Unfolding the Antibacterial Activity and Acetylcholinesterase Inhibition Potential of Benzofuran-Triazole Hybrids: Synthesis, Antibacterial, Acetylcholinesterase Inhibition, and Molecular Docking Studies.

In this study, a series of novel benzofuran-based 1,2,4-triazole derivatives (10a-e) were synthesized and evaluated for their inhibitory potential against acetylcholinesterase (AChE) and bacterial strains (E. coli and B. subtilis). Preliminary results revealed that almost all assayed compounds displayed promising efficacy against AChE, while compound 10d was found to be a highly potent inhibitor of AChE. Similarly, these 5-bromobenzofuran-triazoles 10a-e were screened against B. subtilis QB-928 and E. coli AB-274 to evaluate their antibacterial potential in comparison to the standard antibacterial drug penicillin. Compound 10b was found to be the most active among all screened scaffolds, with an MIC value of 1.25 ± 0.60 µg/mL against B. subtilis, having comparable therapeutic efficacy to the standard drug penicillin (1 ± 1.50 µg/mL). Compound 10a displayed excellent antibacterial therapeutic efficacy against the E. coli strain with comparable MIC of 1.80 ± 0.25 µg/mL to that of the commercial drug penicillin (2.4 ± 1.00 µg/mL). Both the benzofuran-triazole molecules 10a and 10b showed a larger zone of inhibition. Moreover, IFD simulation highlighted compound 10d as a novel lead anticholinesterase scaffold conforming to block entrance, limiting the swinging gate, and disrupting the catalytic triad of AChE, and further supported its significant AChE inhibition with an IC50 value of 0.55 ± 1.00 µM. Therefore, compound 10d might be a promising candidate for further development in Alzheimer's disease treatment, and compounds 10a and 10b may be lead antibacterial agents.

Versatile role of sirtuins in metabolic disorders: From modulation of mitochondrial function to therapeutic interventions.

Sirtuins (SIRT1-7) are distinct histone deacetylases (HDACs) whose activity is determined by cellular metabolic status andnicotinamide adenine dinucleotide (NAD+ ) levels. HDACs of class III are the members of the SIRT's protein family. SIRTs are the enzymes that modulate mitochondrial activity and energy metabolism. SIRTs have been linked to a number of clinical and physiological operations, such as energy responses to low-calorie availability, aging, stress resistance, inflammation, and apoptosis. Mammalian SIRT2 orthologs have been identified as SIRT1-7 that are found in several subcellular sections, including the cytoplasm (SIRT1, 2), mitochondrial matrix (SIRT3, 4, 5), and the core (SIRT1, 2, 6, 7). For their deacetylase or ADP-ribosyl transferase action, all SIRTs require NAD+ and are linked to cellular energy levels. Evolutionarily, SIRT1 is related to yeast's SIRT2 as well as received primary attention in the circulatory system. An endogenous protein, SIRT1 is involved in the development of heart failure and plays a key role in cell death and survival. SIRT2 downregulation protects against ischemic-reperfusion damage. Increase in human longevity is caused by an increase in SIRT3 expression. Cardiomyocytes are also protected by SIRT3 from oxidative damage and aging, as well as suppressing cardiac hypertrophy. SIRT4 and SIRT5 perform their roles in the heart. SIRT6 has also been linked to a reduction in heart hypertrophy. SIRT7 is known to be involved in the regulation of stress responses and apoptosis in the heart.

Ultrasonic-Assisted Synthesis of Benzofuran Appended Oxadiazole Molecules as Tyrosinase Inhibitors: Mechanistic Approach through Enzyme Inhibition, Molecular Docking, Chemoinformatics, ADMET and Drug-Likeness Studies.

Furan-oxadiazole structural hybrids belong to the most promising and biologically active classes of oxygen and nitrogen containing five member heterocycles which have expanded therapeutic scope and potential in the fields of pharmacology, medicinal chemistry and pharmaceutics. A novel series 5a-j of benzofuran-oxadiazole molecules incorporating S-alkylated amide linkage have been synthesized using ultrasonic irradiation and screened for bacterial tyrosinase inhibition activity. Most of the synthesized furan-oxadiazole structural motifs exhibited significant tyrosinase inhibition activity in the micromolar range, with one of the derivatives being more potent than the standard drug ascorbic acid. Among the tested compounds, the scaffold 5a displayed more tyrosinase inhibition efficacy IC50 (11 ± 0.25 µM) than the ascorbic acid IC50 (11.5 ± 0.1 µM). Compounds 5b, 5c and 5d efficiently inhibited bacterial tyrosinase with IC50 values in the range of 12.4 ± 0.0-15.5 ± 0.0 µM. The 2-fluorophenylacetamide containing furan-oxadiazole compound 5a may be considered as a potential lead for tyrosinase inhibition with lesser side effects as a skin whitening and malignant melanoma anticancer agent.

Facile synthesis, antibacterial and protease inhibition studies of ß-amino alcohols prepared via ring opening of epoxides.

A green ultrasound assisted convenient approach has been reported for the ring opening of epoxides. As a result, a series of N-phenyl piperazine and morpholine based ß-amino alcohols has been synthesized under ultrasound irradiation in DMSO for 60 minutes at 70°C. This methodology showed excellent tolerance with various epoxides and provided excellent yields upto 96%. All the synthetic derivatives (4a-e) (5c-d) significantly influence the catalytic activity of protease while 5d exhibited maximum (100%) inhibitory effect with a half-life of 40.76 minutes. Among the target derivatives, compound 4c exhibited significant antibacterial activity against Bacillus subtilis and Escherichia coli bacterial strains with zone of inhibition values 45 mm and 32 mm, respectively.

Exposure of Environmental Contaminants and Development of Neurological Disorders.

In this era of technology, neurological disorders are the most prevalent disorders in growing population. Alzheimer's and Parkinson's diseases are the most common neurological disorders which are manifested by any abnormality in the structure and functions of neurons present in brain and spinal cord. Exposure to environmental pollution is a serious issue which is associated with high morbidity and mortality rate in the worldwide. Air pollutants are the major contributors to induce the inflammation in lungs and brain which ultimately impairs the normal functioning of CNS. Air pollution persuades CNS pathology by inducing the oxidative stress, activation of microglial cells, neuroinflammation and alteration in permeability of blood brain barrier. Similarly, exposure of heavy metals also exhibits the major and long-lasting effects on brain and causes cognitive dysfunction. Likewise, pesticides have also major influence on the etiology of neurological disorders. Pesticides such as paraquat and rotenone are involved in the pathogenesis of Parkinson's disease. Treatment strategy for environmental pollutants-induced neurological disorders is a challenging task because conventional therapeutics are effective but do not have optimum therapeutic efficacy against such type of disorders. This article addresses how the environmental pollutants are involved in the pathogenesis of neurological disorders and treatment strategies to reduce the occurrence of neurological disorders.

A new approach to design 3(3-sulfamoylbenzamido) benzoic acid containing transition metal complexes: Characterization and Biological activities.

Zn, Cu, Co and Ni are biocompatible metals as they are active center of many enzymes in the human body. Incorporation of these biocompatible metals into 3-(o-Sulfamoylphenyl) carbamoylbenzoic acid (I) makes them able to prove an excellent antimicrobial agent. In the present study Ni (II), Co (II), Cu(II) and Zn (II) complexes (III-VI) were synthesized from ligand (I) derive from 3-(o-Sulfamoylphenyl) carbamoylbenzoic acid and zinc, nickel, cobalt acetate tetrahydrate/copper acetate monohydrate. Synthesized complexes (III-VI) were characterized by FT-IR, 1H NMR and 13CNMR. III-VI have 81-93% yield while melting points recorded were in the range of 209-239oC. Purity of ligands and their respective complexes was confirmed by TLC. Results of antibacterial properties suggested that III, IV, V and VI were highly active against gram +ve (S. epidermidis, B. subtilis. S. aureus, S. mutans) and gram -ve bacteria (E. coli and P. aruginosa). Comparison was also performed to check whether metal complexes or ligand with its derivative exhibit best result against all tested strains. The anthelmintic activity of the complexes III-VI against tape worm, liver fluke, thread worm, and hook worm using three different concentrations (15, 30, 45mg/mL), significantly (p<0.01) paralyzed the worms followed by death, which was comparable with that of the standard. Overall results indicated that S. epidermidis, S. mutans, E. coli and B. subtilis are very sensitive to complex III & IV and can be used for treatment of bacterial infections whereas Complex-V, could a potent target for anti-parasite therapy.

Further Stabilization of Alcalase Immobilized on Glyoxyl Supports: Amination Plus Modification with Glutaraldehyde.

Alcalase was immobilized on glyoxyl 4% CL agarose beads. This permitted to have Alcalase preparations with 50% activity retention versus Boc-l-alanine 4-nitrophenyl ester. However, the recovered activity versus casein was under 20% at 50 °C, as it may be expected from the most likely area of the protein involved in the immobilization. The situation was different at 60 °C, where the activities of immobilized and free enzyme became similar. The chemical amination of the immobilized enzyme or the treatment of the enzyme with glutaraldehyde did not produce any significant stabilization (a factor of 2) with high costs in terms of activity. However, the modification with glutaraldehyde of the previously aminated enzyme permitted to give a jump in Alcalase stability (e.g., with most than 80% of enzyme activity retention for the modified enzyme and less than 30% for the just immobilized enzyme in stress inactivation at pH 7 or 9). This preparation could be used in the hydrolysis of casein at pH 9 even at 67 °C, retaining around 50% of the activity after 5 hydrolytic cycles when the just immobilized preparation was almost inactive after 3 cycles. The modified enzyme can be reused in hydrolysis of casein at 45 °C and pH 9 for 6 cycles (6 h) without any decrease in enzyme activity.

Anti-diabetic activity of aqueous extract of Ipomoea batatas L. in alloxan induced diabetic Wistar rats and its effects on biochemical parameters in diabetic rats.

Diabetes is a condition where the fasting blood glucose level elevated above the normal range (80-120mg/dL). This increase in blood glucose level may be due to the insulin deficiency i.e. insulin dependent diabetes mellitus (IDDM or type I) or due to insulin resistance i.e. non-insulin dependent diabetes mellitus (NIDDM or type II). Diabetes leads to severe complications in the body even life treating complications e.g. nephropathy, retinopathy, neuropathy increased vascular permeability and delayed wound healing if left untreated. Different drugs are used for the treatment of diabetes mellitus, but synthetic drugs are costly and possess severe side effects. So, more emphasis is being placed on the use of traditional medicines because these sources have fewer side effects than the synthetics drugs and are economical. So the white skinned sweet potato (Ipomoea batatas L.) peel-off was selected for its anti-diabetic effect as well as to see its effects on biochemical parameters. Both young (3-4 months) and old (up to 1 year) Wistar rats were selected for current study. It was found that the aqueous extract of WSSP peel-off had shown beneficial effects. In addition to the decrease in blood glucose level it also decreased protein glycation level total cholesterol, triglycerides, and LDL-cholesterol. Increase in HDL-cholesterol was also observed after treating the rats with aqueous extract of Ipomoea batatas. Additionally, WSSP peel-off had also shown positive results on total protein concentration, albumin, globulin, and plasma enzymes (SGOT and SGPT). Further research would be needed in order to purify the anti-diabetic components and it should be available in compact dose form for all diabetic patients.

Enhanced production of Lovastatin by filamentous fungi through solid state fermentation.

Lovastatin is a natural competitive inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme-A (HMG-CoA) reductase and inhibits specifically rate limiting step in cholesterol biosynthesis. Further, lovastatin in comparison with synthetic drugs has no well-reported side effects. Four pure isolated filamentous fungal strains including Aspergillus niger IBL, Aspergillus terreus FFCBP-1053, Aspergillus flavus PML and Aspergillus nidulans FFCBP-014 have been cultured by solid state fermentation (SSF) using rice straw as substrate for the synthesis of lovastatin. After selecting Aspergillus terreus FFCBP-1053 as the best producer of lovastatin, various selected physical parameters including pH, temperature, inoculums size and moisture content were optimized through response surface methodology (RSM) under center composite design (CCD) for lovastatin hyper production. Maximum lovastatin production of 2070±91.5 was predicted by the quadratic model in the medium having moisture content 70% and pH 4.5 at 35°C which was verified experimentally to be 2140±93.25µg/g DW of FM (microgram/gram dry weight of fermentation medium), significantly (P<0.05) high as compared to un-optimized conditions while it was noted that lovastatin production is independent on inoculum size (P>0.05) measured by spectrophotometer at 245 nm against standard. It was determined that optimized conditions for the hyper-production of lovastatin from fungal sources have a significant effect.

Role of Interleukin-6 in Development of Insulin Resistance and Type 2 Diabetes Mellitus.

Interleukin-6 (IL-6) is a proinflammatory cytokine that decisively induces the development of insulin resistance and pathogenesis of type 2 diabetes mellitus (T2DM) through the generation of inflammation by controlling differentiation, migration, proliferation, and cell apoptosis. The presence of IL-6 in tissues is a normal consequence, but its irregular production and long-term exposure leads to the development of inflammation, which induces insulin resistance and overt T2DM. There is a mechanistic relationship between the stimulation of IL-6 and insulin resistance. IL-6 causes insulin resistance by impairing the phosphorylation of insulin receptor and insulin receptor substrate-1 by inducing the expression of SOCS-3, a potential inhibitor of insulin signaling. In this article, we have briefly described how IL-6 induces the insulin resistance and pathogenesis of T2DM. The prevention of inflammatory disorders by blocking IL-6 and IL-6 signaling may be an effective strategy for the treatment of insulin resistance and T2DM.

Chemical Composition and in-Vitro Evaluation of the Antimicrobial and Antioxidant Activities of Essential Oils Extracted from Seven Eucalyptus Species.

Eucalyptus is well reputed for its use as medicinal plant around the globe. The present study was planned to evaluate chemical composition, antimicrobial and antioxidant activity of the essential oils (EOs) extracted from seven Eucalyptus species frequently found in South East Asia (Pakistan). EOs from Eucalyptus citriodora, Eucalyptus melanophloia, Eucalyptus crebra, Eucalyptus tereticornis, Eucalyptus globulus, Eucalyptus camaldulensis and Eucalyptus microtheca were extracted from leaves through hydrodistillation. The chemical composition of the EOs was determined through GC-MS-FID analysis. The study revealed presence of 31 compounds in E. citriodora and E. melanophloia, 27 compounds in E. crebra, 24 compounds in E. tereticornis, 10 compounds in E. globulus, 13 compounds in E. camaldulensis and 12 compounds in E. microtheca. 1,8-Cineole (56.5%), α-pinene (31.4%), citrinyl acetate (13.3%), eugenol (11.8%) and terpenene-4-ol (10.2%) were the highest principal components in these EOs. E. citriodora exhibited the highest antimicrobial activity against the five microbial species tested (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Aspergillus niger and Rhizopus solani). Gram positive bacteria were found more sensitive than Gram negative bacteria to all EOs. The diphenyl-1-picrylhydazyl (DPPH) radical scavenging activity and percentage inhibition of linoleic acid oxidation were highest in E. citriodora (82.1% and 83.8%, respectively) followed by E. camaldulensis (81.9% and 83.3%, respectively). The great variation in chemical composition of EOs from Eucalyptus, highlight its potential for medicinal and nutraceutical applications.

Solar light driven degradation of piroxicam and paracetamol by heterogeneous photocatalytic fenton system: Process optimization, mechanistic studies and toxicity assessment.

The widespread occurence of pharmaceutical pollutants seriously threatens the environment and human well-being. In the present study, zinc ferrite nanoparticles (ZnFe2O4 NPs) have been synthesized by co-precipitation method and used as photocatalyst for the degradation of two most commonly prescribed painkillers, piroxicam (PXM) and paracetamol (PCM), via heterogeneous Fenton process under the solar light. The synthesized ZnFe2O4 NPs showed a narrower band gap i.e. 1.87 eV, signifying the ability to efficiently work in visible light range. In context of photocatalytic applications, the operational conditions were optimized to achieve maximum degradation. PCM and PXM were completely degraded (100%) at the optimized photocatalytic dose (20 mg L-1), reaction time (180 min), initial drug concentration (10 mg L-1), and pH (6.0), which is close to the natural environment. The extent of mineralization as estimated by the reduction of total organic carbon (TOC) was observed to be ∼91 and 82% for PCM and PXM respectively. Kinetic studies revealed that photocatalytic degradation followed pseudo-first-order kinetics. Moreover, the ZnFe2O4 NPs retained ∼90 % of photocatalytic activity after five consecutive reaction cycles, showing remarkable reusability and stability of catalyst.

Synergistic Biomedical Potential and Molecular Docking Analyses of Coumarin-Triazole Hybrids as Tyrosinase Inhibitors: Design, Synthesis, In Vitro Profiling, and In Silico Studies.

The tyrosinase enzyme has a vital role in the browning of vegetables and fruits and the biosynthesis of melanin. In this work, we synthesized a diverse library of coumarin-triazole hybrids, and these compounds were characterized by using suitable analytical techniques. Our research work extends beyond the synthetic effort to explore the therapeutic potential of these compounds. We put the synthesized compounds through meticulous in vitro screening against the tyrosinase enzyme, and these coumarin derivatives evinced good IC50 values in the range of 0.339 ± 0.25 µM to 14.06 ± 0.92 µM. In the library of synthesized compounds, six compounds were found to be more potent than standard ascorbic acid (IC50 = 11.5 ± 1.00), and among them, 17e and 17f, being the most active, exhibited remarkable anti-tyrosinase potential, with IC50 values of 0.339 ± 0.25 µM and 3.148 ± 0.23 µM, respectively. Furthermore, an in silico modeling study was carried out to determine the key interactions of these compounds with the tyrosinase protein (PDB ID: 2Y9X) and thus to authenticate our experimental findings. The quantitative SAR studies exhibited a good correlation between the synthesized derivatives of coumarin and their anti-tyrosinase activity. The docking studies verified the experimental results, and ligand 17e showed good interaction with the core residues of tyrosinase. This study not only expands the field of coumarin-triazole hybrid synthesis but also provides valuable insights for the development of novel tyrosinase inhibitors.

Therapeutic Intervention of Serine Protease Inhibitors against Hepatitis C Virus.

Hepatitis C virus (HCV) is a globally prevalent and hazardous disorder that is responsible for inducing several persistent and potentially fatal liver diseases. Current treatment strategies offer limited efficacy, often accompanied by severe and debilitating adverse effects. Consequently, there is an urgent and compelling need to develop novel therapeutic interventions that can provide maximum efficacy in combating HCV while minimizing the burden of adverse effects on patients. One promising target against HCV is the NS3-4A serine protease, a complex composed of two HCV-encoded proteins. This non-covalent heterodimer is crucial in the viral life cycle and has become a primary focus for therapeutic interventions. Although peginterferon, combined with ribavirin, is commonly employed for HCV treatment, its efficacy is hampered by significant adverse effects that can profoundly impact patients' quality of life. In recent years, the development of direct-acting antiviral agents (DAAs) has emerged as a breakthrough in HCV therapy. These agents exhibit remarkable potency against the virus and have demonstrated fewer adverse effects when combined with other DAAs. However, it is important to note that there is a potential for developing resistance to DAAs due to alterations in the amino acid position of the NS3-4A protease. This emphasizes the need for ongoing research to identify strategies that can minimize the emergence of resistance and ensure long-term effectiveness. While the combination of DAAs holds promise for HCV treatment, it is crucial to consider the possibility of drug-drug interactions. These interactions may occur when different DAAs are used concurrently, potentially compromising their therapeutic efficacy. Therefore, carefully evaluating and monitoring potential drug interactions are vital to optimize treatment outcomes. In the pursuit of novel therapeutic interventions for HCV, the field of computational biology and bioinformatics has emerged as a valuable tool. These advanced technologies and methodologies enable the development and design of new drugs and therapeutic agents that exhibit maximum efficacy, reduced risk of resistance, and minimal adverse effects. By leveraging computational approaches, researchers can efficiently screen and optimize potential candidates, accelerating the discovery and development of highly effective treatments for HCV, treatments.

Sirtuin insights: bridging the gap between cellular processes and therapeutic applications.

The greatest challenges that organisms face today are effective responses or detection of life-threatening environmental changes due to an obvious semblance of stress and metabolic fluctuations. These are associated with different pathological conditions among which cancer is most important. Sirtuins (SIRTs; NAD+-dependent enzymes) are versatile enzymes with diverse substrate preferences, cellular locations, crucial for cellular processes and pathological conditions. This article describes in detail the distinct roles of SIRT isoforms, unveiling their potential as either cancer promoters or suppressors and also explores how both natural and synthetic compounds influence the SIRT function, indicating promise for therapeutic applications. We also discussed the inhibitors/activators tailored to specific SIRTs, holding potential for diseases lacking effective treatments. It may uncover the lesser-studied SIRT isoforms (e.g., SIRT6, SIRT7) and their unique functions. This article also offers a comprehensive overview of SIRTs, linking them to a spectrum of diseases and highlighting their potential for targeted therapies, combination approaches, disease management, and personalized medicine. We aim to contribute to a transformative era in healthcare and innovative treatments by unraveling the intricate functions of SIRTs.

Optical, Dielectric, Magnetic, Photocatalytic, and Antibacterial Properties of Ga-Doped BiGaxFe1-xO3 Synthesized by the Microemulsion Approach.

The effect of Ga-substitution on bismuth ferrite BiGaxFe1-xO3 (x = 0, 0.05, 0.10, 0.15, 0.20, and 0.25) properties was investigated, which was fabricated using a microemulsion route. X-ray diffraction analysis confirmed that specimens had a single-phase rhombohedral structure with space group R3̅c. The concentration of Ga had an impact on various properties such as structural parameters, crystalline size, porosity, and unit cell volume. The samples exhibited notable values for the dielectric constant, tangent loss, and dielectric loss in the low-frequency range, which declined as the frequency increased due to different polarizations. The increment in the AC conductivity was associated with rise in frequency. The P-E loops demonstrated that the samples became more resistive as the Ga concentration increased. The retentivity (Mr) and saturation magnetization (Ms) values reduced as the Ga content increased, although all samples had Hc values within the range for electromagnetic materials. The Ga-substitution had a synergistic effect on the electrochemical characteristics of BiGaxFe1-xO3, resulting in greater conductivity than that of undoped BiFeO3. These enhanced properties contributed to their higher photocatalytic activity in the degradation of crystal violet under visible light irradiation. The doped BiGaxFe1-xO3 exhibited 79% dye degradation after 90 min of illumination compared to 54% for pure BiFeO3. Recycling experiments confirmed the stability and reusability of the synthesized nanoparticles. The antibacterial activity of the samples was certified against various microbes, and the doped BiGaxFe1-xO3 showed promising activity. Thus, doped materials are good candidates for memories, dielectric resonators, and photovoltaics because of their high dielectric constant and AC conductivity, while their higher photocatalytic activity under visible light makes them promising photocatalysts for removing noxious and harmful effluents from wastewaters.

Exploring theophylline-1,2,4-triazole tethered N-phenylacetamide derivatives as antimicrobial agents: unraveling mechanisms via structure-activity relationship, in vitro validation, and in silico insights.

Theophylline, a nitrogen-containing heterocycle, serves as a promising focal point for medicinal researchers aiming to create derivatives with diverse pharmacological applications. In this work, we present an improved synthetic method for a range of theophylline-1,2,4-triazole-S-linked N-phenyl acetamides (4a‒g) utilizing ultrasound-assisted synthetic approach. The objective was to assess the effectiveness of synthesized theophylline-1,2,4-triazoles (4a‒g) as inhibitors of HCV serine protease and as antibacterial agents against B. subtilis QB-928 and E. coli AB-274. Theophylline-1,2,4-triazoles were obtained in good to excellent yields (69%-95%) in a shorter time than conventional approach. 4-Chlorophenyl moiety containing theophylline-1,2,4-triazole 4c displayed significantly higher inhibitory activity against HCV serine protease enzyme (IC50 = 0.015 ± 0.25 mg) in comparison to ribavirin (IC50 = 0.165 ± 0.053 mg), but showed excellent binding affinity (-7.55 kcal/mol) with the active site of serine protease, better than compound 4c (-6.90 kcal/mol) as well as indole-based control compound 5 (-7.42 kcal/mol). In terms of percentage inhibition of serine protease, 2-chlorophenyl compound 4b showed the maximum percentage inhibition (86%), more than that of the 3,4-dichlorophenyl compound 4c (76%) and ribavirin (81%). 3,4-Dimethylphenyl-based theophylline-1,2,4-triazole 4g showed the lowest minimum inhibitory concentration (MIC = 0.28 ± 0.50 µg/mL) against the B. subtilis bacterial strain as compared to the standard drug penicillin (MIC = 1 ± 1.50 µg/mL). The other 4-methylphenyl theophylline-1,2,4-triazole 4e (MIC = 0.20 ± 0.08 µg/mL) displayed the most potent antibacterial potential against E. coli in comparison to the standard drug penicillin (MIC = 2.4 ± 1.00 µg/mL). Molecular docking studies further helped in an extensive understanding of all of the interactions between compounds and the enzyme active site, and DFT studies were also employed to gain insights into the molecular structure of the synthesized compounds. The results indicated that theophylline-linked triazole derivatives 4b and 4c showed promise as leading contenders in the fight against the HCV virus. Moreover, compounds 4e and 4g demonstrated potential as effective chemotherapeutic agents against E. coli and B. subtilis, respectively. To substantiate these findings, additional in vivo studies and clinical trials are imperative, laying the groundwork for their integration into future drug design and development.

Discovery of novel 1,2,4-triazole tethered ß-hydroxy sulfides as bacterial tyrosinase inhibitors: synthesis and biophysical evaluation through in vitro and in silico approaches.

In this study, a series of 1,2,4-triazole-tethered ß-hydroxy sulfide scaffolds 11a-h was synthesized in good to remarkable yields (69-90%) through the thiolysis of oxiranes by the thiols in aqueous basic catalytic conditions. The synthesized 1,2,4-triazole-tethered ß-hydroxy sulfides were screened against bacterial tyrosinase enzyme, and Gram-positive and Gram-negative bacterial cultures i.e., (S. aureus) Staphylococcus aureus & (E. coli) Escherichia coli. Among the synthesized derivatives, the molecules 11a (IC50 = 7.67 ± 1.00 µM), 11c (IC50 = 4.52 ± 0.09 µM), 11d (IC50 = 6.60 ± 1.25 µM), and 11f (IC50 = 5.93 ± 0.50 µM) displayed the better tyrosinase inhibitory activity in comparison to reference drugs ascorbic acid (IC50 = 11.5 ± 1.00 µM) and kojic acid (IC50 = 30.34 ± 0.75 µM). The molecule benzofuran-triazol-propan-2-ol 11c proved to be the most potent bacterial tyrosinase inhibitory agent with a minimum IC50 of 4.52 ± 0.09 µM, as compared to other synthesized counterparts and both standards (kojic acid and ascorbic acid). The compound diphenyl-triazol-propan-2-ol 11a and benzofuran-triazole-propan-2-ol 11c showed comparable anti-bacterial chemotherapeutic efficacy with minimum inhibitory concentrations (MIC = 2.0 ± 2.25 mg mL-1 and 2.5 ± 0.00 mg mL-1, respectively) against S. aureus bacterial strain in comparison with standard antibiotic penicillin (MIC = 2.2 ± 1.15 mg mL-1). Furthermore, among the synthesized derivatives, only compound 11c demonstrated better anti-bacterial activity (MIC = 10 ± 0.40 mg mL-1) against E. coli, which was slightly less than the standard antibiotic i.e., penicillin (MIC = 2.4 ± 1.00 mg mL-1). The compound 11c demonstrated a better binding score (-7.08 kcal mol-1) than ascorbic acid (-5.59 kcal mol-1) and kojic acid (-5.78 kcal mol-1). Molecular docking studies also validate the in vitro anti-tyrosinase assay results; therefore, the molecule 11c can be the lead bacterial tyrosinase inhibitor as well as the antibacterial agent against both types of bacterial strains after suitable structural modifications.

Bacterial Tyrosinase Inhibition, Hemolytic and Thrombolytic Screening, and In Silico Modeling of Rationally Designed Tosyl Piperazine-Engrafted Dithiocarbamate Derivatives.

Piperazine is a privileged moiety that is a structural part of many clinical drugs. Piperazine-based scaffolds have attracted the attention of pharmaceutical and medicinal scientists to develop novel, efficient therapeutic agents owing to their significant and promising biological profile. In the current study, an ecofriendly ultrasonic-assisted synthetic approach was applied to achieve a novel series of 1-tosyl piperazine dithiocarbamate acetamide hybrids 4a-4j, which was evaluated for in vitro tyrosinase inhibition and thrombolytic and hemolytic cytotoxic activities. Among all the piperazine-based dithiocarbamate acetamide target molecules 4a-4j, the structural analogs 4d displayed excellent tyrosinase inhibition efficacy (IC50 = 6.88 ± 0.11 µM) which was better than the reference standard drugs kojic acid (30.34 ± 0.75 µM) and ascorbic acid (11.5 ± 1.00 µM), respectively, which was further confirmed by in silico induced-fit docking (IFD) simulation Good tyrosinase activities were exhibited by 4g (IC50 = 7.24 ± 0.15 µM), 4b (IC50 = 8.01 ± 0.11 µM) and 4c (IC50 = 8.1 ± 0.30 µM) dithiocarbamate acetamides, which were also better tyrosinase inhibitors than the reference drugs but were less active than the 4d structural hybrid. All the derivatives are less toxic, having values in the 0.29 ± 0.01% to 15.6 ± 0.5% range. The scaffold 4b demonstrated better hemolytic potential (0.29 ± 0.01%), while a remarkably high thrombolytic chemotherapeutic potential was displayed by analog 4e (67.3 ± 0.2%).

Protease inhibition, in vitro antibacterial and IFD/MM-GBSA studies of ciprofloxacin-based acetanilides.

In this study, we have investigated ciprofloxacin-based acetanilides for their in-vitro inhibitory study against gram +ve, -ve bacteria and serine protease activity. The compounds 4e and 4g showed excellent antibacterial activity against Bacillus subtilis with a zone of inhibition (ZI) values of 40 ± 0.9 mm, 37 ± 1.4 mm and with MIC values of 4.0 ± 0.78 mg/mL, 3.0 ± 0.98 mg/ML respectively, while 4a and 4i were found most active against Escherichia coli, with ZI values 38 ± 0.1 mm, 46 ± 1.8 mm and with MIC values of 1.0 ± 0.25 mg/mL, 1.0 ± 0.23 mg/mL respectively. All derivatives (4a-j) significantly inhibited the catalytic activity of serine protease, while 4a exhibited a maximum (100%) inhibitory effect at 96 minutes having 22.50 minutes [Formula: see text], and non-competitive inhibition with 0.1±0.00µM Ki. The IFD/MM-GBSA studies highlighted the binding mode of 4a for protease inhibition and indicated improved binding affinity with -107.62 kcal/mol of ΔGbind.