The study focuses on Keap1, a key regulator of the Nrf2 pathway, critical for tumor cell regulation. Recent crystallographic insights into Keap1's structure highlight its functional domains and ligand-binding sites, offering opportunities for targeted drug discovery. The aim is to identify small molecules with high affinity for Keap1 to modulate Keap1, SQSTM1/p62, and Nrf2 functions in colorectal cancer (CRC) cells. A high-throughput virtual screening approach was used to screen the ChemBridge small library against the Keap1 protein. Atomistic Molecular Dynamics (MD) simulations were conducted using GROMACS, along with Gibbs binding free energy estimations. HCT116 and Caco-2 cells were used to determine anti-proliferation. Flow cytometry was used to evaluate target + inhibition in HCT116 and Caco-2 cells. The small molecule CB5712809 demonstrated stable interactions with Keap1, supported by molecular dynamics simulations and MM-PBSA analysis. It suppressed the growth of HCT116 and Caco-2 CRC cells with GI50 values of 40.07 nM and 102.80 nM, respectively. Flow cytometry revealed G2/M cell cycle arrest, along with decreased Keap1 levels and increased SQSTM1/p62 and Nrf2 expression, highlighting its potential as a Keap1 modulator. Results of this study provide a basis for further experimental validation to develop CB5712809 as a Keap1 targeted chemotherapeutic against CRC.

Moringa oleifera is used all over the world as an herbal cure for a myriad of diseases. The current research focuses on the extraction of proteins from Moringa oleifera leaves, estimating their total protein content, detecting an insulin-like protein, and evaluating its hypoglycemic effect. With the help of a Tris-HCl buffer solution, the leaf protein extract is obtained through solvent extraction, which is subjected afterward to filtration, centrifugation, and dialysis to provide the purified supernatant and pellet. A total protein content of 8.0 +/- 0.25 g/dL in both fractions is revealed by the serum albumin assay. A visible precipitation with ZnCl2 confirms the presence of an insulin-like protein. Alpha-amylase and alpha-glucosidase enzyme assays are performed to test their hypoglycemic properties. Notably, the protein extract displays strong inhibition against alpha-amylase, having percentage inhibition values of 75.48 and 82.93% and relevant IC50 values of 0.6 and 17.6 mu M for supernatant and pellet, respectively. However, alpha-glucosidase inhibition is modest, with 11.1 and 14.1% for supernatant and pellet, respectively. These findings suggest that the insulin-like protein within the Moringa oleifera leaf protein extract can contribute to its hypoglycemic effect. This study paves the way for further exploration of this protein's potential, possibly leading to novel drug development for managing diabetes mellitus.

A novel series of thiazole-thiadiazole based schiff base derivatives (1-16) were synthesized and examined for their inhibitory profile against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). All the compounds exhibited excellent inhibitory activity ranging from IC50= 1.87 f 1.47 to 27.4 f 2.45 mu M for AChE and 1.72 f 1.43 to 29.4 f 1.87 mu M for BuChE when compared with the standard drug donepezil (IC50= 3.87 f 1.14 mu M and 3.56 f 2.52 mu M for AChE and BuChE, respectively). Among the members of the whole series, compounds-6 (IC50 = 3.49 f 1.20 mu M, 3.18 f 0.27 mu M), 7 (IC50 = 3.20 f 1.14 mu M, 3.21 f 0.49 mu M), 8 (IC50 =1.87 f 1.47 mu M, IC50 = 1.72 f 1.43) and 9 (IC50 = 2.18 f 1.02 mu M, IC50 = 2.02 f 0.49 mu M), showed remarkable potency against AChE and BuChE and emerged as anti-alzheimer's agents. Molecular docking study revealed the excellent binding interactions of ligands with different amino acids of the target enzymes. Structure activity relationship (SAR) study was also conducted to evaluate inhibitory potency of all the derivatives that depends on the position, number and nature of the substituents. Furthermore, ADME outcomes authenticate the drug likeness of the potent analogs. Structural confirmation of the derivatives was achieved through different spectroscopic techniques, including 13C NMR, 1H NMR and HREI-MS.

Diabetes Mellitus (DM), a persistent metabolic disorder was the focus of study in current research work. A novel series of pyrazole based thiazolidinone derivatives (1-15) was designed and efficiently synthesized for the treatment of DM. All the novel synthesized compounds were investigated for their biological inhibitory potential against alpha-amylase and alpha-glucosidase in comparison to standard drug acarbose (IC50 = 7.20 +/- 0.10 mu M and 8.10 +/- 0.20 mu M). Analogue 8 (IC50 = 6.20 +/- 0.20 and 6.80 +/- 0.40 mu M) demonstrated spellbinding inhibition potential surpassing the potency of standard drug. This remarkable potency of the compound 8 is due to the presence of trifluoromethyl moiety, which interacts with amino acids on receptor proteins via strong hydrogen bond. All these interactions were also visualized under in-silico molecular docking study, which revealed the insight into the binding interaction of potent compounds against target enzyme complex. Additionally, to assess drug-likeness and other pharmacokinetic properties of the potent compounds, ADME analysis was also conducted. Moreover, all the synthesized compounds were structurally analyzed via spectral studies comprising of 1H NMR, 13C NMR and HREI-MS.

To illustrate the anti-diabetic properties of Berberis orthobotrys seeds was the aim of the current study. After a series of experiments, two doses of aqueous methanolic extract of the seeds were selected i.e., 151 mg/kg and 301 mg/kg to assess the anti-diabetic potential in normoglycemic, alloxan-induced and glucose-loaded diabetic rats. The effect of the seeds extract on total cholesterol and triglycerides was also assessed. Histological examination of the pancreas and the GC-MS analysis of blood and urine samples of rats were also carried out. At 151 mg/kg and 301 mg/kg doses, the aqueous methanolic extracts of Berberis orthobotrys seeds showed promising results for their anti-diabetic potential comparable to Glibenclamide. Studies on the phytochemistry of AMEBO also exposed the existence of alkaloids, steroids, glycosides, flavonoids and resins. Serum lipid measurements showed a substantial reduction in triglycerides and total cholesterol on days 7 and 15. The pancreas’s islets were protected by the extract, as shown by a histological analysis. The primary metabolite Berberine, which was qualitatively detected by GC-MS in blood and urine samples of rats, may be the alkaloid in command of insulin release or recovery of beta cells after alloxan destruction. More study is necessary to comprehend the underlying signaling process.

The growing rise of multidrug-resistant (MDR) infections, as well as the worldwide prevalence of cancer, one of the major causes of mortality, are two of the most serious and significant issues facing modern medicine. This study evaluated the antimicrobial and anticancer properties of beta lapachone in vitro and in silico. Antimicrobial activity was assessed using established assays such as diffusion methods, MIC and MBC determinations, CFU reduction, biofilm inhibition, oxidative stress analysis, and membrane integrity disruption. The beta lapachone investigated showed strong antimicrobial properties, significantly decreasing microbial viability, preventing biofilm formation, and generating membrane damage and oxidative stress.Anticancer activity was tested on breast cancer cell lines using MTT viability assays, Annexin V/PI flow cytometry, and cell cycle analysis. The beta lapachone had dose-dependent cytotoxic effects, with triggering S-phase arrest, which led to increase apoptosis.Molecular docking investigations showed their affinity for important microbial and cellular targets, proving the hypothesized mechanisms of action. These findings emphasize the beta lapachone therapeutic promise as dual-function medicines capable of treating both MDR infections and malignant tumors, thereby tackling two of the most serious dangers to world health.

Dwarfism is a medical term used to describe individuals with a height-vertex measurement that falls below two standard deviations (-2SD) or the third percentile for their gender and age. Normal development of growth is a complicated dynamic procedure that depends upon the coordination of different aspects involving diet, genetics, and biological aspects like hormones in equilibrium. Any severe or acute pathologic procedure may disturb the individual's normal rate of growth. In this research, we examined four (A-D) Pakistani consanguineous families that exhibited syndromic dwarfism, which was inherited in an autosomal recessive pattern. The genomic DNA of each family member was extracted by using phenol-chloroform and Kit methods. Whole Exome Sequencing (WES) of affected family members (IV-11, III-5, IV-4 and III-13) from each group was performed at the Department of Medical Genetics, University of Antwerp, Belgium. After filtering the exome data, the mutations in PPM1F, FGFR3, ERCC2, and PCNT genes were determined by Sanger sequencing of each gene by using specific primers. Afterward, FGFR3 was found to be a suitable drug target among all the mutations to treat achondroplasia also known as disproportionate dwarfism. BioSolveIT softwares were used to discover the lead active inhibitory molecule against FGFR3. This research will not only provide short knowledge to the concerned pediatricians, researchers, and family physicians for the preliminary assessment and management of the disorder but also provide a lead inhibitor for the treatment of disproportionate dwarfism.

Polycyclic sultams are widely encountered in both natural products and bioactive drug candidates. In cognizance to their synthetic and medicinal chemistry applications, the exploration of facile approaches remains at high demand. In the present work, a straightforward, efficient and operationally simple methodology has been developed. The coupling of β-chloroaldehyde with a diverse range of anilines as bis-nucleophile containing N-C-C fragment was achieved to deliver a sulfostyril-quinoline hybrid framework. The formation of target scaffolds bearing various substituents avoiding the need of column chromatographic purification represents one of the key advantages associated with this transformation. The exclusive regioselectivity achieved for the formation of linear tetracyclic products over angular products was corroborated with density functional theory (DFT) calculations as well as single crystal X-ray analysis. Furthermore, the density functional theory calculations allowed us to understand the formation of tetracyclic sulfostyril-quinoline hybrid skeleton, and are in fair agreement with the observed regioselectivity of this reaction.

Gastric cancers are caused primarily due to the activation and amplification of the EGFR or HER2 kinases resulting in cell proliferation, adhesion, angiogenesis, and metastasis. Conventional therapies are ineffective due to the intra-tumoral heterogeneity and concomitant genetic mutations. Hence, dual inhibition strategies are recommended to increase potency and reduce cytotoxicity. In this study, we have conducted computational high-throughput screening of the ChemBridge library followed by in vitro assays and identified novel selective inhibitors that have a dual impediment of EGFR/HER2 kinase activities. Diversity-based High-throughput Virtual Screening (D-HTVS) was used to screen the whole ChemBridge small molecular library against EGFR and HER2. The atomistic molecular dynamic simulation was conducted to understand the dynamics and stability of the protein-ligand complexes. EGFR/HER2 kinase enzymes, KATOIII, and Snu-5 cells were used for in vitro validations. The atomistic Molecular Dynamics simulations followed by solvent-based Gibbs binding free energy calculation of top molecules, identified compound C3 (5-(4-oxo-4H-3,1-benzoxazin-2-yl)-2-[3-(4-oxo-4H-3,1-benzoxazin-2-yl) phenyl]-1H-isoindole-1,3(2H)-dione) to have a good affinity for both EGFR and HER2. The predicted compound, C3, was promising with better binding energy, good binding pose, and optimum interactions with the EGFR and HER2 residues. C3 inhibited EGFR and HER2 kinases with IC50 values of 37.24 and 45.83 nM, respectively. The GI50 values of C3 to inhibit KATOIII and Snu-5 cells were 84.76 and 48.26 nM, respectively. Based on these findings, we conclude that the identified compound C3 showed a conceivable dual inhibitory activity on EGFR/HER2 kinase, and therefore can be considered as a plausible lead-like molecule for treating gastric cancers with minimal side effects, though testing in higher models with pharmacokinetic approach is required.

Alzheimer's disease, as per reports, 50 million people worldwide suffer from dementia and an increase of 152 million is expected by 2050. This study reports a novel synthetic approach to designing and synthesizing a series of benzothiazole-based fused 1,3,4-triazole/1,3,4-thiadiazole hybrid derivatives (1-19), which show promising potential as therapeutic agents for the treatment of Alzheimer's disease. These derivatives were structurally confirmed through spectroscopic analytical techniques, including C-13 NMR, H-1 NMR and HREI-MS. All the analogs were subjected to biological inhibitory evaluation against AChE and BuChE, in which analog 2 ((IC50 = 3.30 +/- 0.20 and 3.70 +/- 0.40 mu M), 7 (2.70 +/- 0.10 and 3.240 +/- 0.10 mu M), 12 (4.80 +/- 0.30 and 5.40 +/- 0.20 mu M), 15 (2.10 +/- 0.20 and 3.10 +/- 0.50 mu M) and 19 (4.40 +/- 0.20 and 5.10 +/- 0.10 mu M)) exhibited spellbinding potency in contrast to standard Donepezil (IC50 = 4.60 +/- 0.10 mu M for AChE and 5.20 +/- 0.71 mu M for BuChE). The surpassing potential of the analogs is elaborated in SAR analysis, based on number, position and nature of the substituents. In this regard, analog 15 having two flouro groups, was found as the top ranking candidate, inhibiting the enzymes through hydrogen bonding. Additionally, molecular docking study was also performed to investigate the binding modes and interactions between the ligands and the target protein. Furthermore, the drug-likeness of the compounds was evaluated through in silico ADME analysis, which assessed their pharmacokinetic properties and potential to become a successful drug candidate.

A new series of benzothiazole derived thiazole-based bis-benzohydrazide hybrid (1-20) analogs were synthesized. Initially, the product confirmation was identified by employing TLC and the basic skeleton of the new hybrid synthesized compounds was further confirmed through spectroscopic techniques such as 13 CNMR, 1 HNMR and HREI-MS. Moreover, the synthesized analogs were tested for their inhibitory activities against acetylcholinesterase and butyrylcholinesterase. In the whole series, compounds 1 , 2, 3 and 6 were found with potent activity against acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE). Molecular docking inveatigation of the potent compounds was performed within the active site of acetylcholinesterase and butyrylcholinesterase revealing compounds 1 , 2, 3 and 6 showing promising binding orientations against both enzymes as compared to reference drug donepezil with their IC50 50 values 1(2.20 ( 2.20 +/- 1.40 and 3.18 +/- 0.45 mu M), M ), 2 ( 2.89 +/- 1.25 and 2.78 +/- 1.49 mu M), M ), 3 ( 2.94 +/- 1.10 and 3.07 +/- 1.23 mu M), M ), 6 ( 5.83 +/- 1.45 and 6.03 +/- 3.08 mu M), M ), respectively, and reference drug (IC50 50 = 8.73 +/- 2.68 and 9.30 +/- 2.60 mu M M for acetylcholinesterase and butyrylchlinesterase, respectively. In addition, ADME studies were conducted to gain a deeper understanding of the functional mechanisms of a drug on a living organism. It is considered that benzothiazole derived thiazole based bis-benzohydrazide hybrid analogs (1, 2, 3, 6) might be better inhibitors of acetylcholinesterase and butyrylcholinesterase enzymes.

A novel series of varied substituted thiadiazole/oxadiazole based bis-Schiff base derivatives (1-10) was synthesized and characterized using NMR ((CNMR)-C-13 and (HNMR)-H-1) and HREI-mass spectrometry. To determine their anti-diabetic potential, these analogues were examined against alpha-amylase and alpha-glucosidase. These compounds demonstrated varied inhibitory range between IC50 = 1.10 +/- 0.50 to 21.40 +/- 0.20 mu M (alpha-amylase) and 2.50 +/- 0.05 to 21.40 +/- 0.10 mu M (alpha-glucosidase), when contrasted with Acarbose, a well-known marketed drug (IC50 = 3.16 +/- 0.22 & 4.8 +/- 0.21 mu M for alpha-amylase and alpha-glucosidase respectively). Analog-9 having tri-fluoromethyl group at para position of benzene ring emerged as lead candidate among these synthesized compounds. The effective activity of compound-9 may be due to involvement of fluoro atoms interacting via hydrogen-bonding with the selected sites of diabetic enzymes, alpha-amylase and alpha-glucosidase. Furthermore, for exploration of binding interactions of potent drugs and reactivity of potent analogues, molecular docking as well as DFT was performed. For investigation of drug likeness and toxicity, ADME analysis was also conducted.

Diabetes is a prevalent and serious metabolic disorder affecting millions globally, and it poses extensive health risks due to elevated blood glucose levels. One promising approach for managing diabetes is the inhibition of alpha-glucosidase, an enzyme that plays a crucial role in carbohydrate metabolism. Targeting alpha-glucosidase can help delay glucose absorption, thus controlling postprandial blood sugar spikes. Dihydropyrimidones, a core structural class present in various biologically active natural compounds, have been recognized for their diverse therapeutic potential, including anti-diabetic properties. In this study, we evaluated a library of previously synthesized 37 Dihydropyrimidone derivatives to assess their potential as alpha-glucosidase inhibitors. We identified 34 derivatives with significant inhibitory activity, exhibiting IC50 values in the range of 5.30-56.72 mu M. Among these, compounds 2, 4-7, 9-11, 13-16, 31, 32, and 33 demonstrated high potency, with IC50 values below 20 mu M; the most active compound, 5, achieved an IC50 of 5.30 mu M. A detailed kinetic study on compound 5 revealed a competitive inhibition mode with a Ki value of 16.10 +/- 0.0075 mu M. Additionally, cytotoxicity assays confirmed that compound 5 is non-toxic to BJ cell lines, underscoring its safety for therapeutic use. The computational studies further supported the inhibitory potential by illustrating key interactions and binding affinities between the Dihydropyrimidone derivatives and the alpha-glucosidase, highlighting these compounds as promising candidates for diabetes management.

Hydrogels based on biodegradable, biocompatible, and eco-friendly chitosan were prepared by blending polyvinyl alcohol (PVA), and hydroxyapatite (HA). A series of hydrogels (FAH, FAH2, FAH4, and FAH6) were synthesized by adding varying concentrations of modified NanoHalloysite. The characterization of the samples was performed by FTIR, swelling test antimicrobial activity. The swelling tests were performed in water, buffer solutions, and ionic solutions of different pH and different concentrations. A drug release experiment was also performed in PBS and SIF solutions showed maximum release in each time of 7 hours. The antibacterial activity of synthesized hydrogels was studied, and studies show hydrogels are bacteriostatic. The chitosan, PVA, and hydroxyapatite-based hydrogel blends have great prospects for drug delivery and other biomedical applications.

The clinical significance of benzimidazole-containing drugs has increased in the current study, making them more effective scaffolds. These moieties have attracted strong research interest due to their diverse biological features. To examine their various biological significances, several research synthetic methodologies have recently been established for the synthesis of benzimidazole analogs. The present study aimed to efficiently and quickly synthesize a new series of benzimidazole analogs. Numerous spectroscopic techniques, including 1H-NMR, 13C-NMR, and HREI-MS, were used to confirm the synthesized compounds. To explore the inhibitory activity of the analogs against α-amylase and α-glucosidase, all derivatives (1–17) were assessed for their biological potential. Compared to the reference drug acarbose (IC50 = 8.24 ± 0.08 µM), almost all the derivatives showed promising activity. Among the tested series, analog 2 (IC50 = 1.10 ± 0.10 & 2.10 ± 0.10 µM, respectively) displayed better inhibitory activity. Following a thorough examination of the various substitution effects on the inhibitory capacity of α-amylase and α-glucosidase, the structure-activity relationship (SAR) was determined. We looked at the potential mechanism of how active substances interact with the catalytic cavity of the targeted enzymes in response to the experimental results of the anti-glucosidase and anti-amylase. Molecular docking provided us with information on the interactions that the active substances had with the various amino acid residues of the targeted enzymes for this purpose.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Despite the existence of various therapeutic options, NSCLC is still a major health concern due to its aggressive nature and high mutation rate. Consequently, HER3 has been selected as a target protein along with EGFR because of its limited tyrosine kinase activity and ability to activate PI3/AKT pathway responsible for therapy failure. We herein used a BioSolveIT suite to identify potent inhibitors of EGFR and HER3. The schematic process involves screening of databases for constructing compound library comprising of 903 synthetic compounds (602 for EGFR and 301 for HER3) followed by pharmacophore modeling. The best docked poses of compounds with the druggable binding site of respective proteins were selected according to pharmacophore designed by SeeSAR version 12.1.0. Subsequently, preclinical analysis was performed via an online server SwissADME and potent inhibitors were selected. Compound 4k and 4m were the most potent inhibitors of EGFR while 7x effectively inhibited the binding site of HER3. The binding energies of 4k, 4m, and 7x were −7.7, −6.3 and −5.7 kcal/mol, respectively. Collectively, 4k, 4m and 7x showed favorable interactions with the most druggable binding sites of their respective proteins. Finally, in silico pre-clinical testing by SwissADME validated the non-toxic nature of compounds 4k, 4m and 7x providing a promising treatment option for chemoresistant NSCLC.

Different research synthetic methods have been developed recently for the synthesis of bis-benzimidazole analogs to investigate various biological significances. In this present study, an attempt was made to synthesize a new series of bis-benzimidazole analogs in a fast and efficient method. A variety of spectroscopic techniques, including 13C NMR, 1H NMR, and HREI-MS, were used to establish the existence of every synthesized scaffold. Molecular docking profiles were also carried out to ascertain the binding interactions of the compounds. All derivatives (1–18) were evaluated for their biological potential to investigate the inhibitory activity of α-amylase and α-glucosidase through SAR study. Almost all derivatives were found to be engaged in a highly promising activity when compared to referenced drug acarbose (IC50 = 8.24 ± 0.08 µM), in this regard among the tested series analog 9 (IC50 = 0.10 ± 0.50 and 0.20 ± 0.50 µM respectively), showed excellent activity. Moreover, ADME predictions were also studied for potent compounds, exhibited drug like properties.

Prodigiosin pigment has high medicinal value, so exploring this compound is a top priority. This report presents a prodigiosin bioactive compound isolated from Serratia marcescens JSSCPM1, a new strain. The purification process of this compound involves the application of different chromatographic methods, including UV-visible spectroscopy, high-performance liquid chromatography (HPLC), and liquid chromatography–mass spectrometry (LC/MS). Subsequent analysis was performed using nuclear magnetic resonance (NMR) to achieve a deeper understanding of the compound’s structure. Finally, through a comprehensive review of the existing literature, the structural composition of the isolated bioactive compound was found to correspond to that of the well-known compound prodigiosin. The isolated prodigiosin compound was screened for antibacterial activity against both Gram-positive and Gram-negative bacteria. The compound inhibited the growth of Gram-negative bacterial strains compared with Gram-positive bacterial strains. It showed a maximum minimum inhibitory concentration against Escherichia coli NCIM 2065 at a 15.9 ± 0.31 μg/mL concentration. The potential binding capabilities between prodigiosin and the OmpF porin proteins (4GCS, 4GCP, and 4GCQ) were determined using in silico studies, which are generally the primary targets of different antibiotics. Comparative molecular docking analysis indicated that prodigiosin exhibits a good binding affinity toward these selected drug targets.

In the current scenario, the importance of cardiac biomarkers in diagnosing, assessing, and managing people with cardiovascular discomfort is required. This cross-sectional study examined the relationship between serum leptin and resistin levels among obese people with acute myocardial infarction (AMI) with varying body mass index (BMI). The cardio and diabetic biomarkers among the 77 Saudi patients with hypoxia who lived in the Asir region were analyzed in the study. The patients were categorized into three groups, namely, group 1 (control), group 2 (AMI with normal BMI), and group 3 (AMI with varying BMI). Our results showed a positive correlation between serum glucose, HbA1C, triglycerides, Troponin-I (cTnI), creatine kinase MB (CK-MB), leptin, and resistin in patients with AMI. We also observed significantly lower HbA1C, cholesterol, and insulin values in groups 2 and 3. A statistical difference between the groups with and without AMI and between the genders was noticed. BMI with leptin showed a positive connection in group 3 but no association was observed for groups 1 and 2. A stronger relationship between BMI and leptin levels in men in Group 3 than in women was observed. In all three groups, resistin levels did not correlate with BMI. Thus, circulating leptin concentrations do not significant impact AMI compared to participants with and without AMI. However, resistin levels were considerably higher in obese individuals with AMI. Therefore, we suggest that resistin can be used as a pro-inflammatory marker to detect AMI disorder with varying BMI and as a prognostic marker associated with AMI.