

4,6-diarylpyrimidones as constrained chalcone analogues have been synthesised in the present study. The synthesised compounds were evaluated agaisnt a panel of human cancer cell lines. Striking selectivity was displayed by the compounds against MiaPaca-2 (Breast) cell lines while PC-3 (prostate) and A-549 (lung) cell lines were almost resistant to...

Molecular hybridization (MH) is a strategy of rational design of such ligands or prototypes based on the recognition of pharmacophoric sub-units in the molecular structure of two or more known bioactive derivatives which, through the adequate fusion of these sub-units, lead to the design of new hybrid architectures that maintain pre-selected charac...

Numerous reports highlighting the cytotoxic effects of 3,5-diaryl N-acetyl-pyrazolines and isatin tempted us to synthesise conjugates of the functionalities via alkyl armed triazole tetheration. The hybrids were synthesized by click chemistry approach and were evaluated against a panel of cell lines i.e. viz HeLa (cervix cancer), CAKI-I (Renal canc...

Abstract Keeping in view the recent success of molecular hybridization technique in drug design, 2,4-diarylpyrano[3,2-c]chromen-5(4H)-ones as conjugates of coumarins and chalcones have been designed and synthesized in the present study. The catalytic efficiency of various Lewis acids for the synthesis of designed conjugates under neat conditions wa...

Pyrimidine ring is the building unit of DNA and RNA and thus pyrimidine based chemical architectures exhibit diverse pharmacological activities. Among the reported medicinal attributes of pyrimidines, anticancer activity is most extensively reported. The anticancer potential of pyrimidines in fused scaffolds has also been evidenced through number o...

Asthma is characterized by persistent airway inflammation caused by over expression of pro-inflammatory immune response, predominantly by eosinophils and lymphocytes. Lymphocytes (CD4+ Th2) have been documented to be responsible for the pathogenesis of asthma by secreting Th2 cytokines and activating eosinophils, leading to airway hypersensitivity....

The present study involves the design of a series of 3-aryl-9-acetyl-pyridazino[3,4-b]indoles as constrained chalcone analogues. A retrosynthetic route was proposed for the synthesis of target compounds. All the synthesized compounds were evaluated for in-vitro cytotoxicity against THP-1, COLO-205, HCT-116 and A-549 human cancer cell lines. The res...

In view of reported xanthine oxidase inhibitory potential of naphthopyrans and flavones, naphthoflavones as hybrids of the two were designed, synthesized and evaluated for in vitro xanthine oxidase inhibitory activity in the present study. The results of the assay revealed that the naphthoflavones possess promising inhibitory potential against the...

A series of 4,6-diaryl/heteroarylpyrimidones was synthesized employing silica-supported fluoroboric acid under solvent-free conditions in a microwave reactor. The catalytic influence of HBF4-SiO2 was investigated in detail to optimize the reaction conditions. The synthesized compounds were evaluated for in vitro xanthine oxidase (XO) inhibitory act...

The molecular hybridization (MH) is a strategy of rational design of such ligands or prototypes based on the recognition of pharmacophoric sub-units in the molecular structure of two or more known bioactive derivatives which, through the adequate fusion of these sub-units, lead to the design of new hybrid architectures that maintain pre-selected ch...

A Hybrid drug which comprises the incorporation of two drug pharmacophores in one single molecule are basically designed to interact with multiple targets or to amplify its effect through action on another bio target as one single molecule or to counterbalance the known side effects associated with the other hybrid part(.) The present review articl...

Cited By (since 1996):1, Export Date: 18 October 2014