Exploring the Potential of New Benzamide-Acetamide Pharmacophore Containing Sulfonamide as Urease Inhibitors: Structure-Activity Relationship, Kinetics Mechanism, and In Silico Studies.

The search for novel drug scaffolds that can improve effectiveness and safety through drug conjugates is a promising approach. Consequently, drug conjugates constitute a dynamic field of study and advancement within medicinal chemistry. This research demonstrates the conjugation of diclofenac and mefenamic acid with sulfa drugs and their screening for urease inhibition. These conjugates' structural confirmation was performed using elemental analysis and spectroscopic methods, including IR, 1H NMR, and 13C NMR. Diclofenac conjugated with sulfanilamide (4), sulfacetamide (10), and mefenamic acid conjugated with sulfanilamide (12), and sulfamethoxazole (17) was found potent and demonstrated urease inhibition competitively, with IC50 (µM) values 3.59 ± 0.07, 5.49 ± 0.34, 7.92 ± 0.27, and 8.35 ± 0.26, respectively. Diclofenac conjugated with sulfathiazole (6), sulfamerazine (8), and sulfaguanidine (11), while mefenamic acid conjugated with sulfisoxazole (13), sulfathiazole (14), and sulfadiazine (15) exhibited a mixed mode of urease inhibition. The IC50 (µM) values were 16.19 ± 0.21, 9.50 ± 0.28, 4.35 ± 0.23, 15.86 ± 0.25, 14.80 ± 0.27, and 7.92 ± 0.27, respectively. Furthermore, molecular docking studies were employed to predict the binding pose of competitive inhibitors at the urease active site. These conjugates generated stable complexes with the urease protein observed through molecular dynamics (MD) simulations, where no conformational changes occurred throughout the simulations. These results highlight the potential for approved therapeutic molecule conjugates to give rise to new categories of pharmacological agents for urease inhibition. The structural similarity of sulfonamides with urea allows them to compete with urea for binding to the active site of the urease enzyme. Sulfonamides and nonsteroidal anti-inflammatory drugs (NSAIDs) can interact hydrophobically with the active site of the urease enzyme, which may disturb its structure and catalytic activity. Therefore, these conjugates may be helpful in the development of novel pharmacological agents for the treatment of a variety of illnesses in which the urease enzyme is involved.

Acetylsalicylic acid-sulfa drugs conjugates as potential urease inhibitors and anti-inflammatory agents: bio-oriented drug synthesis, molecular docking, and dynamics simulation studies.

To explore the new mode of action and reduce side effects, making conjugates of existing drugs is becoming an attractive tool in the realm of medicinal chemistry. In this work, we exploited this approach and synthesized new conjugates to assess their activities against the enzymes involved in different pathological conditions. Specifically, we design and synthesized conjugates involving acetylsalicylic acid and sulfa drugs, validating the newly crafted conjugates using techniques like IR, 1HNMR, 13CNMR, and elemental analysis. These conjugates underwent assessment for their ability to inhibit cyclooxygenase-2 (COX-2), urease enzymes, and their anti-inflammatory potential. A competitive mode of urease inhibition was observed for acetylsalicylic acid conjugated with sulfanilamide, sulfacetamide, and sulfadiazine with IC50 of 2.49 ± 0.35 µM, 6.21 ± 0.28 µM, and 6.57 ± 0.44 µM, respectively. Remarkably, the acetylsalicylic acid-sulfamethoxazole conjugate exhibited exceptional anti-inflammatory activity, effectively curtailing induced edema by 83.7%, a result akin to the reference anti-inflammatory drug indomethacin's performance (86.8%). Additionally, it demonstrated comparable COX-2 inhibition (75.8%) to the reference selective COX-2 inhibitor celecoxib that exhibited 77.1% inhibition at 10 µM concentration. To deepen our understanding, we employed molecular docking techniques to predict the binding interactions of competitive inhibitors with COX-2 and urease receptors. Additionally, MD simulations were carried out, confirming the stability of inhibitor-target complexes throughout the simulation period, devoid of significant conformational changes. Collectively, our research underscores the potential of coupling approved medicinal compounds to usher in novel categories of pharmacological agents, holding promise for addressing a wide spectrum of pathological disorders involving COX-2 and urease enzymes.Communicated by Ramaswamy H. Sarma.

Exploring the potential of propanamide-sulfonamide based drug conjugates as dual inhibitors of urease and cyclooxygenase-2: biological and their in silico studies.

Derivative synthesis has been a crucial method for altering the effects of already-approved medications, especially to lessen adverse effects and enhance results. Making use of this multi-target approach, a series of naproxen-sulfa drug conjugates was designed and synthesized. The newly designed conjugates were confirmed by spectroscopic techniques like IR, 1HNMR, 13CNMR, and elemental analysis. The conjugates were screened for anti-inflammatory, urease, and cyclooxygenase-2 (COX-2) inhibition. Naproxen conjugated with sulfanilamide, sulfathiazole, and sulfaguanidine was found potent and showed a competitive mode of urease inhibition, with IC50 (µM) values 6.69 ± 0.11, 5.82 ± 0.28, 5.06 ± 0.29, respectively. When compared to other screened conjugates, the naproxen-sulfamethoxazole conjugation showed better anti-inflammatory action by inhibiting induced edema by 82.8%, which is comparable to the medication indomethacin (86.8% inhibition). Whereas it exhibited 75.4% inhibition of COX-2 at 10 µM concentration which is comparable with the reference drug (celecoxib, 77.1% inhibition). Moreover, the binding modes of competitive inhibitors with the urease and COX-2 receptor were predicted through molecular docking studies and their stability analysis through MD simulations showed that these compounds made stable complexes with the respective targets and there were no conformational changes that occurred during simulation. The obtained results showed that the conjugates of approved therapeutic molecules may lead to the development of novel types of pharmacological agents in the treatment of several pathological disorders where urease and COX-2 enzymes are involved.

New Acetamide-Sulfonamide-Containing Scaffolds: Antiurease Activity Screening, Structure-Activity Relationship, Kinetics Mechanism, Molecular Docking, and MD Simulation Studies.

The development of novel scaffolds that can increase the effectiveness, safety, and convenience of medication therapy using drug conjugates is a promising strategy. As a result, drug conjugates are an active area of research and development in medicinal chemistry. This research demonstrates acetamide-sulfonamide scaffold preparation after conjugation of ibuprofen and flurbiprofen with sulfa drugs, and these scaffolds were then screened for urease inhibition. The newly designed conjugates were confirmed by spectroscopic techniques such as IR, 1HNMR, 13CNMR, and elemental analysis. Ibuprofen conjugated with sulfathiazole, flurbiprofen conjugated with sulfadiazine, and sulfamethoxazole were found to be potent and demonstrated a competitive mode of urease inhibition, with IC50 (µM) values of 9.95 ± 0.14, 16.74 ± 0.23, and 13.39 ± 0.11, respectively, and urease inhibition of 90.6, 84.1, and 86.1% respectively. Ibuprofen conjugated with sulfanilamide, sulfamerazine, and sulfacetamide, whereas flurbiprofen conjugated with sulfamerazine, and sulfacetamide exhibited a mixed mode of urease inhibition. Moreover, through molecular docking experiments, the urease receptor-binding mechanisms of competitive inhibitors were anticipated, and stability analysis through MD simulations showed that these compounds made stable complexes with the respective targets and that no conformational changes occurred during the simulation. The findings demonstrate that conjugates of approved therapeutic molecules may result in the development of novel classes of pharmacological agents for the treatment of various pathological conditions involving the urease enzyme.

MF-Storm: a maximum flow-based job scheduler for stream processing engines on computational clusters to increase throughput.

Background: A scheduling algorithm tries to schedule multiple computational tasks on a cluster of multiple computing nodes to maximize throughput with optimal utilization of computational and communicational resources. A Stream Processing Engine (SPE) is deployed to run streaming applications (computational tasks) on a computational cluster which helps execution and coordination of these applications. It is observed that there is a gap in the optimal mapping of a computational and communicational load of a streaming application on the underlying computational and communication power of the resources (cluster). Frequently communicated tasks are scheduled at different processing nodes with relatively slow communicating links. This increases network latency with a decrease in resource utilization. Hence, reduces the achieved throughput of the cluster significantly. Methods: MF-Storm, a max-flow min-cut based job scheduler is presented to achieve a near-optimum schedule to maximize throughput. It schedules a streaming application by considering the processing, communication demands, available computational and communicational resources in a heterogeneous cluster, dynamically with minimized scheduling cost. To keep the scheduling cost minimum, the scheduler is built in a pipeline with two major stages: in the first stage, the application's tasks graph is partitioned using the max-flow min-cut algorithm to minimize inter-partition traffic, and in the second stage, these partitions are assigned to computing nodes according to the computational power of the cluster's nodes. Results: Extensive experiments were done to evaluate the performance of MF-Storm using different topologies with multiple scenarios on a physical cluster implementation. Results showed on average 148% improvement in throughput with 30% less computational resources as compared to different state-of-the-art schedulers.

Folate Conjugated Polyethylene Glycol Probe for Tumor-Targeted Drug Delivery of 5-Fluorouracil.

A targeted delivery system is primarily intended to carry a potent anticancer drug to specific tumor sites within the bodily tissues. In the present study, a carrier system has been designed using folic acid (FA), bis-amine polyethylene glycol (PEG), and an anticancer drug, 5-fluorouracil (5-FU). FA and PEG were joined via an amide bond, and the resulting FA-PEG-NH2 was coupled to 5-FU producing folate-polyethylene glycol conjugated 5-fluorouracil (FA-PEG-5-FU). Spectroscopic techniques (UV-Vis, 1HNMR, FTIR, and HPLC) were used for the characterization of products. Prodrug (FA-PEG-5-FU) was analyzed for drug release profile (in vitro) up to 10 days and compared to a standard anticancer drug (5-FU). Folate conjugate was also analyzed to study its folate receptors (FR) mediated transport and in vitro cytotoxicity assays using HeLa cancer cells/Vero cells, respectively, and antitumor activity in tumor-bearing mice models. Folate conjugate showed steady drug release patterns and improved uptake in the HeLa cancer cells than Vero cells. Folate conjugate treated mice group showed smaller tumor volumes; specifically after the 15th day post-treatment, tumor sizes were decreased significantly compared to the standard drug group (5-FU). Molecular docking findings demonstrated importance of Trp138, Trp140, and Lys136 in the stabilization of flexible loop flanking the active site. The folic acid conjugated probe has shown the potential of targeted drug delivery and sustained release of anticancer drug to tumor lesions with intact antitumor efficacy.

Impact of Graphene Derivatives as Artificial Extracellular Matrices on Mesenchymal Stem Cells.

Thanks to stem cells' capability to differentiate into multiple cell types, damaged human tissues and organs can be rapidly well-repaired. Therefore, their applicability in the emerging field of regenerative medicine can be further expanded, serving as a promising multifunctional tool for tissue engineering, treatments for various diseases, and other biomedical applications as well. However, the differentiation and survival of the stem cells into specific lineages is crucial to be exclusively controlled. In this frame, growth factors and chemical agents are utilized to stimulate and adjust proliferation and differentiation of the stem cells, although challenges related with degradation, side effects, and high cost should be overcome. Owing to their unique physicochemical and biological properties, graphene-based nanomaterials have been widely used as scaffolds to manipulate stem cell growth and differentiation potential. Herein, we provide the most recent research progress in mesenchymal stem cells (MSCs) growth, differentiation and function utilizing graphene derivatives as extracellular scaffolds. The interaction of graphene derivatives in human and rat MSCs has been also evaluated. Graphene-based nanomaterials are biocompatible, exhibiting a great potential applicability in stem-cell-mediated regenerative medicine as they may promote the behaviour control of the stem cells. Finally, the challenges, prospects and future trends in the field are discussed.

Recent Advances in Chitin and Chitosan/Graphene-Based Bio-Nanocomposites for Energetic Applications.

Herein, we report recent developments in order to explore chitin and chitosan derivatives for energy-related applications. This review summarizes an introduction to common polysaccharides such as cellulose, chitin or chitosan, and their connection with carbon nanomaterials (CNMs), such as bio-nanocomposites. Furthermore, we present their structural analysis followed by the fabrication of graphene-based nanocomposites. In addition, we demonstrate the role of these chitin- and chitosan-derived nanocomposites for energetic applications, including biosensors, batteries, fuel cells, supercapacitors and solar cell systems. Finally, current limitations and future application perspectives are entailed as well. This study establishes the impact of chitin- and chitosan-generated nanomaterials for potential, unexplored industrial applications.

Curcumin: Synthesis optimization and in silico interaction with cyclin dependent kinase.

Curcumin is a natural product with enormous biological potential. In this study, curcumin synthesis was revisited using different reaction solvents, a catalyst (n-butylamine) and a water scavenger [(n-BuO)3B], to develop the optimal procedure for its rapid acquisition. During synthesis, solvent choice was found to be an important parameter for better curcumin yield and high purity. In a typical reaction, acetyl acetone was treated with boron trioxide, followed by condensation with vanillin in the presence of tri-n-butyl borate as water scavenger and n-butylamine as catalyst at 80 °C in ethyl acetate to afford curcumin. Moreover, curcumin was also extracted from turmeric powder and spectroscopic properties such as IR, MS, 1H NMR and 13C NMR with synthetic curcumin were established to identify any impurity. The purity of synthetic and extracted curcumin was also checked by TLC and HPLC-DAD. To computationally assess its therapeutic potential against cyclin dependent kinases (CDKs), curcumin was docked in different isoforms of CDKs. It was observed that it did not dock at the active sites of CDK2 and CDK6. However, it could enter into weak interactions with CDK4 protein.

Evaluation of Phenolic Compounds and Antioxidant and Antimicrobial Activities of Some Common Herbs.

The study was designed to evaluate the phenolic, flavonoid contents and antioxidant and antimicrobial activities of onion (Allium cepa), garlic (Allium sativum), mint (Mentha spicata), thyme (Thymus vulgaris), oak (Quercus), aloe vera (Aloe barbadensis Miller), and ginger (Zingiber officinale). All extracts showed a wide range of total phenolic contents, that is, 4.96 to 98.37 mg/100 g gallic acid equivalents, and total flavonoid contents, that is, 0.41 to 17.64 mg/100 g catechin equivalents. Antioxidant activity (AA) was determined by measuring reducing power, inhibition of peroxidation using linoleic acid system, and 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) scavenging activity. Different extracts inhibited oxidation of linoleic acid by 16.6-84.2% while DPPH radical scavenging activity (IC50 values) ranged from 17.8% to 79.1 µg/mL. Reducing power at 10 mg/mL extract concentration ranged from 0.11 to 0.84 nm. Furthermore the extracts of these medicinal herbs in 80% methanol, 80% ethanol, 80% acetone, and 100% water were screened for antimicrobial activity by disc diffusion method against selected bacterial strains, Staphylococcus aureus, Escherichia coli, Bacillus subtilis, and Pasteurella multocida, and fungal strains, Aspergillus niger, Aspergillus flavus, Rhizopus solani, and Alternaria alternata. The extracts show better antimicrobial activity against bacterial strains as compared to fungal strains. Results of various assays were analyzed statistically by applying appropriate statistical methods.

A Novel Method for the Synthesis of (99m)Tc-Ofloxacin Kits Using D-Penicillamine as Coligand and Their Application as Infection Imaging Agent.

The employment of radiopharmaceuticals is increasing nowadays for infection imaging and early execution of patients having infectious or inflammatory complaints. The main aim of this study was to discover a novel method for the labeling of ofloxacin with (99m)Tc, optimization of labelling conditions to get higher percent yield, to assess kits radiochemical purity, in vitro stability, partition coefficient, protein binding, and intracellular accumulation in Pseudomonas aeruginosa, Salmonella typhi, and Escherichia coli in infected rabbits. Maximum labeling efficiency was achieved when 1.5 mg ofloxacin was labeled with 10-20 mCi sodium pertechnetate in the presence of 3 mg D-penicillamine, 75 µg SnCl2. In vitro binding and biodistribution in Pseudomonas aeruginosa, Salmonella typhi, and Escherichia coli showed good results. This new complex is efficient for the imaging of infections caused by Gram-positive and Gram-negative bacteria.

Synthesis, characterization, and antibacterial activities of novel sulfonamides derived through condensation of amino group containing drugs, amino acids, and their analogs.

Novel sulfonamides were developed and structures of the new products were confirmed by elemental and spectral analysis (FT-IR, ESI-MS, (1)HNMR, and (13)CNMR). In vitro, developed compounds were screened for their antibacterial activities against medically important gram (+) and gram (-) bacterial strains, namely, S. aureus, B. subtilis, E. coli, and K. pneumoniae. The antibacterial activities have been determined by measuring MIC values (µg/mL) and zone of inhibitions (mm). Among the tested compounds, it was found that compounds 5a and 9a have most potent activity against E. coli with zone of inhibition: 31 ± 0.12 mm (MIC: 7.81 µg/mL) and 30 ± 0.12 mm (MIC: 7.81 µg/mL), respectively, nearly as active as ciprofloxacin (zone of inhibition: 32 ± 0.12 mm). In contrast, all the compounds were totally inactive against the gram (+) B. subtilis.