Nitrogen-doped carbon quantum dots as a novel treatment for black fungal bone infections (Mucormycosis): in vitro and in vivo study.

Most fungal bone and joint infections (arthritis) are caused by Mucormycosis (Mucor indicus). These infections may be difficult to treat and may lead to chronic bone disorders and disabilities, thus the use of new antifungal materials in bone disorders is vital, particularly in immunocompromised individuals, such as those who have contracted coronavirus disease 2019 (COVID-19). Herein, we reported for the first time the preparation of nitrogen-doped carbon quantum dots (N/CQDs) and a nitrogen-doped mesoporous carbon (N/MC) using a quick micro-wave preparation and hydrothermal approach. The structure and morphology were analysed using X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM) and surface area analyser. Minimum inhibitory concentration (MIC), disc diffusion tests, minimum fungicidal concentration (MFC) and antifungal inhibitory percentages were measured to investigate the antifungal activity of N/CQDs and N/MC nanostructures. In addition to the in vivo antifungal activity in rats as determined by wound induction and infection, pathogen count and histological studies were also performed. According to in vitro and in vivo testing, both N/CQDs with small size and N/MC with porous structure had a significant antifungal impact on a variety of bone-infecting bacteria, including Mucor infection. In conclusion, the present investigation demonstrates that functional N/CQDs and N/MC are effective antifungal agents against a range of microbial pathogenic bone disorders in immunocompromised individuals, with stronger and superior fungicidal activity for N/CQDs than N/MC in vitro and in vivo studies.

Development and optimization of vildagliptin solid lipid nanoparticles loaded ocuserts for controlled ocular delivery: A promising approach towards treating diabetic retinopathy.

Diabetes mellitus (DM) is the most prevalent cause of diabetic retinopathy (DRP). DRP has been recognized for a long time as a microvascular disease. Many drugs were used to treat DRP, including vildagliptin (VLD). In addition to its hypoglycemic effect, VLD minimizes ocular inflammation and improves retinal blood flow for individuals with type 2 diabetes mellitus. Nevertheless, VLD can cause upper respiratory tract infections, diarrhea, nausea, hypoglycemia, and poor tolerability when taken orally regularly due to its high water solubility and permeability. Effective ocular administration of VLD is achieved using solid lipid nanoparticles (SLNPs), which improve corneal absorption, prolonged retention, and extended drug release. Ocuserts (OCUs) are sterile, long-acting ocular dosage forms that diminish the need for frequent dosing while improving residence time and stability. Therefore, this study intends to develop VLD solid lipid nanoparticle OCUs (VLD-SLNPs-OCUs) to circumvent the issues commonly associated with VLD. SLNPs were prepared using the double-emulsion/melt dispersion technique. The optimal formula has been implemented in OCUs. Optimization and development of VLD-SLNPs-OCUs were performed using a Box-Behnken Design (BBD). VLD-SLNPs-OCUs loading efficiency was 95.28 ± 2.87%, and differential scanning calorimetry data (DSC) showed the full transformation of VLD to an amorphous state and the excellent distribution in the prepared OCUs matrices. The in vivo release of VLD from the optimized OCUs after 24 h was 35.12 ± 2.47%, consistent with in vitro drug release data of 36.89 ± 3.11. The optimized OCUs are safe to use in the eye, as shown by the ocular irritation test. VLD-SLNPs-OCUs provide extended VLD release, an advantageous alternative to conventional oral dose forms, resulting in fewer systemic adverse effects and less variation in plasma drug levels. VLD-SLNPs-OCUs might benefit retinal microvascular blood flow beyond blood glucose control and may be considered a promising approach to treating diabetic retinopathy.

Novel Monosulfonated Azo Dyes: Design, Synthesis, and Application as Disperse Dyes on Polyester Fabrics.

This study synthesizes and characterizes a series of disperse dyes based on azo Schiff bases, compounds 8-10. Their structures were identified using various analytical techniques, such as FT-IR, 1H/13C NMR, and mass spectrometry. The study's primary objective was to investigate the behavior of disperse dyes 8-10 when used for dyeing polyester fabrics under different conditions, including variations in time, temperature, shade, and pH. The polyester fabric was chosen for this research due to its wide usage and popularity in the textile industry. By examining the effect of temperature and time on the dyeing process, it was observed that increasing the dyeing temperature from low to high (ranging from 90 to 120 °C) and extending the dyeing time from 10 to 30 min resulted in higher K/S values for the polyester samples dyed with disperse dyes. Additionally, dyes 9 and 10 exhibited the most excellent K/S values among the tested dyes. Furthermore, the study found that dye 8 showed the best dyeing performance as the pH of the dye bath increased to 6.

Electronic, mechanical, and thermal properties of zirconium dioxide nanotube interacting with poly lactic-co-glycolic acid and chitosan as potential agents in bone tissue engineering: insights from computational approaches.

For the first time, the interaction of the Poly lactic-co-glycolic acid (PLGA) and Chitosan (CH) with Zirconium dioxide (ZrO2) nanotube was studied using density functional theory (DFT). The binding energies of the most stable configurations of PLGA and CH monomers absorbed on ZrO2 were calculated using density functional theory (DFT) methods. The obtained results indicate that both CH and PLGA monomers were chemisorbed on the surface of ZrO2. The interaction between PLGA and ZrO2 is stronger than that of CH due to its shorter equilibrium interval and higher binding energy. In addition, the electronic density of states (DOS) of the most stable configuration was computed to estimate the electronic properties of the PLGA/CH absorbed on ZrO2. Also, the molecular dynamics (MD) simulations were computed to investigate the mechanical properties of all studied compounds in individual and nanocomposite phases. MD simulation revealed that the shear and bulk moduli of PLGA, CH as well as Young's modulus increase upon interacting with the ZrO2 surface. As a result, the mechanical properties of PLGA and CH are improved by adding ZrO2 to the polymer matrix. The results showed that the elastic modulus of PLGA and CH nanocomposites decreased with increasing temperature. These findings indicate that PLGA-ZrO2 nanocomposites have mechanical and thermal properties, suggesting that they could be exploited as potential agents in biomedical sectors such as bone tissue engineering and drug delivery.Communicated by Ramaswamy H. Sarma.

Symbiotic Antidiabetic Effect of Lactobacillus casei and the Bioactive Extract of Cleome droserifolia (Forssk.) Del. on Mice with Type 2 Diabetes Induced by Alloxan.

The consumption of probiotics protects pancreatic ß-cells from oxidative damage, delaying the onset of type 2 diabetes mellitus (T2DM) and preventing microvascular and macrovascular complications. This study aimed to evaluate the antidiabetic activity of CDE fermented by Lactobacillus casei (ATCC 39539) (LC) in alloxan-induced diabetic rats. The oxidative stress identified by catalase (CAT), serum AST, ALT, ALP, creatinine, urea, and uric acid were measured. The chemical profiles of the plant extract and the fermented extract were studied using HPLC/MS. The potential of the compounds towards the binding pockets of aldose reductase and PPAR was discovered by molecular docking. A significant reduction in fasting blood glucose in alloxan-treated rats. The CAT showed a significant decrease in diabetic rats. Also, serum AST, ALT, ALP, creatinine, urea, and uric acid were significantly decreased in the mixture group. Mild histological changes of pancreatic and kidney tissues suggested that the mixture of probiotics and cleome possesses a marked anti-diabetic effect. Overall, the study suggests that the combination of Cleome droserifolia fermented by Lactobacillus casei exhibits significant antidiabetic activity (p-value=0.05), reduces oxidative stress, improves lipid profiles, and shows potential for the treatment of diabetes.

A study on the therapeutic potential of graphene titanate nanocomposite for treating chemically induced arthritis in rats.

Nanotechnology holds substantial promise in the innovative therapies for rheumatoid arthritis (RA). The current study was designed to synthesize and characterize a new graphene titanate nanocomposite (GTNc) and explore its anti-arthritic, anti-inflammatory, and antioxidant potencies against Complete Freund's adjuvant (CFA)-induced arthritis in rats, as well as investigate the underlying molecular mechanisms. Our characterization methods included XRD, FT-IR, SEM, EDX, zeta potential, practical size, and XRF to characterize the novel GTNc. Our findings revealed that arthritic rats treated with GTNc exhibited lower levels of RF, CRP, IL-1ß, TNF-α, IL-17, and ADAMTS-5, and higher levels of IL-4 and TIMP-3. In arthritic rats, GTNc reduced LPO levels while increasing GSH content and GST antioxidant activity. Additionally, GTNc decreased the expression of the TGF-ß mRNA gene in arthritic rats. Histopathological investigation showed that GTNc reduced inflammatory cell infiltration, cartilage degradation, and bone destruction in joint injuries caused by CFA in the arthritic rats. Collectively, the anti-arthritic, anti-inflammatory, and antioxidant properties of GTNc appear promising for future arthritis treatments and bone disability research.

Characterization and Bio-Evaluation of the Synergistic Effect of Simvastatin and Folic Acid as Wound Dressings on the Healing Process.

Wound healing is a significant healthcare problem that decreases the patient's quality of life. Hence, several agents and approaches have been widely used to help accelerate wound healing. The challenge is to search for a topical delivery system that could supply long-acting effects, accurate doses, and rapid healing activity. Topical forms of simvastatin (SMV) are beneficial in wound care. This study aimed to develop a novel topical chitosan-based platform of SMV with folic acid (FA) for wound healing. Moreover, the synergistic effect of combinations was determined in an excisional wound model in rats. The prepared SMV-FA-loaded films (SMV-FAPFs) were examined for their physicochemical characterizations and morphology. Box-Behnken Design and response surface methodology were used to evaluate the tensile strength and release characteristics of the prepared SMV-FAPFs. Additionally, Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), X-ray diffraction pattern (XRD), and animal studies were also investigated. The developed SMV-FAPFs showed a contraction of up to 80% decrease in the wound size after ten days. The results of the quantitative real-time polymerase chain reaction (RT-PCR) analysis demonstrated a significant upregulation of dermal collagen type I (CoTI) expression and downregulation of the inflammatory JAK3 expression in wounds treated with SMV-FAPFs when compared to control samples and individual drug treatments. In summary, it can be concluded that the utilization of SMV-FAPFs holds great potential for facilitating efficient and expeditious wound healing, hence presenting a feasible substitute for conventional topical administration methods.

Therapeutic Potential of Zeolites/Vitamin B12 Nanocomposite on Complete Freund's Adjuvant-Induced Arthritis as a Bone Disorder: In Vivo Study and Bio-Molecular Investigations.

Rheumatoid arthritis (RA) is a long-term autoimmune disease. As nanotechnology has advanced, a growing number of nanodrugs have been used in the treatment of RA due to their unique physical and chemical properties. The purpose of this study was to assess the therapeutic potential of a novel zeolite/vitamin B12 nanocomposite (Nano ZT/Vit B12) formulation in complete Freund's adjuvant (CFA)-induced arthritis. The newly synthesized Nano ZT/Vit B12 was fully characterized using various techniques such as XRD, FT-IR, BET analysis, HERTEM, SEM, practical size, zeta potential, XRF, and EDX. The anti-arthritic, anti-inflammatory, and antioxidant activities as well as the immunomodulation effect of Nano ZT/Vit B12 on the CFA rat model of arthritis were examined. Histopathologic ankle joint injuries caused by CFA intrapedal injection included synovium hyperplasia, inflammatory cell infiltration, and extensive cartilage deterioration. The arthritic rats' Nano ZT/Vit B12 supplementation significantly improved these effects. Furthermore, in arthritic rats, Nano ZT/Vit B12 significantly reduced serum levels of RF and CRP, as well as the levels of IL-1ß, TNF-α, IL-17, and ADAMTS-5, while increasing IL-4 and TIMP-3 levels. Nano-ZT/Vit B12 significantly declined the LPO level and increased antioxidant activities, such as GSH content and GST activity, in the arthritic rats. In arthritic rats, Nano ZT/Vit B12 also reduced TGF-ß mRNA gene expression and MMP-13 protein levels. Collectively, Nano ZT/Vit B12 seems to have anti-arthritic, anti-inflammatory, and antioxidant properties, making it a promising option for RA in the future.

Exploring the Antimicrobial Activity of Sodium Titanate Nanotube Biomaterials in Combating Bone Infections: An In Vitro and In Vivo Study.

The majority of bone and joint infections are caused by Gram-positive organisms, specifically staphylococci. Additionally, gram-negative organisms such as E. coli can infect various organs through infected wounds. Fungal arthritis is a rare condition, with examples including Mucormycosis (Mucor rhizopus). These infections are difficult to treat, making the use of novel antibacterial materials for bone diseases crucial. Sodium titanate nanotubes (NaTNTs) were synthesized using the hydrothermal method and characterized using a Field Emission Scanning Electron Microscope (FESEM), High-Resolution Transmission Electron Microscope (HRTEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FTIR), Brunauer-Emmett-Teller (BET), and Zeta sizer. The antibacterial and antifungal activity of the NaTNT framework nanostructure was evaluated using Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), Disc Diffusion assays for bacterial activity, and Minimum Fungicidal Concentration (MFC) for antifungal investigation. In addition to examining in vivo antibacterial activity in rats through wound induction and infection, pathogen counts and histological examinations were also conducted. In vitro and in vivo tests revealed that NaTNT has substantial antifungal and antibacterial effects on various bone-infected pathogens. In conclusion, current research indicates that NaTNT is an efficient antibacterial agent against a variety of microbial pathogenic bone diseases.

Evaluating the ability of some natural phenolic acids to target the main protease and AAK1 in SARS COV-2.

Researchers are constantly searching for drugs to combat the coronavirus pandemic caused by SARS-CoV-2, which has lasted for over two years. Natural compounds such as phenolic acids are being tested against Mpro and AAK1, which are key players in the SARS-CoV-2 life cycle. This research work aims to study the ability of a panel of natural phenolic acids to inhibit the virus's multiplication directly through Mpro and indirectly by affecting the adaptor-associated protein kinase-1 (AAK1). Pharmacophore mapping, molecular docking, and dynamic studies were conducted over 50 ns and 100 ns on a panel of 39 natural phenolic acids. Rosmarinic acid (16) on the Mpro receptor (- 16.33 kcal/mol) and tannic acid (17) on the AAK1 receptor (- 17.15 kcal/mol) exhibited the best docking energy against both receptors. These favourable docking score values were found to be superior to those of the co-crystallized ligands. Preclinical and clinical research is required before using them simultaneously to halt the COVID-19 life cycle in a synergistic manner.

A Novel Hydroxyapatite/Vitamin B12 Nanoformula for Treatment of Bone Damage: Preparation, Characterization, and Anti-Arthritic, Anti-Inflammatory, and Antioxidant Activities in Chemically Induced Arthritic Rats.

The usage of nanomaterials for rheumatoid arthritis (RA) treatment can improve bioavailability and enable selective targeting. The current study prepares and evaluates the in vivo biological effects of a novel hydroxyapatite/vitamin B12 nanoformula in Complete Freund's adjuvant-induced arthritis in rats. The synthesized nanoformula was characterized using XRD, FTIR, BET analysis, HERTEM, SEM, particle size, and zeta potential. We synthesized pure HAP NPs with 71.01% loading weight percentages of Vit B12 and 49 mg/g loading capacity. Loading of vitamin B12 on hydroxyapatite was modeled by Monte Carlo simulation. Anti-arthritic, anti-inflammatory, and antioxidant effects of the prepared nanoformula were assessed. Treated arthritic rats showed lower levels of RF and CRP, IL-1ß, TNF-α, IL-17, and ADAMTS-5, but higher IL-4 and TIMP-3 levels. In addition, the prepared nanoformula increased GSH content and GST antioxidant activity while decreasing LPO levels. Furthermore, it reduced the expression of TGF-ß mRNA. Histopathological examinations revealed an improvement in joint injuries through the reduction of inflammatory cell infiltration, cartilage deterioration, and bone damage caused by Complete Freund's adjuvant. These findings indicate that the anti-arthritic, antioxidant, and anti-inflammatory properties of the prepared nanoformula could be useful for the development of new anti-arthritic treatments.

Curcumin and vitamin C improve immunity of kidney via gene expression against diethyl nitrosamine induced nephrotoxicity in rats:In vivo and molecular docking studies.

Kidney has a crucial role in immunity, so any toxicity occurs for the kidney will result in reduced immunity. The aim of this study is to improve the immune response of insufficient kidneys through immune-related genes. Diethyl Nitrosamine has been used to cause kidney damage in animal models, vitamin C and curcumin have been used to treat impaired kidney. Renal function (urea, uric acid and creatinine) and oxidative stress parameters (superoxide dismutase, malondialdehyde and glutathione peroxidase) will be evaluated in this research work. Molecular docking also will be performed to investigate the role of vitamin C and curcumin in targeting immune response proteins. Also, Complementary component 3, Lipocalin-2, Toll-like receptor 2,Toll-like receptor 4, Kidney injury molecule-1, Interleukin 6, Interleukin-10, Tumor necrosis factor and p38 mitogen-activated protein kinases will be investigated. The obtained results showed that vitamin C and curcumin have good effects in the treatment of impaired kidneys, this was also observed in renal function and oxidative stress parameters, expression levels of proteins and histopathological examinations.

Promoter methylation might shift the balance of Galectin-3 & 12 expression in de novo adult acute myeloid leukemia patients.

Acute myeloid leukemia (AML) was reported as the most common type of leukemia among adults. Galectins constitute a family of galactose-binding proteins reported to play a critical role in many malignancies including AML. Galectin-3 and -12 are members of the mammalian galectin family. To understand the contribution of galectin-3 and -12 promoter methylation to their expression, we performed bisulfite methylation-specific (MSP)-PCR and bisulfite genomic sequencing (BGS) of primary leukemic cells in patients with de novo AML before receiving any therapy. Here, we show a significant loss of LGALS12 gene expression in association with promoter methylation. The lowest degree of expression was found in the methylated (M) group while the highest degree was in the unmethylated (U) group and the partially methylated (P) group expression lies in between. This was not the case with galectin-3 in our cohort unless the CpG sites analyzed were outside the frame of the studied fragment. We were also able to identify four CpG sites (CpG number 1, 5, 7& 8) in the promoter region of galectin-12; these sites must be unmethylated so that expression can be induced. As far as the authors know, these findings were not previously concluded in earlier studies.

Novel Hybrid Indole-Based Caffeic Acid Amide Derivatives as Potent Free Radical Scavenging Agents: Rational Design, Synthesis, Spectroscopic Characterization, In Silico and In Vitro Investigations.

Antioxidant small molecules can prevent or delay the oxidative damage caused by free radicals. Herein, a structure-based hybridization of two natural antioxidants (caffeic acid and melatonin) afforded a novel hybrid series of indole-based amide analogues which was synthesized with potential antioxidant properties. A multiple-step scheme of in vitro radical scavenging assays was carried out to evaluate the antioxidant activity of the synthesized compounds. The results of the DPPH assay demonstrated that the indole-based caffeic acid amides are more active free radical scavenging agents than their benzamide analogues. Compared to Trolox, a water-soluble analogue of vitamin E, compounds 3a, 3f, 3h, 3j, and 3m were found to have excellent DPPH radical scavenging activities with IC50 values of 95.81 ± 1.01, 136.8 ± 1.04, 86.77 ± 1.03, 50.98 ± 1.05, and 67.64 ± 1.02 µM. Three compounds out of five (3f, 3j, and 3m) showed a higher capacity to neutralize the radical cation ABTS•+ more than Trolox with IC50 values of 14.48 ± 0.68, 19.49 ± 0.54, and 14.92 ± 0.30 µM, respectively. Compound 3j presented the highest antioxidant activity with a FRAP value of 4774.37 ± 137.20 µM Trolox eq/mM sample. In a similar way to the FRAP assay, the best antioxidant activity against the peroxyl radicals was demonstrated by compound 3j (10,714.21 ± 817.76 µM Trolox eq/mM sample). Taken together, compound 3j was validated as a lead hybrid molecule that could be optimized to maximize its antioxidant potency for the treatment of oxidative stress-related diseases.

Anti-Tumor Activity of Orally Administered Gefitinib-Loaded Nanosized Cubosomes against Colon Cancer.

Gefitinib (GFT) is a tyrosine kinase inhibitor drug used as a first-line treatment for patients with advanced or metastatic non-small cell lung, colon, and breast cancer. GFT exhibits low solubility and hence low oral bioavailability, which restricts its clinical application. One of the most important trends in overcoming such problems is the use of a vesicular system. Cubosomes are considered one of the most important vesicular systems used to improve solubility and oral bioavailability. In this study, GFT cubosomal nanoparticles (GFT-CNPs) were prepared by the emulsification method. The selected formulation variables were analyzed and optimized by full factorial design and response surface methodology. Drug entrapment efficiency (EE%), transmission electron microscopy, particle size, polydispersity index, in vitro release and its kinetics, and the effect of storage studies were estimated. The chosen GFT-CNPs were subjected to further investigations as gene expression levels of tissue inhibitors of metalloproteinases-1 (TIMP-1) and matrix metalloproteinases-7 (MMP-7), colon biomarkers, and histopathological examination of colon tissues. The prepared GFT-CNPs were semi-cubic in shape, with high EE%, smaller vesicle size, and higher zeta potential values. The in vivo data showed a significant decrease in the serum level of embryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and gene expression level of TIMP-1 and MMP-7. Histopathological examination showed enhancement in cancer tissue and highly decreased focal infiltration in the lamina propria after treatment with GFT-CNPs.

Metformin ameliorates doxorubicin-induced cardiotoxicity targeting HMGB1/TLR4/NLRP3 signaling pathway in mice.

AIMS: Oxidative stress and inflammation have been linked to doxorubicin (DOX)-induced cardiotoxicity, while the exact molecular processes are currently under investigation. The goal of this study is to investigate Metformin's preventive role in cardiotoxicity induced by DOX. MATERIALS AND METHODS: Male albino mice were divided randomly into 4 groups. Metformin (Met) 200 mg/kg orally (p.o.) was given either alone or when combined with a single DOX (15 mg/kg; i.p.). A control group of 5 mice was also provided. Met was initiated 7 days before DOX, lasting for 14 days. Besides, docking studies of Met towards HMGB1, NF-kB, and caspase 3 were performed. KEY FINDINGS: Heart weight, cardiac troponin T (cTnT), creatine kinase Myocardial Band (CK-MB) levels, malondialdehyde (MDA), and nitric oxide (NO) contents all increased significantly when comparing the DOX group to the control normal group. Conversely, there was a substantial decline in superoxide dismutase (SOD) and glutathione peroxidase (GSH). DOX group depicts a high expression of TLR4, HMGB1, and caspase 3. Immunohistochemical staining revealed an increase in NLRP3 inflammasome and NF-κB expressions alongside histopathological modifications. Additionally, Met dramatically decreased cardiac weight, CK-MB, and cTnT while maintaining the tissues' histological integrity. Inflammatory biomarkers, including HMGB1, TLR4, NF-κB, inflammasome, and caspase 3 were reduced after Met therapy. Furthermore, molecular docking studies suggested the antagonistic activity of Met towards HMGB1, NF-κB, and caspase 3 target receptors. SIGNIFICANCE: According to recent evidence, Met is a desirable strategy for improving cardiac toxicity produced by DOX by inhibiting the HMGB1/NF-κB inflammatory pathway, thus preserving heart function.

Optimization of tamoxifen solubility in carbon dioxide supercritical fluid and investigating other molecular targets using advanced artificial intelligence models.

Particle size, shape and morphology can be considered as the most significant functional parameters, their effects on increasing the performance of oral solid dosage formulation are indisputable. Supercritical Carbon dioxide fluid (SCCO2) technology is an effective approach to control the above-mentioned parameters in oral solid dosage formulation. In this study, drug solubility measuring is investigated based on artificial intelligence model using carbon dioxide as a common supercritical solvent, at different pressure and temperature, 120-400 bar, 308-338 K. The results indicate that pressure has a strong effect on drug solubility. In this investigation, Decision Tree (DT), Adaptive Boosted Decision Trees (ADA-DT), and Nu-SVR regression models are used for the first time as a novel model on the available data, which have two inputs, including pressure, X1 = P(bar) and temperature, X2 = T(K). Also, output is Y = solubility. With an R-squared score, DT, ADA-DT, and Nu-SVR showed results of 0.836, 0.921, and 0.813. Also, in terms of MAE, they showed error rates of 4.30E-06, 1.95E-06, and 3.45E-06. Another metric is RMSE, in which DT, ADA-DT, and Nu-SVR showed error rates of 4.96E-06, 2.34E-06, and 5.26E-06, respectively. Due to the analysis outputs, ADA-DT selected as the best and novel model and the find optimal outputs can be shown via vector: (x1 = 309, x2 = 317.39, Y1 = 7.03e-05).

Microwave-assisted synthesis, spectroscopic characterization, and biological evaluation of fused thieno[2,3-d]pyrimidines as potential anti-cancer agents targeting EGFRWT and EGFRT790M.

Epidermal growth factor receptor (EGFR) is a transmembrane protein tyrosine kinase that is usually overexpressed in many types of cancers. In the present study, an effort was done in synthesis of new 3,4-diaminothieno[2,3-b] thiophene-2,5-dicarbonitrile derivatives 2-8, assisted by a microwave device. Different spectroscopic instruments were used for their analysis and confirmed their chemical structures. The antimicrobial properties of the produced compounds were investigated and found to be promising. Next, they were tested for cytotoxicity against MCF-7, HepG-2, HCT-116, and A549 cell lines. Moreover, in vitro cytotoxicity evaluation against well-known standards, namely, gefitinib and erlotinib was achieved using MTT method. The obtained compounds (2-8) were found to be more effective against the two tested cancer cell lines than erlotinib. In MCF-7 and A549 cells, compound 3 was found to be 4.42 and 4.12 times more active than erlotinib, respectively. The activity of radical scavenging was inhibited by 78%. The most cytotoxic compounds were subsequently studied for their kinase inhibitory effect against EGFRWT and EGFRT790M using the HTRF assay. Compound 3 was shown to be the most powerful against both kinds of EGFR, with IC50 values of 0.28 and 5.02. Furthermore, compound 2 demonstrated the highest antioxidant activity as it has a radical scavenging activity of 78%. Compounds 2,6,7 and 8 revealed to be the most safe compounds, none hepatotoxic, none carcinogenic, none immunotoxic, none mutagenic and none cytotoxic.

Thieno[2,3-b]thiophene Derivatives as Potential EGFRWT and EGFRT790M Inhibitors with Antioxidant Activities: Microwave-Assisted Synthesis and Quantitative In Vitro and In Silico Studies.

Microwave-assisted synthesis and spectral analysis of certain novel derivatives of 3,4-diaminothieno[2,3-b]thiophene-2,5-dicarbonitrile 1-7 were carried out. Compounds 1-7 were examined for cytotoxicity against MCF-7 and A549 cell lines using the quantitative MTT method, and gefitinib and erlotinib were used as reference standards. Compounds 1-7 were shown to be more active than erlotinib against the two cell lines tested. Compound 2 outperformed regular erlotinib by 4.42- and 4.12-fold in MCF-7 and A549 cells, respectively. The most cytotoxic compounds were subsequently studied for their suppression of kinase activity using the homogeneous time-resolved fluorescence assay versus epidermal growth factor receptor (EGFRWT) and EGFR790M. With IC50 values of 0.28 ± 0.03 and 5.02 ± 0.19, compound 2 was demonstrated to be the most effective against both forms of EGFR. Furthermore, compound 2 also had the best antioxidant property, decreasing the radical scavenging activity by 78%. Molecular docking research, on the other hand, was carried out for the analyzed candidates (1-7) to study their mechanism of action as EGFR inhibitors. In silico absorption, distribution, metabolism, excretion, and toxicity tests were also performed to explain the physicochemical features of the examined derivatives.