Biological Evaluation Research Articles

Biological Evaluation of Dibenzo-α-Pyrone Derivatives in Neuronal Ischemia by Sciatic Nerve Ligation in Wistar Rats

Biological Evaluation of Dibenzo-α-Pyrone Derivatives in Neuronal Ischemia by Sciatic Nerve Ligation in Wistar Rats

Design, synthesis, biological evaluation, and molecular modeling studies of some quinazolin-4(3H)-one-benzenesulfonamide hybrids as potential α-glucosidase inhibitors

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia, posing serious health risks and becoming increasingly prevalent. Prolonged hyperglycemia can lead to complications such as nephropathy, neuropathy, retinopathy, cardiovascular damage, and blindness. Controlling hyperglycemia through α-glucosidase inhibitors, which slow down carbohydrate breakdown, is an effective treatment strategy. However, current inhibitors like acarbose, voglibose, and miglitol while used to manage type 2 diabetes, have significant side effects. Therefore, developing new α-glucosidase inhibitors that are more effective and have fewer side effects is crucial. In this study, a series of novel quinazolin-4(3H)-one-benzenesulfonamide hybrid compounds were designed, synthesized, and evaluated for in vitro α-glucosidase inhibitory activity. The compounds showed higher enzyme inhibition potency, with IC50 values ranging between 129.2 ± 0.5 and 558.7 ± 13.7 µM, compared to acarbose (IC50=814.3 ± 13.5 µM). Among the tested compounds, compound 10, bearing a 4-chlorophenyl ring on the nitrogen atom of the sulfonamide group, was the most active, with an IC50 value of 129.2 ± 0.5 µM. Enzyme kinetics analyses and molecular modeling studies were conducted to understand their inhibition mechanisms and interactions with the enzyme. The kinetic studies revealed a mixed-type inhibition model, indicating that the compounds bind to the enzyme-substrate complex with higher affinity than to the free enzyme. Molecular modeling results confirmed these findings. Additionally, in silico prediction studies showed that the selected compounds have favourable physicochemical and drug-like properties. These results suggest these compounds have potential for further optimization and development as effective α-glucosidase inhibitors for diabetes treatment.

Synthesis and Biological Evaluation of N-(1H-Indol-6-ylmethyl)benzenesulfonamide Analogs as Metabolic Inhibitors of Mitochondrial ATP Production in Pancreatic Cancer Cells.

A library of 26 indolyl sulfonamides and 12 amide and ester analogs based upon the 6-indolyl framework has been synthesized in an effort to target pancreatic cancer. The cytotoxicity of the indolyl sulfonamide compounds has been determined using a traditional (48-h compound exposure) assay against 7 pancreatic cancer cell lines and 1 non-cancerous cell line. The potential role of the compounds as metabolic inhibitors of ATP production was evaluated using a rapid screening (2-h compound exposure) assay developed within our laboratories. The IC50 values of the active compounds were determined using the rapid assay and six compounds displayed an IC50 value <5 μM against one or more pancreatic cancer cell lines. The ester analogs also display activity as potential metabolic inhibitors of ATP production with four of the six compounds displaying an IC50 value <5 μM against one or more pancreatic cancer cell lines.

Discovery of 5-Nitro-N-(3-(trifluoromethyl)phenyl) Pyridin-2-amine as a Novel Pure Androgen Receptor Antagonist against Antiandrogen Resistance.

The transformation of clinical androgen receptor (AR) antagonists into agonists driven by AR mutations poses a significant challenge in treating prostate cancer (PCa). Novel anti-AR therapeutics combating mutation-induced resistance are required. Herein, by combining structure-based virtual screening and biological evaluation, a high-affinity agonist E10 was first discovered. Then guided by the representative conformation of State 1 at the free energy landscape, the structural optimization of E10 was performed, and pure AR antagonists EL15 (IC50 = 0.94 μM) and EF2 (IC50 = 0.30 μM) were successfully identified. Both can antagonize wild-type and variant drug-resistant ARs. Therein, EF2 demonstrated potent inhibition of the AR pathway and effectively suppressed tumor growth in a C4-2B xenograft mouse model following oral administration. Further molecular dynamics simulation and mutagenesis studies revealed atomic insights into the mode of action of EF2 which may serve as a novel lead compound for developing therapeutics against AR-driven PCa.

Novel indole based fused triazole-thiadiazole derivatives as anti-diabetic agents: in vitro and in silico approaches.

Aim: The current research presents novel library of indole derived fused triazole-thiadiazole derivatives (1-17) for treatment of diabetes mellitus.Methods & results: These compounds were synthesized by treating 2-(1H-indol-3-yl)acetic acid with hydrazinecarbothiohydrazide followed by treating the resultant compound with substituted benzoic acid. Structural validation was achieved spectroscopically (1HNMR, 13CNMR and HREI-MS). The synthesized compounds were subjected to biological evaluation to assess their potential as anti-diabetic. Molecular docking study was employed to investigate the binding interactions of these analogs with relevant proteins. ADMET analysis was used to predict their drug-like properties. Notably, compound-10 (IC50 = 1.27±1.25 and 2.18±2.45 μM) bearing para-substituted F atom exhibited the highest potency due to strong inhibitory interactions through hydrogen bonding.Conclusion: This study identifies promising compounds with anti-diabetic activity, paving the way for the treatment of diabetes mellitus.

Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H3 Agents: Synthesis and Biological Evaluation

In this research, a variety of novel amphetamine derivatives were synthesized and assessed for their potential as multifaceted antidepressant agents. Among these compounds, compound 11b demonstrated potent inhibitory effects on both serotonin and noradrenaline transporters (SERT/NET) and high affinity for histamine H3 receptor (H3R), and displayed low affinity for off-target receptors (H1, α1) and hERG channels, which can reduce the prolongation of the QT interval. Molecular docking studies offered a rational binding model of compound 11b when it forms a complex with SERT, NET, and the histamine H3 receptor. In vivo behavioral studies, compound 11b dose-dependently reduced the immobility duration in the mouse FST and TST assays without a stimulatory effect on the locomotor activity. Furthermore, compound 11b had a favorable pharmacokinetic profile in rats. Thus, compound 11b has the potential to develop a novel class of drugs for the treatment of depression.

Dual inhibition strategy addressing hyperuricemia and oxidative stress: design, biological evaluation and stability studies of febuxostat-probenecid mutual prodrug

Dual inhibition strategy addressing hyperuricemia and oxidative stress: design, biological evaluation and stability studies of febuxostat-probenecid mutual prodrug

Biological Characterization and Evaluation of the Therapeutic Value of Vibrio Phages 4141 and MJW Isolated from Clinical and Sewage Water Samples of Kolkata

The growing prevalence of antimicrobial resistance (AMR) necessitates the development of new treatment methods to combat diseases like cholera. Lytic bacteriophages are viruses that specifically target and lyse bacteria upon infection, making them a possible treatment option for multi-drug-resistant pathogens. The current study investigated the potential role of bacteriophages isolated from clinical stool and sewage water samples in treating multi-drug-resistant Vibrio cholerae infection, finding that over 95% of the strains were susceptible. Whole-genome sequencing (WGS) analysis revealed that both Vibrio phage 4141 (4141) and Vibrio phage MJW (MJW) contain double-stranded DNA genomes consisting of 38,498 bp (43% GC) and 49,880 bp (42.5% GC) with 46 and 64 open reading frames (ORFs), respectively. Transmission electron microscope (TEM) and WGS analysis of Vibrio phage 4141 and Vibrio phage MJW validated that they are classified under the family Autographiviridae and Zobellviridae, respectively. Furthermore, both the phages showed highly significant biofilm degradation properties. The characterization of the phages and their strict host range, high spectrum of lytic ability, high efficiency of biofilm degradation, and close genetic similarity to the therapeutic phages indicates that these phages may be useful for therapeutic purposes for treating MDR V. cholerae infection in the future.

Synthesis and biological evaluation of novel aminoguanidine derivatives as potential antibacterial agents

In an effort to identify novel antibacterial agents, we presented two series of aminoguanidine derivatives that were designed by incorporating 1,2,4-triazol moieties. All compounds exhibited strong in vitro antibacterial activity against a variety of testing strains. Compound 5f was identified as a potent antibacterial agent with a minimum inhibitory concentration (MIC) of 2–8 µg/mL against S. aureus, E. coli, S. epidermidis, B. subtilis, C. albicans, multi-drug resistant Staphylococcus aureus and multi-drug resistant Escherichia coli and low toxicity (Hela > 100 µM). Membrane permeability and transmission electron microscopy (TEM) image studies demonstrated that compound 5f permeabilized bacterial membranes, resulting in irregular cell morphology and the rapid death of bacteria. The results of the present study suggested that aminoguanidine derivatives with 1,2,4-triazol moieties were the intriguing scaffolds for the development of bactericidal agents.

A Comprehensive Journey of a Vanillic Aldehyde-Chloroaniline Schiff Base from Solvent-Free Synthesis to Electronic Structure, In Silico and In Vitro Biological Analysis

Schiff bases possess a range of unique physical, chemical and medicinal properties, which contribute to their potency as biological agents. A Schiff base was synthesized, which consisted of 4-chloro aniline and vanillin. The successful formation of the compound was confirmed by their comparable FTIR, UV–Vis, 1HNMR and [Formula: see text]CNMR spectra. The compound was analyzed using X-ray crystallography, which revealed that it crystallizes in the monoclinic system with the space group P21/c. The Hirshfeld surface analysis revealed valuable information about the intermolecular interactions present in the crystal lattice. The most common contacts observed were between hydrogen and hydrogen, as well as carbon and hydrogen. The obtained fluorescence values of 375 nm and 412 nm at excitation wavelength 322 nm strongly indicated the luminescent nature of the compound. The thermal stability of the compound was assessed through thermogravimetric analysis (TGA). DFT was used to optimize the geometry using the B3LYP/cc-pVDZ basis set. The compound exhibited an energy gap of 2.35 electron volts (eV). According to the analysis of molecular electrostatic potential, C and O atoms were found to be electrophilic. According to Mulliken charge analysis, C atoms possess both positive and negative charges, hydrogen atoms exclusively carry positive charges, and Cl, O and N atoms exclusively carry negative charges. Upon analysis of the molecule, the electron localization function discovered that the atoms of carbon, nitrogen and chlorine exhibited delocalized electron density. Also, the localized orbital locator identified the localized orbital positions in the hydrogen atoms. The reduced density gradient (RDG) maps exhibit a wide range of noncovalent interactions. In comparison to the standard amoxicillin, the synthesized compound demonstrated moderate antimicrobial efficacy against the gram-positive bacteria Klebsiella pneumoniae and the fungi Candida albicans. The compound’s concentration-dependent antioxidant and anti-inflammatory properties were demonstrated through in vitro biological evaluation using 2,2-diphenyl-1-picrylhydrazyl and human red blood cell (HRBC) methods. The compound was docked using the proteins 7BYE and 4LEB were chosen from both organisms. The lowest binding attractions obtained were -3.40 kcal/mol for 7BYE and -4.51 kcal/mol for 4LEB. To investigate the stability of the protein–ligand complex, molecular dynamic simulation was employed. The ligands in silico toxicity potentialities were analyzed using seven toxicity models and the results indicated that the ligand is biocompatible.

Evaluation of a Radioiodinated G-Quadruplex Binder in Cervical Cancer Models.

We herein describe the radiosynthesis of a 125I-labeled acridine orange derivative ([125I]-C8), acting as a G-quadruplex binder, and its biological evaluation in cervical cancer models, aiming to enlighten its potential as a radioligand for Auger Electron Radiopharmaceutical Therapy (AE-RPT) of cancer. [125I]-C8 was synthesized with a moderate radiochemical yield (ca. 60 %) by a [125I]iodo-destannylation reaction. Its evaluation in cervical cancer HeLa cells demonstrated that the radiocompound has a significant cellular internalization with a notorious accumulation in the cell nucleus. In line with these results, [125I]-C8 strongly compromised the viability of HeLa cells in a dose-dependent manner, inducing non-repairable DNA lesions that are most probably due to the AEs emitted by 125I in close proximity to the DNA molecule. Biodistribution studies in a murine HeLa xenograft model showed that [125I]-C8 has fast blood clearance and high in vivo stability but poor tumor uptake, after systemic administration. The respective supramolecular conjugate with the AS1411 aptamer ([125I]-C8/AS1411) led to a slower blood clearance in the same animal tumor model, although without improving the tumor uptake. To take advantage of the radiotoxicity of [125I]-C8 against cervical cancer cells other strategies need to be studied, based namely on alternative nanodelivery carriers and/or intratumoral injection approaches.

Design, Synthesis, and Biological Evaluation of 3-Amino-pyrazine-2-carboxamide Derivatives as Novel FGFR Inhibitors

Design, Synthesis, and Biological Evaluation of 3-Amino-pyrazine-2-carboxamide Derivatives as Novel FGFR Inhibitors

Sequential Aerial Oxidation and Atom‐Economical C‐3 Chalcogenation of Indolines Facilitated by Potassium tert‐Butoxide

AbstractAn operationally straightforward and highly efficient potassium tert‐butoxide facilitated protocol for the C‐3 chalcogenation of indolines under catalyst and additive‐free conditions has been established under ambient temperature. The salient features of the process include the development of transition metal‐free, oxidant‐free and iodine‐free, atom‐economic and cost‐effective reaction conditions at room temperature in DMSO as solvent for regioselective generation of 3‐chalcogenyl indoles in high yields. The mechanistic interpretation through controlled experiments and analysis of intermediates suggests the prevalence of the ionic pathway. The reaction is scalable to gram‐scale without a significant decrease in product yield, indicating its potential for large‐scale applications. This protocol offers a practical and environment friendly approach to accessing a diverse range of 3‐arylthioindoles and 3‐arylselenylindoles withstanding electron releasing and withdrawing substituents in good to excellent yields. Interestingly, the biological evaluation of the 3‐arylselenylindole products exhibited significant activity against breast cancer and triple‐negative breast cancer cell lines MCF‐7, and MDA‐MB 231. These results indicate the derivatives to be potent candidates for further SAR study.

Design, synthesis, and in vitro and in vivo biological evaluation of triazolopyrimidine hybrids as multitarget directed anticancer agents.

In response to the urgent need for new anti-proliferative agents, four novel series of triazolopyrimidine compounds (7a-e, 9a-d, 11a-f, and 13a-e) were synthesized and evaluated for in vitro anticancer efficacy against HCT116, HeLa, and MCF-7 cell lines. Compound 13c emerged as the most potent, with IC50 values of 6.10, 10.33, and 2.42 μM respectively, while 11e and 7c also showed strong activity. In multi-target suppression tests, 13c exhibited the highest inhibition against EGFR, TOP-II, HER-2, and ARO (IC50: 0.087, 31.56, 0.078, and 0.156 μM, respectively). Flow cytometry revealed 13c's ability to suppress the S-phase cell population in MCF-7 cells. In vivo studies of 13c demonstrated significant tumor growth inhibition, comparable to the positive control. Molecular docking studies supported the experimental findings, confirming the binding of the novel motifs to the target enzymes' active sites. This comprehensive evaluation highlights the potential of these triazolopyrimidine compounds, particularly 13c, as promising anticancer agents, warranting further investigation.

Biological evaluation of ZrO2 composites modified with different ceramics additives

In this work, zirconia (ZrO2) composites modified with bioactive hydroxyapatite (HAp), hexagonal boron nitride (hBN), bioglass (BG), and bioglass with copper (BGCu) via the hydrothermal method were synthesized. The aim was to obtain highly bioactive and cytocompatible materials that could combine beneficial properties of inert and bioactive ceramics. Such materials could be applied as fillers for tooth extraction cavities, guaranteeing osseintegration without the need to introduce additional bone cements or other adhesives. It was proven that while all materials were favourable towards cells adhesion and growth, the HAp and BG-doped ones facilitated early adhesion, especially when compared to unmodified ZrO2. Only the HAp-doped materials showed satisfactory bioactivity results, with a well-developed apatite layer forming on their surfaces. This study confirms that the Hap-doped ZrO2 is suitable for treating bone defects.

Design, in silico studies and biological evaluation of novel chalcones tethered triazolo[3,4-a]isoquinoline as EGFR inhibitors targeting resistance in non-small cell lung cancer

A novel series of six [1,2,4]triazolo[3,4-a]isoquinolin-3-yl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)prop-2-en-1-ones (3a–3f) was designed and synthesized. They were characterized based on spectral and elemental analyses. In silico studies were also committed to provide insights and a better understanding of their structural features. The six compounds were screened for their antiproliferative activity using the MTT assay against five human cancer cell lines, namely, A549, HCT116, PC3, HT29, and MCF-7 in parallel with the non-cancerous human lung cell line WI-38. The results showed that 3e and 3f have potential cytotoxic activities, especially on A549 cells with IC50 = 2.3 µM and 1.15 µM, respectively. Meanwhile, they recorded a minimal cytotoxic effect on WI-38 cells. Concerning the molecular mechanism of action, the present study showed the inhibitory effect of the six compounds against total EGFR. The most potent EGFR inhibitors were 3e and 3f with IC50 = 0.031 µM and 0.023 µM, respectively. The selectivity index of 3f for EGFRT790M was 1.81 times more selective than that of lapatinib. In addition, 3e and 3f initiated cell cycle arrest at the G2/M and pre-G1 phases along with the downregulation of anti-apoptotic protein Bcl2 and the upregulation of pro-apoptotic proteins: p53, Bax, and caspases 3, 8, and 9. Further studies are recommended to evaluate animal models’ promising anticancer activity and molecular mechanism of triazolo[3,4-a]isoquinoline derivatives 3e and 3f.

Design, synthesis, biological evaluation and computational studies of 4-Aminopiperidine-3, 4-dihyroquinazoline-2-uracil derivatives as promising antidiabetic agents

A novel series of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives (9a-9 L) were logically designed and synthesized as potent DPP4 inhibitors as antidiabetic agents. Chemical structure of all new compounds were confirmed by different spectroscopic methods. The designed compounds were evaluated using a MAK 203 kit as DPP4 inhibitors in comparison with Sitagliptin. The biological evaluation revealed that compound 9i bearing chloro substitution on phenyl moiety of 6-bromo quinazoline ring had promising inhibitory activity with IC50 = 9.25 ± 0.57 µM. The toxicity test of all compounds confirmed safety profile of them. Kinetic studies showed that compound 9i exhibited a competitive-type inhibition with a Ki value of 12.01 µM. Computational approach supported the rationality of our design strategy, as 9i represented appropriate binding interactions with the active sites of DPP4 target. MD simulation outputs validated the stability of ligand 9i at DPP4 active site. Also, Density functional theory (DFT) including HOMO-LUMO energies, ESP map, thermochemical parameters, and theoretical IR spectrum was employed to study the reactivity descriptors of 9i and 9a as the most and least potent compounds respectively. Based on the DFT study, compound 9i was softer and, as a result, more reactive than 9a. Taken together, our results showed the potential of 4-aminopiperidin-3,4-dihyroquinazoline-2-uracil derivatives as promising candidates for developing some novel DPP4 inhibitors for managing of type 2 diabetes.

Synthesis, biological evaluation and in silico study of 4-(benzo[d]thiazole-2-yl) phenols based on 4-hydroxy coumarin as acetylcholinesterase inhibitors

Alzheimer’s disease, characterized by cognitive decline and memory loss, is associated with decreased acetylcholine levels due to acetylcholinesterase (AChE) activity. Compounds containing a coumarin heterocyclic core coupled with thiazole exhibit excellent acetylcholinesterase inhibitory activity. In this work, we designed and synthesized a series of 4-(benzo[d]thiazole-2-yl) phenols based on 4-hydroxycoumarin. The compounds were synthesized and their inhibitory activities were evaluated through in vitro biological assays. Of the compounds investigated, 3i exhibited the strongest inhibitory activity, with an IC50 value of 2.7 µM. Molecular docking and molecular dynamics simulations were employed to elucidate the binding interactions and stability of the synthesized compounds with AChE. The results demonstrated promising inhibitory activity, suggesting potential therapeutic applications for Alzheimer’s disease. This research contributes to the development of coumarin-based heterocyclic compounds as effective AChE inhibitors.

Exploration of 1,3,5-trisubstituted pyrazoline derivatives as human carbonic anhydrase inhibitors: Synthesis, biological evaluation and in silico studies

The human carbonic anhydrase (hCA) IX and XII isoforms are overexpressed in hypoxic conditions, contributing to cancer. Lack of isoform selectivity has been one of the main challenges associated with the existing drugs targeting hCAs. Hence, the development of alternative approaches, such as tail approach to develop more selective hCA IX and XII inhibitors is need of the hour. In the present work, we designed and synthesized 24 new 1,3.5-trisubstituted-pyrazoline derivatives with diverse substitutions. The synthesized analogs were evaluated for their hCA inhibitory activities against hCA I, II, IX, and XII isoforms. Among the tested compounds, derivative 8 displayed good inhibitory activity against hCA IX (Ki = 331 nM) and XII (Ki = 96.7 nM). In addition, 9a-g also exhibited some inhibitory activities against hCA IX and XII, with Kis ranging from 574 to 799 nM and 137–369 nM, respectively. Molecular modelling studies of compound 8 displayed metal coordination with zinc ion and hydrophobic, hydrophilic interactions with adjacent amino acid residues, and maintained stable interactions throughout 100 ns. In addition, ADMET studies demonstrated that compound 8 obeyed the Lipinski's rule of five and was found to be druggable and non-toxic. Hence, compound 8 was identified as potential lead for further development.

Various crystalline forms of realgar exhibit differentiated anti-abscess and anticancer effects based on a PXRD analysis and biological evaluation

Various crystalline forms of realgar exhibit differentiated anti-abscess and anticancer effects based on a PXRD analysis and biological evaluation