AIM:The increasing burden of breast cancer and drug resistance highlights the need for new chemotherapeutic agents. This study aimed to design and evaluate novel cycloarylchalcone derivatives as potential anticancer candidates targeting microtubules. MATERIALS & METHODS:A series of cycloarylchalcone derivatives containing a cyclohexenone core (CY1-10) were synthesized via Claisen-Schmidt condensation followed by Michael addition. Structural variations at the R and R1 positions were introduced to optimize activity. The cytotoxicity of the compounds was evaluated against MCF-7 and MDA-MB-231 breast cancer cell lines using the MTT assay, with colchicine as the reference drug. Molecular docking was performed using Schrödinger Maestro against the tubulin colchicine-binding site (PDB ID: 1SA0). ADME and toxicity profiles were also assessed. RESULTS:Compound CY2 demonstrated the most potent cytotoxicity with IC50 values of 4.34 ± 0.37 µM (MCF-7) and 5.19 ± 0.26 µM (MDA-MB-231). Electron-donating substituents at both R and R1 positions enhanced activity. CY1 exhibited the best docking score (-7.506 kcal/mol) with key interactions at CYS241. ADME screening suggested good oral bioavailability, and compounds displayed acceptable toxicity (LD50 = 860-2000 mg/kg). CONCLUSIONS:Cycloarylchalcone derivatives exhibited promising anticancer activity and represent potential leads for further preclinical development.

Alzheimer's disease (AD) is an irreversible neurodegenerative disorder characterised by progressive cognitive decline, neuronal loss and accumulation of β-amyloid plaques and neurofibrillary tangles. Even after many years of intensive research, scientists still have not found a cure for AD. The current medications can only help to manage the symptoms of AD or slow down the disease progression. This highlights an urgent and unmet need for the development of novel therapeutic agents capable of simultaneously modulating the multifactorial pathological pathways that drive the onset and progression of AD. The multitarget-directed ligand approach has garnered considerable attention in this context, aiming to simultaneously modulate multiple disease-relevant targets, including AChE, BChE, MAO-A and MAO-B, BACE1, and oxidative stress mediators. Indole, a fortunate heterocyclic scaffold, has become a valuable tool for the design and development of multi-target directed ligands in anti-Alzheimer drug discovery due to its favourable physicochemical properties, BBB permeability and medicinal attributes. This review summarises recent advancements in the medicinal chemistry of indole hybrids as anti-Alzheimer agents, highlighting the impact of structural modifications on biological activity, including the underlying molecular mechanisms, structure-activity relationships, and computational studies. The findings summarised in the article can pave the way for future anti-Alzheimer drug discovery.

AIM:Inspired by our previous research findings and to explore the effect of N-3 and C-5 substitution in relation to pancreatic lipase (PL) inhibitory activity, the present study aims at the design and synthesis of a series of disubstituted thiazolidinedione (TZD) derivatives and to evaluate their PL inhibitory activity. METHODS:A series of disubstituted TZD derivatives was synthesized by condensing various aldehydes on C-5 and substituting 4-fluorobenzyl on N-3 of TZD. The synthesized derivatives were screened for PL inhibitory activity. Further, kinetic study and various in silico studies were also performed. RESULTS AND CONCLUSION:Compound 16f displayed most potent inhibitory activity with IC50 value of 4.58 μM. Kinetic studies revealed competitive mode of inhibition for 16f, 16g, and 16r with Ki values 1.479, 1.827, and 1.939 μM; while their Vmax values were found to be 0.611, 0.958, and 0.939 μM, respectively. Docking studies confirmed good binding affinities of synthesized derivatives toward the active site of PL. Molecular dynamic simulation of 16f revealed stability of the protein-ligand complex. Moreover, compound 16f was predicted to have a satisfactory drug likeness profile. Compound 16f can be used as a leading candidate for further structural optimization to identify more potent and efficacious PL inhibitors as anti-obesity agents.

The ongoing challenge of addressing breast cancer, one of the most prevalent cancers and a principal cause of mortality among women globally, has reached a critical juncture with the advent of precision medicine and the promise of nanotechnology. As the scientific community’s understanding of breast cancer’s genomic landscape has deepened, it has become evident that a one-size-fits-all approach to treatment is obsolete. The evolution from rudimentary immunohistochemical classifications to intricate molecular profiling has ushered in an era where therapy is increasingly tailored to the individual’s genetic makeup, environmental factors, and lifestyle choices. This shift towards personalized, biomarker-driven treatments not only aims to enhance prognosis but also to minimize adverse effects by meticulously matching therapy to the unique molecular characteristics of each tumor. The integration of nanotechnology, particularly through the deployment of nanoparticles for targeted drug delivery and nano-theranostics, represents a groundbreaking stride in oncological treatment. This convergence of precision medicine and nanotechnology in breast cancer care suggests a future where combination therapies and multifunctional approaches could potentially outsmart drug resistance and augment treatment efficacy. However, the path forward is fraught with challenges such as overcoming inherent tumor heterogeneity and improving the accessibility of cutting-edge treatments. The exploration of these innovative strategies in breast cancer therapeutics underscores the critical need for a multifaceted approach to cancer care, emphasizing the potential of these advances to revolutionize treatment paradigms and offer new hope to patients.

In the current study, a series of 22 prenylated arylidene appended thiazolidinedione derivatives were designed, synthesized, and evaluated for pancreatic lipase (PL) inhibitory activity. The study led to the identification of compounds exhibiting potent to moderate inhibitory activities with IC50 values ranging between 6.18 ± 0.46 and 52.75 ± 2.34 µM. Among them, compound 22b demonstrated remarkable PL inhibitory activity with an IC50 value of 6.18 ± 0.46 µM. Enzyme kinetics studies revealed a reversible competitive mode of inhibition for 22b with a Ki value of 4.1 μM. The results of in vitro findings further supported the outcome of in silico studies, which correlate the strong binding affinity of compound 22b for PL. Molecular docking studies confirmed satisfactory binding mode of compounds within the active site of PL by exhibiting various interactions such as H-bonding, π-π stacking, and hydrophobic interactions. A 100 ns molecular dynamics simulation study of protein-ligand complex with compound 22b revealed good binding and stability. The MM-GBSA analysis revealed strong binding affinity toward the active site of PL as compared with the reference ligand. Further, all derivatives were predicted to exhibit good pharmacokinetic properties, devoid of toxicity (toxicity class 4) and drug likeness.

P21-activated kinase 1 (PAK1) is a protein kinase involved in various cancers, making it an attractive target for therapeutic intervention. This study employed a comprehensive computational approach, including pharmacophore modeling, three dimensional-quantitative structure-activity relationship (3D-QSAR) analysis, virtual screening, and molecular dynamics (MD) simulations, to identify novel PAK1 inhibitors. A total of 46 pyrazolo[3,4-d]pyrimidine derivatives were used as a dataset to generate pharmacophore and 3D-QSAR models. The pharmacophore model DHRRR_1 exhibited the highest survival score of 5.80 and a site score of 0.92. The 3D-QSAR analysis yielded robust models with high predictive power, including an atom-based QSAR model with R2 = 0.7209 and Q2 = 0.6649 and a field-based QSAR model with R2 = 0.9072 and Q2 = 0.8464. These models guided the screening of 40,000 novel derivatives through R-group enumeration. The compounds 1a, 1b and 1c was screened as the potetial compounds through R-group enumeration study. Additionally, compounds from the ZINC database showed strong docking results, such as ZINC93921464, ZINC92210618, ZINC40387740, and ZINC90059146. The novel compounds were compared with the original QSAR dataset and the ZINC-screened compounds. MD simulations provided insights into the dynamic behavior of PAK1-ligand complexes, emphasizing the importance of interactions with Leu347 and Arg299. The screened compounds of the study may be used for further development of novel compounds as anticancer agents against PAK1 kinase.

AIM:This study aimed to design, synthesize, and evaluate a hybrid chalcone-pyrazoline derivatives as potential anticancer agents targeting B-Raf kinase in lung cancer. MATERIAL & METHODS:Chalcone-pyrazoline derivatives (PY1-PY10) were synthesized via Claisen-Schmidt condensation followed by cyclization, characterized using FT-IR, NMR, and LC-MS. In vitro cytotoxic activity was assessed against A549 human lung cancer cells using the MTT assay. Molecular docking studies were performed with B-Raf kinase (PDB ID: 2FB8) using Schrödinger software. ADME properties were predicted using SwissADME. RESULT:Compound PY7 exhibited the most potent cytotoxicity (IC₅₀ = 6.45 µM) and the highest docking score (-8.89 kcal/mol), showing strong binding interactions with GLN530 in B-Raf kinase. Structure Activity Relationship analysis revealed that electron-withdrawing para-nitro substituents enhanced potency, while electron-donating groups generally reduced activity. ADME profiling confirmed all compounds complied with Lipinski's Rule of Five, had high gastrointestinal absorption, and displayed favorable drug-likeness. CONCLUSION:The findings identify PY7 as a promising lead candidate with potent anticancer activity, strong B-Raf binding affinity, and favorable pharmacokinetics. This work supports chalcone-pyrazole scaffolds as viable templates for the development of novel targeted lung cancer therapeutics.

The estrogen receptor is a central mediator of estrogen-driven gene expression, influencing a wide array of physiological processes. Conventional endocrine therapies, including selective estrogen receptor modulators (SERMs) and degraders (SERDs), often face limitations due to acquired resistance and reduced efficacy in ERα-mutant cancers. Proteolysis-targeting chimeras (PROTACs) serve as a next-generation therapeutic strategy designed to selectively and efficiently degrade estrogen receptor alpha (ERα). The approval of elacestrant further expanded interest in developing novel ERα degraders, shifting the paradigm of drug discovery in this area. This review highlights the mechanism of action of PROTACs, structural and functional domains of ERα, design of PROTACs, and their application in targeting the ERα receptor. Special emphasis is also given on structure activity relationship (SAR) studies and strategies of designing PROTACs reported in the literature, along with in vitro and in vivo studies data. Collectively, these strategies provide valuable insights for designing effective PROTACs to overcome endocrine resistance and advance therapeutic options in ERα-positive breast cancers.

Acquired Immune Deficiency Syndrome (AIDS) is an ailment that progressively weakens the immune system and is responsible for being the sole cause of 630,000 deaths worldwide in 2023. It is a potentially fatal condition that promotes the growth of malignancies and secondary infection. Viruses like Human Immunodeficiency Virus (HIV-1) and Hepatitis B virus (HBV) employ an enzyme, reverse transcriptase (RT), to replicate their genomes and spread across the host genome. RT has proved to be one of the most important therapeutic targets for the treatment of AIDS as well as for the development of new HIV-1 medications. The pyrimidine nucleus has been described as a dynamic cornerstone in developing new anti-HIV-1 medications and represents a familiar motif found in various marketed anti-HIV-1 drugs, such as diaryl pyrimidines (DAPYs). The rapid emergence of drugresistant viral strains due to mutations in the HIV-1 RT structure along with their unfavourable pharmacokinetics present new challenges. Recent years have witnessed tremendous progress in the design and discovery of new substituted pyrimidines as potent and selective non-nucleoside reverse transcriptase inhibitors (NNRTIs). Further, the current developments in the field of X-ray crystallography and molecular modeling have remarkably augmented the design strategies, with simultaneous improvement in the resistance profiles. This article comprehensively reviews recent trends in the design and development of pyrimidine-based HIV-1 NNRTIs. The study emphasizes their biological activities, structure-activity relationship, and docking studies to guide the rational design of NNRTIs with desired potency, safety, and efficacy.

Thymidylate Synthase (TS) is a validated therapeutic target against cancer. The research examined whether the anticancer effects of lead compound 4d surpassed the action of 5-fluorouracil (5-FU) while monitoring its impact on MCF-7 breast cancer cells under both 2D and 3D experimental conditions. The treatment of MCF-7 cells with 4d at 1 μM and 5 μM concentrations and 5-FU at 1 μM level allowed researchers to measure cytotoxicity, apoptosis, and cell cycle arrest activities. Furthermore, ROS production and TS expression levels, including migration dynamics and 3D spheroid structure integrity, were also examined. The cell viability declined dramatically when cells were exposed to compound 4d, which causes cell cycle blockage at the G2/M phase and elevated ROS levels, while reducing TS expression. Severe, destructive effects on cell movement and spheroid organization resulted in a dose-dependent death of cells. The compound 4d demonstrated effects that matched the results obtained from using 5-FU. The potential of TS-targeted therapeutic candidate status for breast cancer treatment appears promising, because compound 4d demonstrates strong anticancer effects through multiple pathways.

The present work examined the neuroprotective and anti-Parkinsonian properties of derivatives of hydrazide and carboxylate. The synthesized compounds structures were confirmed by analysing their spectrum data. It was shown that both drugs worked well against the oxidative stress and catalepsy induced by Rotenone and Paraquat in mice. Various derivatives of Carboxylates and Hydrazide were synthesized and screened for potential anti-parkinsonian activity through molecular docking study and two derivatives i.e., SH-4 and SH-9 were selected for further in-vivo activity. The PQ model provided a suitable method for examining neuropsychiatric dysfunction, particularly changes in depressive and anxiety-like behavior. The synthesized compounds, SH-4 and SH-9 represented anti-parkinsonian activity comparable to standard drug.

Heterocyclic compounds are emerging as a privileged scaffold with a plethora of biological activities. In recent years, interest in thiazolopyrimidine chemistry has significantly increased due to its diverse pharmacological activities, such as anticancer, antimicrobial, analgesic, antioxidant, anti-inflammatory, and so on. It provides various opportunities for structural modifications. The thiazolopyrimidine scaffold provides a key intermediate for the synthesis of various fused heterocycles and compounds of medicinal importance. By considering the role of this privileged scaffold, researchers have designed different synthetic protocols for the synthesis of thiazolopyrimidine derivatives. In the present review, several advancements in the synthetic methodology for the synthesis of thiazolopyrimidine derivatives with different substitutions have been discussed along with pharmacological activity, which provides key insights into the synthetic protocol and role of different substitutions on the core moiety for rational drug design and drug discovery.

Imidazo[2,1-b]thiazole represents a privileged heterocyclic moiety in medicinal chemistry which garnered huge attention among the researchers because of its extensive biological properties and ease of synthetic feasibility. Substituted imidazo[2,1-b]thiazole analogs with diverse therapeutic outcomes play a crucial role in the cure or management of various human ailments. The impact of this moiety in drug discovery can be realized from the fact that drugs based on this scaffold are used clinically. Medicinal and synthetic chemists have widely explored the chemical space around this scaffold for the generation of novel molecules capable of interacting with different biological targets of therapeutic concern. Due to its fascinating pharmacological profile, chemists have unfolded different facile and efficient synthetic protocols for imidazo[2,1-b]thiazole-based molecules. The present review highlights its outstanding role in drug discovery including different approaches for the synthesis of imidazo[2,1-b]thiazole hybrids. The recent advancements in the medicinal chemistry of imidazo[2,1-b]thiazole based analogs along with structure-activity relationships (SARs) and molecular docking studies have been compiled. The present review provides valuable insights for the design and development of imidazo[2,1-b]thiazole based bioactive agents as potential therapeutic candidates with desired efficacy and safety profile.

INTRODUCTION:Aurora kinases (AKs) play key roles during carcinogenesis and show a close relationship with many cellular effects including mitotic entry, spindle assembly and chromosomal alignment biorientation. Indeed, elevated levels of AKs have been reported in several different tumor types, leading research scientists to investigate ways that we can target AKs for the purpose of developing new anticancer therapeutics. AREA COVERED:This review examines the design, discovery, and development of Aurora kinase inhibitors (AKIs) as anticancer agents and delineates their roles in cancer progression or development. Various databases like PubMed, Scopus, Google scholar, SciFinder were used to search the relevant information. This article provides a comprehensive overview of recent advances in the medicinal chemistry of AKIs including the candidates under clinical development and list of patents filed. In addition, their mechanistic findings, SARs, and in silico studies have also been discussed to offer prospects in this field. EXPERT OPINION:The integration of artificial intelligence and computational approaches is poised to accelerate the development of AKIs as anticancer agents. However, the associated challenges currently hindering its impact in drug development must be overcome before drugs can successfully translate from early drug development into clinical practice.

Diabetes is a serious health threat across the globe, claiming millions of lives worldwide. Among the various strategies employed, inhibition of alpha-amylase is a therapeutic protocol for the management of Type 2 diabetes mellitus. alpha-Amylase is a crucial enzyme involved in the breakdown of dietary starch into simpler units. However, the clinically used alpha-amylase inhibitors have various drawbacks. Therefore, design and development of novel alpha-amylase inhibitors have gained significant attention. The pyrazole motif has been identified as a versatile scaffold in medicinal chemistry, and recent studies have led to the identification of various pyrazole-based alpha-amylase inhibitors. This review compiles therapeutic implications of pyrazole-appended alpha-amylase inhibitors; their synthesis, biological activities, structure-activity relationships and molecular docking studies are discussed.

Catechin is one of the prestigious phytoconstituent obtained from the divine wealth of nature. It is a polyphenolic constituent which is broadly distributed in plant kingdom and tea, legumes and rubeaceous plants are rich sources of it. Various research groups have extracted and isolated it by using different analytical techniques due to its diverse pharmacological profile. It is evident in nature that catechin possesses promising anti-inflammatory, neuroprotective, antioxidant, antibacterial, anticancer and anti-viral properties. There are several formulations reported which are intended for multiple uses where catechins are important ingredient. This review discusses the various analytical techniques employed for the extraction and isolation of catechins from various sources, as well as a summary of various reported formulations. The authors also discuss the various pharmacological activities exhibited by catechins, along with the significant outcomes and plausible mode of action. In addition, the review provides an insight into various synthetic and biosynthetic procedures for catechins, along with a description of various clinical trials and patents. In the lateral sections of this compilation, an insight to various synthetic/biosynthetic procedures for catechins has been provided along with description to various clinical trials and patents. Although a lot of progress has been made towards exploration of catechins, still these are associated with some issues of bioavailability and unclear modes of action, which need to be resolved in upcoming times. This review is more comprehensive on catechins, as it covers a wider range of topic includings; analytical techniques for the extraction and isolations of catechins, formulations containing catechins, pharmacological activities, synthetic and biosynthetic procedure, clinical trials as well as patents. The review also provide a more in-depth discussion of the pharmacological activities of catechins, including the significant outcomes and plausible mode of action. The article also highlights the need for the further research to address the issues of bioavailability and unclear modes of action associated with the catechin. This is an important area of research, as it is essential to understand the ADME to develop effective catechin-based therapies.

A series of new 2,5-disubstituted arylidene derivatives of thiazolidinedione (16a-e, 17a-d, 18a-c) designed using molecular hybridization approach were synthesized, structurally characterized, and explored for their anti-obesity potential via inhibition of Pancreatic Lipase (PL). Compound 18a presented the most potent PL inhibitory activity with IC50 = 2.71 +/- 0.31 mu M, as compared to the standard drug, Orlistat (IC50 = 0.99 mu M). Kinetic study revealed reversible competitive mode of enzyme inhibition by compound 18a with an inhibitory constant value of 1.19 mu M. The most promising compound 18a revealed satisfactory binding mode within the active site of the target protein (human PL, PDB ID: 1LPB). Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analysis were performed for the most promising compound 18a, which showed potent inhibition according to the results of in vitro studies. Furthermore, a stable conformation of the 1LPB-ligand suggested the stability of this compound in the dynamic environment. The ADME and toxicity analysis of the compounds were examined using web-based online platforms. Results of in vivo studies confirmed the anti-obesity efficacy of compound 18a, wherein oral treatment with compound 18a (30 mg/kg) resulted in a significant reduction in the body weight, BMI, Lee index, feed intake (in Kcal), body fat depots and serum triglycerides. Compound 18a significantly decreased the levels of serum total cholesterol (TC) to 128.6 +/- 0.59 mg/dl and serum total triglycerides (TG) to 95.73 +/- 0.67 mg/dl as compared to the HFD control group. The present study identified disubstituted TZD derivatives as a new promising class of anti-obesity agents.

In the realm of enzymology, Carbonic anhydrase (CA) emerges as a pivotal protagonist orchestrating the rapid conversion of carbon dioxide and water into bicarbonate ions and hydrogen ions, respectively. Carbonic anhydrase inhibitors (CAIs) are the class of drugs that target various isoforms of the enzyme, and these inhibitors play a crucial role in the treatment and management of multiple diseases such as cancer, glaucoma, high altitude sickness, rheumatoid arthritis, obesity, epilepsy, and sleep apnea. Several structural classes of CAIs developed till date possess unique architects of the pharmacophoric requirements around the central core moiety for the selective targeting of various isoforms of the CA. Recent advancements in drug design and development, along with technologies that aid in structure determination, have led to the development of several isoform-selective inhibitors of CA enzymes. However, their clinical development was hampered by the lack of desired therapeutic efficacy, isoform selectivity and safety profile. This review covers the most recent approaches used by different researchers concerned with the development of isoform-selective carbonic anhydrase inhibitors belonging to distinct structural classes like sulphonamides, carbazoles, selenols, coumarin, organotelluride, topiramate, thiophene, triazole, uracil-modified benzylic amines, and thiourea etc. In addition, their structure-activity relationships, biological evaluation, and in silico studies inlcuding the forthcoming avenues of advancements have been discussed. This review serves as a valuable resource for developing potent and efficacious CAIs with remarkable therapeutic implications; offering insights into their potency, specificity, and potential clinical applications.

Synthesis and biological evaluation of TZD-based hybrids.

Diabetes is one of the fastest-growing metabolic disorders, nearly doubling the number of patients each year. There are different treatment approaches available for the management of diabetes, which lacks due to their side effects. The inhibition of enzymes involved in the metabolism of complex polysaccharides to monosaccharides has proven beneficial in patients with type 2 diabetes mellitus. Two enzymes, alpha-amylase and alpha-glucosidase, have emerged as potential drug targets and are widely explored for drug development against type 2 diabetes mellitus. In this context, thiazolidine-2,4-diones (TZDs) have emerged as potential drug candidates for developing newer molecules against alpha-amylase and alpha-glucosidase. Nineteen TZD-hybrids were synthesized and evaluated in vitro alpha-amylase and alpha-glucosidase inhibitory activity. The compounds 7i, 7k, and 7p have emerged as the best dual inhibitors with IC50 of 10.33 +/- 0.11-20.94 +/- 0.76 mu M and 10.19 +/- 0.25-24.07 +/- 1.56 mu M against alpha-glucosidase and alpha-amylase, respectively. The derivatives had good anti-oxidant activity, displaying IC50 = 14.95 +/- 0.65-23.27 +/- 0.99 mu M. The compounds 7k and 7p showed the best inhibition of reactive oxygen species in the PNAC-1 cells. The molecules exhibit good binding within the active site of alpha-amylase (PDB id: 1B2Y) and alpha-glucosidase (PDB id: 3W37), displaying binding energies of -7.5 to -10.7 kcal/mol and -7.4 to -10.3 kcal/mol, respectively. Further, the compounds were nontoxic (LD50 = 500-1311 mg/kg) and possessed good GI absorption. The compounds 7i, 7k, and 7p were evaluated in vivo antidiabetic activity in an STZ-induced diabetic model in Wistar rats. The compound 7p emerged as the best compound in the in vivo studies; however, the activity was lesser than that of the standard drug pioglitazone.