Biological Evaluation Research Articles

Synthesis and Biological Evaluation of 3-(2-Benzoyl-4-chlorophenyl)-4H-spiro [indole-3,2-[1,3]thiazolidine]-2,4(1H)- dione Derivatives for Anti-tubercular and Antimicrobial Activities

Synthesis and Biological Evaluation of 3-(2-Benzoyl-4-chlorophenyl)-4H-spiro [indole-3,2-[1,3]thiazolidine]-2,4(1H)- dione Derivatives for Anti-tubercular and Antimicrobial Activities

Design, Synthesis and Biological Evaluation of 7-Azaindole Analogues as Novel Antiproliferative Agent and Tyrosine Protein Kinase SRC Inhibitors

Design, Synthesis and Biological Evaluation of 7-Azaindole Analogues as Novel Antiproliferative Agent and Tyrosine Protein Kinase SRC Inhibitors

Tributelosides A-D: Four Undescribed Spirostan Glycosides Isolated from the Branches and Leaves of Tribulus terrestris with Their NO Production Inhibitory Activity in LPS Activated RAW 264.7 Cells.

Four undescribed spirostan glycosides, (25S)-5α-spirostan-12-one-2α,3β-diol-3-O-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside (1), (25S)-5α-spirostan-12-one-2α,3β-diol-3-O-β-D-galatopyranosyl-(1→2)-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside (2), (25S)-5α-spirostan-12-one-2α,3β-diol-3-O-β-D-glucopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→3)]-β-D-glucopyranosyl-(1→4)-β-D-galactopyranoside (3), and hecogenin 3-O-β-D-glucopyranosyl-(1→3)-[β-D-xylopyranosyl-(1→2)]-β-D-glucopyranosyl-(1→4)-[α-L-rhamnopyranosyl-(1→2)]-β-D-galactopyranoside (4), together with eleven known compounds (5-15) were isolated from the branches and leaves of Tribulus terrestris. Their chemical structures were established through spectroscopic methods. including HR-ESI-MS, 1D-, and 2D-NMR spectra. Preliminary biological evaluation on NO production inhibitory activity in LPS activated RAW 264.7 cells showed that compounds 1-3, 5, and 6 had significant inhibitory effects with IC50 values ranging from 2.4 to 18.3 µM, compared to that of the positive control compound, dexamethazone (IC50 13.6 µM).

Development of natural perfume as potential fungicide candidates: construction and biological evaluation of vanillin analogs bearing the 1,3,4-oxadiazole/1,3-thiazolidin-4-one fragments.

Two series of vanillin derivatives containing 1,3,4-oxadiazole and 1,3-thiazolidin-4-one scaffolds were prepared and evaluated for their antifungal activity. The results revealed that compounds 6j (29.73 μg/ml) and 7a (38.15 μg/ml) displayed excellent inhibitory activity against the spore of Fusarium solani. The inhibitory activity of compound 7d (10.53 μg/ml) against the spore of Alternaria solani was more than 42-fold that of vanillin. Compound 7a (37.54 μg/ml) showed better antifungal activity against the spore of B. cinerea than positive controls. The cytotoxicity assay confirmed that compounds 6k, 7a, and 7d showed good selectivity and less toxicity to normal mammalian cells.

Biomimetic-inspired piezoelectric ovalbumin/BaTiO3 scaffolds synergizing with anisotropic topology for modulating Schwann cell and DRG behavior.

The treatment of peripheral nerve injury is a clinical challenge that tremendously affected the patients' health and life. Anisotropic topographies and electric cues can simulate the regenerative microenvironment of nerve from physical and biological aspects, which show promising application in nerve regeneration. However, most studies just unilaterally emphasize the effect of sole topological- or electric- cue on nerve regeneration, while rarely considering the synergistic function of both cues simultaneously. In this study, a biomimetic-inspired piezoelectric topological ovalbumin/BaTiO3 scaffold that can provide non-invasive electrical stimulation in situ was constructed by combining piezoelectric BaTiO3 nanoparticles and surface microtopography. The results showed that the incorporation of piezoelectric nanoparticles could improve the mechanical properties of the scaffolds, and the piezoelectric output of the scaffolds after polarization was significantly increased. Biological evaluation revealed that the piezoelectric topological scaffolds could regulate the orientation growth of SCs, promote axon elongation of DRG, and upregulate the genes expression referring to myelination and axon growth, thus rapidly integrated chemical-mechanical signals and transmitted them for effectively promoting neuronal myelination, which was closely related to peripheral neurogenesis. The study suggests that the anisotropic surface topology combined with non-invasive electronic stimulation of the ovalbumin/BaTiO3 scaffolds possess a promising application prospect in the repair and regeneration of peripheral nerve injury.

18F-Radiolabeling and Evaluation of an AMD3465 Derivative for PET Imaging of CXCR4 in a Mouse Breast Tumor Model.

The exploration of pharmaceutically active agents and positron emission tomography (PET) tracers targeting CXCR4 has been a focal point in cancer research given its pivotal role in the development and progression of various cancers. While significant strides have been made in PET imaging with radiometal-labeled tracers, the landscape of 18F-labeled small molecule tracers remains relatively limited. Herein, we introduce a novel and promising derivative, [18F]SFB-AMD3465, as a targeted PET tracer for CXCR4. The compound was synthesized by modifying the pyridine ring of AMD3465, which was subsequently labeled with 18F using [18F]SFB. The study provides comprehensive insights into the design, synthesis, and biological evaluation of [18F]SFB-AMD3465. In vitro and in vivo assessments demonstrated the CXCR4-dependent, specific, and sensitive uptake of [18F]SFB-AMD3465 in the CXCR4-overexpressing 4T1 cell line and the corresponding xenograft-bearing mouse model. These findings contribute to bridging the gap in 18F-labeled PET tracers for CXCR4 and underscore the potential of [18F]SFB-AMD3465 as a PET radiotracer for in vivo CXCR4 imaging.

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents

Design, synthesis and biological evaluation of 1-aryldonepezil analogues as anti-Alzheimer's disease agents

Synthesis and Biological Evaluation of a Voltage-Gated Sodium Channel Inhibitor

Synthesis and Biological Evaluation of a Voltage-Gated Sodium Channel Inhibitor

Synthesis, molecular docking study and biological evaluation of new pyrrole scaffolds as potential antitubercular agents for dual targeting of enoyl ACP reductase and dihydrofolate reductase.

In this study, new series of N'-(2-(substitutedphenoxy)acetyl)-4-(1H-pyrrol-1-yl)benzohydrazides (3a-j) 4-(2,5-dimethyl-1H-pyrrol-1-yl)-N'-(2-(substitutedphenoxy)acetyl)benzohydrazides (5a-j) were synthesized, characterized and assessed as inhibitors of enoyl ACP reductase and DHFR. Most of the compounds exhibited dual inhibition against the enzymes enoyl ACP reductase and DHFR. Several synthesized substances also demonstrated significant antibacterial and antitubercular properties. A molecular docking analysis was conducted in order to determine the potential mechanism of action of the synthesized compounds. The results indicated that there were binding interactions seen with the active sites of dihydrofolate reductase and enoyl ACP reductase. Additionally, important structural details were identified that play a critical role in sustaining the dual inhibitory activity. These findings were useful for the development of future dual inhibitors. Therefore, this study provided strong evidence that several synthesized molecules could exert their antitubercular properties at the cellular level through multi-target inhibition. By shedding light on the mechanisms through which these compounds exert their inhibitory effects, this research opens up promising avenues for the future development of dual inhibitors with enhanced antibacterial and antitubercular properties. The study's findings underscore the importance of multi-target approaches in drug design, providing a strong foundation for the design and optimization of novel compounds that can effectively target bacterial infections at the cellular level.

Design, Synthesis and Biological Evaluation of Novel Gypsogenin Derivatives as Potential Anticancer and Antimicrobial Agents.

Natural compounds are important sources for the treatment of chronic disorders such as cancer and microbial infectious disorders. In this research, Gypsogenin and its derivatives (2 a-2 f) have been tested against different cancer cell lines (MCF-7, HeLa, Jurkat and K562 cell lines) and further analyzed for cell proliferation, cell death type, and for act of the mechanism. Cell proliferation was determined by the MTT method and cell death types were analyzed with HO/PI staining. Fibroblast Growth Factor 1 (FGF-1), Interleukin 1 (IL-1), Interleukin 6 (IL-6), and Tumor Necrosis Factor Alpha (TNF-α), key players in breast cancer development and progression, were determined by Elisa kits. Results showed that compound 2 e inhibited the MCF-7 cell line proliferation with an IC50 value of 0.66±0.17 μM with 93.38 % apoptosis rate. Compound 2 e also decreased FGF-1, IL-1, IL-6, and TNF-α levels. Molecular docking studies performed in the binding site of FGFR-1 indicated that compound 2 e formed key hydrogen bonding with Arg627 and Asn568. Besides, compounds 2 a-2 f were evaluated for their antimicrobial activities against gram-negative and gram-positive bacteria and C. albicans via the microdilution method. Overall, compound 2 e stands out as a potential anticancer agent for future studies.

Novel angiogenesis inhibitors with superoxide anion radical amplification effect: Surmounting the Achilles’ heels of angiogenesis inhibitors and photosensitizers

Angiogenesis inhibitors and photosensitizers are pivotal in tumor clinical treatment, yet their utilization is constrained. Herein, eleven novel angiogenesis inhibitors were developed through hybridization strategy to overcome their clinical limitations. These title compounds boast excitation wavelengths within the “therapeutic window”, enabling deep tissue penetration. Notably, they could generate superoxide anion radicals via the Type I mechanism, with compound 36 showed the strongest superoxide anion radical generating capacity. Biological evaluation demonstrated remarkable cellular activity of all the title compounds, even under hypoxic conditions. Among them, compound 36 stood out for its superior anti-proliferative activity in both normoxic and hypoxic environments, surpassing individual angiogenesis inhibitors and photosensitizers. Compound 36 induced cell apoptosis via superoxide anion radical generation, devoid of dark toxicity. Molecular docking revealed that the target-recognizing portion of compound 36 was able to insert into the ATP binding pocket of the target protein similar to sorafenib. Collectively, our results suggested that hybridization of angiogenesis inhibitors and photosensitizers was a potential strategy to address the limitations of their clinical use.

Design, synthesis and biological evaluation of 5H-[1,2,4]triazino[5,6-b]indole derivatives bearing a pyridinocycloalkyl moiety as iron chelators.

The avidity of cancer cells for iron highlights the potential for iron chelators to be used in cancer therapy. Herein, we designed and synthesized a novel series of 5H-[1,2,4]triazino[5,6-b]indole derivatives bearing a pyridinocycloalkyl moiety using a ring-fusion strategy based on the structure of an iron chelator, VLX600. The antiproliferative activity evaluation against cancer cells and normal cells led to the identification of compound 3k, which displayed the strongest antiproliferative activity in vitro against A549, MCF-7, Hela and HepG-2 with IC50 values of 0.59, 0.86, 1.31 and 0.92μM, respectively, and had lower cytotoxicity against HEK293 than VLX600. Further investigations revealed that unlike VLX600, compound 3k selectively bound to ferrous ions, but not to ferric ions, and addition of Fe2+ abolished the cytotoxicity of 3k. Flow cytometry assays demonstrated that 3k arrested the cell cycle at the G1 phase and induced significant apoptosis in A549 cells in dose and time-dependent manners, corresponding to JC-1 staining assay results. Western blot analysis of Bcl-2, Bax and cleaved caspase-3 proteins further provided evidences that induction of apoptosis by 3k in A549 cells might be at least via the mitochondria pathway. These above results highlight that 3k is a valuable lead compound that deserves further investigation as an iron chelator for the treatment of cancer.

Rational design, synthesis, biological evaluation, and molecular modeling of novel naphthamide derivatives possessing potent, reversible, and competitive inhibitory mode of action over human monoamine oxidase.

Herein, a novel series of naphthamide derivatives has been rationally developed, synthesized, and evaluated for their inhibitory activity against monoamine oxidase (MAO) and cholinesterase (ChE) enzymes. Compared to the reported naphthalene-based hit IV, the new naphthamide hybrids 2a, 2c, 2g and 2h exhibited promising MAO inhibitory activities; with an IC50 value of 0.294μM, compound 2c most potently inhibited MAO-A, while compound 2g exhibited most potent MAO-B inhibitory activity with an IC50 value of 0.519μM. Compounds 2c and 2g showed selectivity index (SI) values of 6.02 for MAO-A and 2.94 for MAO-B, respectively. On the other hand, most compounds showed weak inhibitory activity against ChEs except 2a and 2h over butyrylcholinesterase (BChE). The most potent compounds 2c and 2g were found to be competitive and reversible MAO inhibitors based on kinetic and reversibility studies. Plausible interpretations of the observed biological effects were provided through molecular docking simulations. The drug-likeness predicted by SwissADME and Osiris property explorer showed that the most potent compounds (2a, 2c, 2g, and 2h) obey Lipinski's rule of five. Accordingly, in the context of neurological disorders, hybrids 2c and 2g may contribute to the identification of safe and potent therapeutic approaches in the near future.

Advances in the Chemistry and Biology of Specialised Pro-Resolving Mediators (SPMs)

This review article assembles key recent advances in the synthetic chemistry and biology of specialised pro-resolving mediators (SPMs). The major medicinal chemistry developments in the design, synthesis and biological evaluation of synthetic SPM analogues of lipoxins and resolvins have been discussed. These include variations in the top and bottom chains, as well as changes to the triene core, of lipoxins, all changes intended to enhance the metabolic stability whilst retaining or improving biological activity. Similar chemical modifications of resolvins are also discussed. The biological evaluation of these synthetic SPMs is also described in some detail. Original investigations into the biological activity of endogenous SPMs led to the pairing of these ligands with the FPR2/LX receptor, and these results have been challenged in more recent work, leading to conflicting results and views, which are again discussed.

Discovery of LC-MI-3: A Potent and Orally Bioavailable Degrader of Interleukin-1 Receptor-Associated Kinase 4 for the Treatment of Inflammatory Diseases.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a promising therapeutic target in inflammation-related diseases. However, the inhibition of IRAK4 kinase activity may lead to moderate anti-inflammatory efficacy owing to the dual role of IRAK4 as an active kinase and a scaffolding protein. Herein, we report the design, synthesis, and biological evaluation of an efficient and selective IRAK4 proteolysis-targeting chimeric molecule that eliminates IRAK4 scaffolding functions. The most potent compound, LC-MI-3, effectively degraded cellular IRAK4, with a half-maximal degradation concentration of 47.3 nM. LC-MI-3 effectively inhibited the activation of downstream nuclear factor-κB signaling and exerted more potent pharmacological effects than traditional kinase inhibitors. Furthermore, LC-MI-3 exerted significant therapeutic effects in lipopolysaccharide- and Escherichia coli-induced acute and chronic inflammatory skin models compared with kinase inhibitors in vivo. Therefore, LC-MI-3 is a candidate IRAK4 degrader in alternative targeting strategies and advanced drug development.

Deep learning based linear energy transfer calculation for proton therapy.

This study aims to address the limitations of traditional methods for calculating linear energy transfer (LET), a critical component in assessing relative biological effectiveness (RBE). Currently, Monte Carlo (MC) simulation, the gold-standard for accuracy, is resource-intensive and slow for dose optimization, while the speedier analytical approximation has compromised accuracy. Our objective was to prototype a deep-learning-based model for calculating dose-averaged LET (LETd) using patient anatomy and dose-to-water (DW) data, facilitating real-time biological dose evaluation and LET optimization within proton treatment planning systems.
Approach: 275 4-field prostate proton Stereotactic Body Radiotherapy (SBRT) plans were analyzed, rendering a total of 1100 fields. Those were randomly split into 880, 110, and 110 fields for training, validation, and testing. A 3D Cascaded UNet model, along with data processing and inference pipelines, was developed to generate patient-specific LETd distributions from CT images and DW. The accuracy of the LETd of the test dataset was evaluated against MC-generated ground truth through voxel-based mean absolute error (MAE) and gamma analysis.
Main Results: The proposed model accurately inferred LETd distributions for each proton field in the test dataset. A single-field LETd calculation took around 100 ms with trained models running on a NVidia A100 GPU. The selected model yielded an average MAE of 0.94±0.14 MeV/cm and a gamma passing rate of 97.4% ± 1.3% when applied to the test dataset, with the largest discrepancy at the edge of fields where the dose gradient was the largest and counting statistics was the lowest.
Significance: This study demonstrates that deep-learning-based models can efficiently calculate LETd with high accuracy as a fast-forward approach. The model shows great potential to be utilized for optimizing the RBE of proton treatment plans. Future efforts will focus on enhancing the model's performance and evaluating its adaptability to different clinical scenarios.

Inhibition of Shikimate Kinase from Methicillin-Resistant Staphylococcus aureus by Benzimidazole Derivatives. Kinetic, Computational, Toxicological, and Biological Activity Studies

Antimicrobial resistance (AMR) is one of the biggest threats in modern times. It was estimated that in 2019, 1.27 million deaths occurred around the globe due to AMR. Methicillin-resistant Staphylococcus aureus (MRSA) strains, a pathogen considered of high priority by the World Health Organization, have proven to be resistant to most of the actual antimicrobial treatments. Therefore, new treatments are required to be able to manage this increasing threat. Under this perspective, an important metabolic pathway for MRSA survival, and absent in mammals, is the shikimate pathway, which is involved in the biosynthesis of chorismate, an intermediate for the synthesis of aromatic amino acids, folates, and ubiquinone. Therefore, the enzymes of this route have been considered good targets to design novel antibiotics. The fifth step of the route is performed by shikimate kinase (SK). In this study, an in-house chemical library of 170 benzimidazole derivatives was screened against MRSA shikimate kinase (SaSK). This effort led to the identification of the first SaSK inhibitors, and the two inhibitors with the greatest inhibition activity (C1 and C2) were characterized. Kinetic studies showed that both compounds were competitive inhibitors with respect to ATP and non-competitive for shikimate. Structural analysis through molecular docking and molecular dynamics simulations indicated that both inhibitors interacted with ARG113, an important residue involved in ATP binding, and formed stable complexes during the simulation period. Biological activity evaluation showed that both compounds were able to inhibit the growth of a MRSA strain. Mitochondrial assays showed that both compounds modify the activity of electron transport chain complexes. Finally, ADMETox predictions suggested that, in general, C1 and C2 can be considered as potential drug candidates. Therefore, the benzimidazole derivatives reported here are the first SaSK inhibitors, representing a promising scaffold and a guide to design new drugs against MRSA.

Synthesis, Biological Evaluation, and Docking Study of a New Series of Thiophene Derivatives Based on 3‐Oxobutanamidothiophene as an Anticancer Agent

AbstractHerein, the constructing synthon 3‐oxobutanamidothiophene derivatives 2 a and 2 b were synthesized and utilized for building a wide variety of pyran, thiazole, pyrazole or pyrimidine ring heterocyclic compounds that can be used as anticancer medications. 3‐Oxobutanamidothiophene derivatives 2 a,b were coupled with 4‐substitutedphenyl diazonium chloride to produce the corresponding hydrazones derivatives 3 a–f. Various thiophene‐pyran derivatives 4 a,b were synthesized through the treatment of thiophene components 2 a,b with different arylidene‐malononitrile. 2‐Aminothiophene derivatives 5 were prepared via Gewald's reaction between 2 a,b, elemental sulfur, and various activated nitrile derivatives. The 3‐oxobutanamidothiophene derivatives 2 a,b were reacted with PhNCS and the potassium salt intermediates 6 a,b with ethyl bromoacetate to pick up the corresponding thiophene‐thiazolidin‐4‐one derivatives 7. Treatment of the conforming thiocarbamoyl compounds 8 a,b, which undergo heating with three types of α‐halogenated reagents to afford the corresponding substitutedthiophene‐3‐carboxamides 9 a,b. Condensation of keteneN,S‐acetals 10 a,b with hydrazines furnished the thiophene‐pyrazole‐4‐carboxamide hybrids 11 a,b, while condensation with urea and/or thiourea afforded the corresponding thiophene‐pyrimidine‐5‐carboxamides 12 a,b. The recently synthesized thiophene compounds were characterized there in vitro anticancer properties against HepG2 (hepatocellular carcinoma) and MDA‐MB‐231 (breast cancer) were evaluated. Molecular docking was also performed to predict the binding modes of synthesized derivatives with the good anticancer results designed as potential inhibitors for a specific target.

Gold Nanoparticles Decorated Chitosan-Agarose Modified Magnetic Nanocomposite: Catalytic Application for the Preparation of Tetrazoles and Biological Evaluation for the Treatment of Lung Carcinoma

Gold Nanoparticles Decorated Chitosan-Agarose Modified Magnetic Nanocomposite: Catalytic Application for the Preparation of Tetrazoles and Biological Evaluation for the Treatment of Lung Carcinoma

Biological Evaluation of Oral Care Products Using 3D Tissue-Engineered In Vitro Models of Plaque-Induced Gingivitis

Background: The aim of this study was to investigate and visualize the anti-inflammatory and anti-bacterial effects of different oral care products using an infected and inflamed 3D tissue-engineered gingival mucosal model. Methods: A 3D full-thickness oral mucosal model was engineered inside tissue culture inserts using collagen hydrogels populated with human gingival fibroblasts and THP-1 monocytes and layered with oral epithelial cell lines. Oral saliva bacteria were cultured and added to the surface of the models and inflammation was further simulated with lipopolysaccharide (LPS) of Escherichia coli. The 3D models were exposed to three different types of toothpastes, a chlorhexidine antiseptic mouthwash, different antibiotics, and a mechanical rinse with phosphate-buffered saline (PBS) prior to biological evaluation using the PrestoBlue tissue viability assay, histology, optical coherence tomography (OCT), confocal microscopy, and measurement of the release of the inflammatory markers IL-1β, IL-6, and IL-8 with ELISA. Results: Multiple-endpoint analyses of the infected oral mucosal models treated with different anti-bacterial agents showed consistent outcomes in terms of tissue viability, histology, OCT, and confocal microscopy findings. In terms of anti-inflammatory testingz, the positive control group showed the highest level of inflammation compared with all other groups. Depending on the anti-bacterial and anti-inflammatory potential of the test groups, different levels of inflammation were observed in the test groups. Conclusions: The inflamed 3D oral mucosal model developed in this study has the potential to be used as a suitable in vitro model for testing the biocompatibility, anti-inflammatory, and anti-bacterial properties of oral care products including mouthwashes and toothpastes. The results of this study indicate that the chlorhexidine mouthwash has both anti-bacterial and cytotoxic effects on the 3D oral mucosal model. Hyaluronic-acid-containing toothpaste has significant anti-bacterial and anti-inflammatory effects on the 3D oral mucosal model.