Discovery of new naphthyridine hybrids against enoyl-ACP reductase (inhA) protein target of Mycobacterium tuberculosis: Molecular docking, molecular dynamics simulations studies

Tuberculosis (TB) is caused by Mycobacterium tuberculosis (Mtb) and remains a significant global public health concern, with many new cases reported annually. Despite advancements in TB treatment and control, the emergence of drug-resistant strains has presented a considerable challenge to eradication efforts. One crucial area that necessitates further research in antituberculosis is the development of effective treatments for drug-resistant strains, particularly multidrug resistance tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB), and totally drug–resistant tuberculosis (TDR-TB). The limited and often unsatisfactory treatment options available for drug-resistant strains require the exploration of novel drugs and treatment regimens to combat this escalating issue. This study focuses on designing and developing a series of new 1,8-naphthyridine derivatives for their potential antitubercular activity. The compounds were designed and evaluated through in-silico screening using Molinspiration Cheminformatics, Osiris Property Explorer, AdmetSAR, and SwissADME. The initial filtering process identified the top 16 hybrids, which were then subjected to docking using the AutoDock tool. These compounds' binding energies were higher than the standard drug isoniazid, indicating a potentially more substantial interaction with the target. Based on the promising in silico and docking results, further investigations were conducted on the top 3 compounds, namely ST03, ST09, and ST14. To assess the stability and binding energies observed during the initial docking process, molecular dynamics simulations were performed over a 100 ns period. Both the docking and simulation studies consistently demonstrated that the 1,8-naphthyridine hybrid ST09 exhibited stable and efficient binding energies, suggesting its potential as an effective antituberculosis agent

Molecular docking and molecular dynamics simulations discover curcumin analogs as potential wound healing agents

Chronic non-healing wounds impose a significant economic burden on the healthcare system. Among the existing strategies in wound healing therapy, targeting specific enzymes, namely tyrosyl-tRNA synthetase, TGFBR1, IL-1β, and Pseudomonas aeruginosa MvfR, represents an important aspect of the strategy of wound healing. Our research focuses on creating new curcumin hybrids (SV01-SV20) for harnessing wound healing activities and possesses considerable therapeutic implications. The compounds were designed and evaluated through in-silico screening using Molinspiration Cheminformatics, Osiris Property Explorer, AdmetSAR, and SwissADME. The initial filtering process identified the top 19 hybrids, which were then subjected to docking using the AutoDock tool. The results of the molecular docking analysis indicate that the curcumin hybrids, specifically tyrosyl-tRNA synthetase (SV09, SV15), TGFBR1 (SV01, and SV11), IL-1β (SV07, SV08), and Pseudomonas aeruginosa MvfR (SV09, SV13), showed the most significant binding energies (-8.69, -9.01, -8.49, -8.13, -8.48, -6.14, -9.7, and -9.2 kcal/mol, respectively) among the designed compounds. The binding energies were higher than the standard curcumin, indicating a potentially more substantial interaction with the target. Extensive molecular dynamics simulations confirmed the stability of these derivatives throughout the 100 ns simulation; the ligand-protein complexes maintained structural stability. The designed compounds demonstrated favorable pharmacokinetic properties, drug-likeness scores, bioactivity assessments, adherence to Lipinski's rule of five, and low toxicity risks. Overall, results consistently demonstrated that SV01, SV07, SV08, SV09, SV11, SV13, and SV15 compounds hold significant potential as effective agents in treating chronic wounds

Synthesis and antimicrobial activities of 1-(3-benzyl-4-oxo-3H-quinazolin-2-yl)-4-(substituted)thiosemicarbazide derivatives

A series of 1-(3-benzyl-4-oxo-3H-quinazolin-2-yl)-4-(substituted) thiosemicarbazides (AS1-AS10) were obtained by the reaction of 2-hydrazino- 3-benzyl quinazolin-4(3H)-one (6) with different dithiocarbamic acid methyl ester derivatives. The key intermediate 3-benzyl-2-thioxo-2,3-dihydro-1Hquinazolin-4-one (4) was obtained by reacting benzyl amine (1) with carbon disulphide and sodium hydroxide in dimethyl sulphoxide to give sodium dithiocarbamate, which was methylated with dimethyl sulfate to yield the dithiocarbamic acid methyl ester (2) and condensed with methyl anthranilate (3) in ethanol yielded the desired compound (4) via the thiourea intermediate. The SH group of compound (4) was methylated for the favorable nucleophilic displacement reaction with hydrazine hydrate, which afford 2-hydrazino-3- benzyl-3H-quinazolin-4-one (6). The IR, 1H, and 13C NMR spectrum of these compounds showed the presence of peaks due to thiosemicarbazides, carbonyl (C=O), NH and aryl groups. The quinazolin-4-one moiety molecular ion peaks (m/z 144) were observed all the mass spectrum of compounds (AS1-AS10). Elemental (C, H, N) analysis satisfactorily confirmed purity of the synthesized compounds and elemental composition. All synthesized compounds were also screened for their antimicrobial activity against selective gram positive and gram negative by agar dilution method. In the present study compounds AS8 and AS9 were emerged as the most active compounds of the series

Recent Advances in Silver Nanoparticles Containing Nanofibers for Chronic Wound Management

Infections are the primary cause of death from burns and diabetic wounds. The clinical difficulty of treating wound infections with conventional antibiotics has progressively increased and reached a critical level, necessitating a paradigm change for enhanced chronic wound care. The most prevalent bacterium linked with these infections is Staphylococcus aureus, and the advent of community-associated methicillin-resistant Staphylococcus aureus has posed a substantial therapeutic challenge. Most existing wound dressings are ineffective and suffer from constraints such as insufficient antibacterial activity, toxicity, failure to supply enough moisture to the wound, and poor mechanical performance. Using ineffective wound dressings might prolong the healing process of a wound. To meet this requirement, nanoscale scaffolds with their desirable qualities, which include the potential to distribute bioactive agents, a large surface area, enhanced mechanical capabilities, the ability to imitate the extracellular matrix (ECM), and high porosity, have attracted considerable interest. The incorporation of nanoparticles into nanofiber scaffolds constitutes a novel approach to “nanoparticle dressing” that has acquired significant popularity for wound healing. Due to their remarkable antibacterial capabilities, silver nanoparticles are attractive materials for wound healing. This review focuses on the therapeutic applications of nanofiber wound dressings containing Ag-NPs and their potential to revolutionize wound healing

Emerging Trends in Curcumin Embedded Electrospun Nanofibers for Impaired Diabetic Wound Healing

Chronic wounds impose a significant burden on individuals and healthcare systems all over the world. Through clinical and preclinical investigations, inflammation and oxidative damage have been established as the primary causes of chronic wounds. These skin sores are easily exposed to microorganisms, which in turn cause inflammation and hinder the healing process. Additionally, microorganisms may cause an infection that prevents collagen production and reepithelialization. Curcumin’s antioxidant, anti-inflammatory, and anti-infectious characteristics, among others, have been identified as useful for diabetic wound healing management. However, curcumin has a few disadvantages, such as limited bioavailability, pH-dependent instability, water insolubility, slow cell absorption, and fast intracellular metabolism. These constraints necessitates the development of a suitable transporter to improve curcumin’s stability, bioavailability, therapeutic efficacy, and solubility. In recent years, Electrospun nanofiber mats have been an excellent choice for drug delivery because of their numerous advantages and inherent properties. Electrospun nanofibers have shown considerable promise as wound dressing materials. This review highlights the potential properties and recent advancements in using curcumin-loaded nanofibers for diabetic wound healing

Emerging Trends in Curcumin Embedded Electrospun Nanofibers for Impaired Diabetic Wound Healing

Chronic wounds impose a significant burden on individuals and healthcare systems all over the world. Through clinical and preclinical investigations, inflammation and oxidative damage have been established as the primary causes of chronic wounds. These skin sores are easily exposed to microorganisms, which in turn cause inflammation and hinder the healing process. Additionally, microorganisms may cause an infection that prevents collagen production and reepithelialization. Curcumin’s antioxidant, anti-inflammatory, and anti-infectious characteristics, among others, have been identified as useful for diabetic wound healing management. However, curcumin has a few disadvantages, such as limited bioavailability, pH-dependent instability, water insolubility, slow cell absorption, and fast intracellular metabolism. These constraints necessitates the development of a suitable transporter to improve curcumin’s stability, bioavailability, therapeutic efficacy, and solubility. In recent years, Electrospun nanofiber mats have been an excellent choice for drug delivery because of their numerous advantages and inherent properties. Electrospun nanofibers have shown considerable promise as wound dressing materials. This review highlights the potential properties and recent advancements in using curcumin-loaded nanofibers for diabetic wound healing

A novel synthetic trivalent single chain variable fragment (tri-scFv) construction platform based on the SpyTag/SpyCatcher protein ligase system

Abstract Background Advances in antibody engineering provide strategies to construct recombinant antibody-like molecules with modified pharmacokinetic properties. Multermerization is one strategy that has been used to produce antibody-like molecules with two or more antigen binding sites. Multimerization enhances the functional affinity (avidity) and can be used to optimize size and pharmacokinetic properties. Most multimerization strategies involve genetically fusing or non-covalently linking antibody fragments using oligomerization domains. Recent studies have defined guidelines for producing antibody-like molecules with optimal tumor targeting properties, which require intermediates size (70–120 kDa) and bi- or tri-valency. Results We described a highly modular antibody-engineering platform for rapidly constructing synthetic, trivalent single chain variable fragments (Tri-scFv) using the SpyCatcher/SpyTag protein ligase system. We used this platform to construct an anti-human epidermal growth factor receptor 3 (HER3) Tri-scFv. We generated the anti-HER3 Tri-scFv by genetically fusing a SpyCatcher to the C-terminus of an anti-HER3 scFv and ligating it to a synthetic Tri-SpyTag peptide. The anti-HER3 Tri-scFv bound recombinant HER3 with an apparent KD of 2.67 nM, which is approximately 12 times lower than the KD of monomeric anti-HER3 scFv (31.2 nM). Anti-HER3 Tri-scFv also bound endogenous cell surface expressed HER3 stronger than the monomer anti-HER3 scFv. Conclusion We used the SpyTag/SpyCatcher protein ligase system to ligate anti-HER3 scFv fused to a SpyCatcher at its C-termini to a Tri-SpyTag to construct Tr-scFv. This system allowed the construction of a Tri-scFv with all the scFv antigen-binding sites pointed outwards. The anti-HER3 Tri-scFv bound recombinant and endogenously expressed HER3 with higher functional affinity (avidity) than the monomeric anti-HER3 scFv. The Tri-scFv had the size, valency, and functional affinity that are desired for therapeutic and imaging applications. Use of the SpyTag/SpyCatcher protein ligase system allows Tri-scFvs to be rapidly constructed in a simple, modular manner, which can be easily applied to scFvs or other antibody fragments targeting other antigens

Design, synthesis, in silico, and pharmacological evaluation of novel quinoline derivatives containing substituted piperazine moieties as potential anti-breast cancer agents

Quinoline derivatives are important heterocyclic compounds with potential medicinal values, especially for treating cancers like breast cancer. However, drug resistance and potential toxicity can limit their effectiveness. New derivatives are needed to specifically target cancer cells, particularly in breast cancer, while minimizing harm to normal cells and side effects for better treatment outcomes. Thus, this study aims to design and synthesize novel quinoline derivatives incorporating substituted piperazine moieties to enhance their anticancer efficacy by inhibiting EGFR, a key therapeutic target for breast cancer. Therefore, in this study, structural elucidation of the synthesized compounds was confirmed by using various analytical techniques, including IR, MASS, and NMR spectral data. Subsequently, these analogs were analyzed for their binding affinity using the molecular docking study, while anticancer efficacy was evaluated against MCF-7 cell lines, followed by an in vivo study in a DMBA-induced rat model. Initially, docking studies of synthesized analogs (8a–i) at the ATP binding site of the EGFR showed better docking scores and MM/GBSA energy, indicating their increased binding affinity to the EGFR. Further, the in vitro evaluation of all compounds (8a–i) showed that the compounds effectively inhibit the EGFR-TK enzyme, with compound 8i showing the highest potency at 87.5%. Moreover, the anti-breast cancer efficacy of compound 8i is attributed to electron-donating groups, which enhance interactions with biological targets. Compound 8i exhibited promising anti-breast cancer activity and was confirmed in vitro and in vivo studies, warranting further investigation as a potential anticancer property