C3-Symmetric ligands in drug design: An overview of the challenges and opportunities ahead.

C3-symmetry is a type of star-shaped molecule consisting of a central core and three symmetrically attached chains. These molecules are used in drug discovery due to their unique three-fold rotational symmetry, which allows for specific binding interactions and improved molecular recognition. In this text, we provide an overview of synthetic approaches with C3-symmetry as a pharmaceutical tool: progress, challenges, and opportunities. C3-symmetric ligands offer both challenges and opportunities in drug design. Their unique symmetry can enhance binding interactions, but careful consideration of rigidity, synthetic complexity, and target compatibility is crucial. Further research and advancements in synthetic methods and modeling tools will likely drive their exploration in drug discovery, leading to the discovery of potent C3-symmetric ligands.

Biochemical, Toxicological, and in Silico Aspects of Trillium govanianum Wall. ex D.Don (Trilliaceae): A Rich Source of Natural Bioactive Compounds.

Trillium govanianum is a high-value medicinal herb, having multifunctional traditional and culinary uses. The present investigation was carried out to evaluate the phytochemical, biological and toxicological parameters of the T. govanianum Wall. ex D. Don (Family: Trilliaceae) roots collected from Azad Kashmir, Pakistan. Phytochemical profiling was achieved by determining total bioactive contents (total phenolic and flavonoid contents) and UHPLC-MS analysis. For biological evaluation, antioxidant activities (DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum, and metal chelation assays) and enzyme inhibition activities (against AChE, BChE, glucosidase, amylase, and tyrosinase) were performed. Moreover, cytotoxicity was assessed against three human carcinoma cell lines (MDA-MB-231, CaSki, and DU-145). The tested extract was found to contain higher total phenolics (7.56 mg GAE/g dry extract) as compared to flavonoid contents (0.45 mg RE/g dry extract). Likewise, for the antioxidant activity, higher CUPRAC activity was noted with 39.84 mg TE/g dry extract values. In the case of enzyme assays, higher activity was pointed out against the cholinesterase, glucosidase and tyrosinase enzymes. The plant extract displayed significant cytotoxicity against the cell lines examined. Moreover, the in-silico studies highlighted the interaction between the important phytochemicals and tested enzymes. To conclude, the assessed biological activity and the existence of bioactive phytochemicals in the studied plant extract may pave the way for the development of novel pharmaceuticals.

Unrivalled insight into possible biopharmaceutical application of Justicia vahlii Roth. (Acanthaceae).: Chemodiversity, in vitro bioactivities, and computational analysis.

Justicia vahliiRoth. is an important wild medicinal food plant traditionally used for treating inflammation and various common ailments. This study investigated the chemical composition,antioxidant, enzyme inhibition and toxicity profiles of n-hexane (nHEJv) and chloroform (CEJv) extracts of J. vahlii. Moreover, the effect of the extracts was evaluated on CCl4 induced liver injury. The total phenolic and flavonoid contents were present in both extracts in significant amount. The UPLC-Q-TOF-MS and GC-MS profiling of CEJv tentatively identified several important phytocompounds. The CEJv extract was comparatively more active for antioxidant activity and α-amylase inhibition, whereas the nHEJv extract presented higher inhibition potential against urease, tyrosinase, and α-glucosidase enzymes. Similarly, the in-silico study of four major compounds, i.e., 1-acetoxypinoresinol, 3-hydroxysebacic acid, nortrachelogenin, and viscidulin-III have shown a good docking score against the clinically significant enzymes. The acute oral toxicity and brine shrimp lethality assaysrevealed the extracts as non-toxic. The CCl4 treated animals showed a geared depletion of various antioxidant enzymes which were significantly reversed with the treatment of the extracts. Overall, the study's findings revealed J. vahliiwith antioxidant mediated hepatoprotective and enzyme inhibition potential and warrant further research on isolation of the bioactive compounds.

Synthesis, in silico ADMET prediction analysis, and pharmacological evaluation of sulfonamide derivatives tethered with pyrazole or pyridine as anti-diabetic and anti-Alzheimer's agents.

Based on previous developments of our research programs in trying to find new compounds with multiple biological targets such as antioxidant, anti-diabetic, anti-Alzheimer's, and anti-arthritic agents. In the context, a novel series of sulfonamide derivatives based on the pyrazole or pyridine moieties 3a, b, 7-9, 11-13, 15a, b, and 16 were synthesized from amine compounds with sulfonyl chloride derivatives. The structures of sulfonamide derivatives were elucidated via spectroscopy (1H and 13C NMR). The sulfonamide derivatives were biologically assessed in vitro for their anti-diabetic (α-amylase and α-glucosidase inhibition) and anti-Alzheimer's (acetylcholinesterase inhibition) activities. The biological results revealed that compound 15a is a powerful enzyme inhibitor for α-amylase and α-glucosidase. Also, compound 15b demonstrated inhibitor activity against the acetylcholinesterase enzyme. The structure-activity relationship study of sulfonamide derivatives was accomplished. Furthermore, complementary in silico molecular properties, drug-likeness, ADMET prediction, and surface properties of the two more powerful derivatives 15a and 15b were fulfilled and computed. These studies recommend 15a and 15b as candidates with modifications in their structures before the in vivo assays.

Anticancer Potential of Sulfonamide Moieties via In-Vitro and In-Silico Approaches: Comparative Investigations for Future Drug Development.

Several kinds of anticancer drugs are presently commercially accessible, but low efficacy, solubility, and toxicity have reduced the overall therapeutic indices. Thus, the search for promising anticancer drugs continues. The interactions of numerous essential anticancer drugs with DNA are crucial to their biological functions. Here, the anticancer effects of N-ethyl toluene-4-sulphonamide (8a) and 2,5-Dichlorothiophene-3-sulphonamide (8b) on cell lines from breast and cervical cancer were investigated. The study also compared how these substances interacted with the hearing sperm DNA. The most promising anticancer drug was identified as 2,5-Dichlorothiophene-3-sulfonamide (8b), which showed GI50 of 7.2 ± 1.12 µM, 4.62 ± 0.13 µM and 7.13 ± 0.13 µM against HeLa, MDA-MB231 and MCF-7 cells, respectively. Moreover, it also exhibited significant electrostatic and non-electrostatic contributions to the binding free energy. The work utilized computational techniques, such as molecular docking and molecular dynamic (MD) simulations, to demonstrate the strong cytotoxicity of 2,5-Dichlorothiophene-3-sulfamide (8b) in comparison to standard Doxorubicin and cisplatin, respectively. Molecular docking experiments provided additional support for a role for the minor groove in the binding of the 2,5-Dichlorothiophene-3-sulfamide (8b)-DNA complex. The molecular docking studies and MD simulation showed that both compounds revealed comparable inhibitory potential against standard Doxorubicin and cisplatin. This study has the potential to lead to the discovery of new bioactive compounds for use in cancer treatment, including metallic and non-metallic derivatives of 2,5-Dichlorothiophene-3-sulfonamide (8b). It also emphasizes the worth of computational approaches in the development of new drugs and lays the groundwork for future research.

Toxicity Study and Binding Analysis of Newly Synthesized Antifungal N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazinecarbothioamide Derivative with Bovine Serum Albumin.

The presence of the p-aryl/cyclohexyl ring in the N-(4-aryl/cyclohexyl)-2-(pyridine-4-yl carbonyl) hydrazine carbothioamide derivative (2C) is reported to enhance the antifungal properties when compared to those of itraconazole. Serum albumins present in plasma bind and transport ligands, including pharmaceuticals. This study explored 2C interactions with BSA using spectroscopic methods such as fluorescence and UV-visible spectroscopy. In order to acquire a deeper comprehension of how BSA interacts with binding pockets, a molecular docking study was carried out. The fluorescence of BSA was quenched by 2C via a static quenching mechanism since a decrease in quenching constants was observed from 1.27 × 105 to 1.14 × 105. Thermodynamic parameters indicated hydrogen and van der Waals forces responsible for the BSA-2C complex formation with binding constants ranging between 2.91 × 105 and 1.29 × 105, which suggest a strong binding interaction. Site marker studies displayed that 2C binds to BSA's subdomains IIA and IIIA. Molecular docking studies were conducted to further comprehend the molecular mechanism of the BSA-2C interaction. The toxicity of 2C was predicted by Derek Nexus software. Human and mammalian carcinogenicity and skin sensitivity predictions were associated with a reasoning level of equivocal, inferring 2C to be a potential drug candidate.

Integrated Structural, Functional, and ADMET Analysis of 2-Methoxy-4,6-diphenylnicotinonitrile: The Convergence of X-ray Diffraction, Molecular Docking, Dynamic Simulations, and Advanced Computational Insights.

This study systematically investigates the molecular structure and electronic properties of 2-methoxy-4,6-diphenylnicotinonitrile, employing X-ray diffraction (XRD) and sophisticated computational methodologies. XRD findings validate the compound's orthorhombic crystallization in the P21212 space group, composed of a pyridine core flanked by two phenyl rings. Utilizing the three-dimensional Hirshfeld surface, the research decodes the molecule's spatial attributes, further supported by exhaustive statistical assessments. Key interactions, such as π-π stacking and H⋯X contacts, are spotlighted, underscoring their role in the crystal's inherent stability and characteristics. Energy framework computations and density functional theory (DFT) analyses elucidate the prevailing forces in the crystal and reveal geometric optimization facets and molecular reactivity descriptors. Emphasis is given to the exploration of frontier molecular orbitals (FMOs), aromaticity, and π-π stacking capacities. The research culminates in distinguishing electron density distributions, aromatic nuances, and potential reactivity hotspots, providing a holistic view of the compound's structural and electronic landscape. Concurrently, molecular docking investigates its interaction with the lipoprotein-associated phospholipase A2 protein. Notably, the compound showcases significant interactions with the protein's active site. Molecular dynamics simulations reveal the compound's influence on protein stability and flexibility. Although the molecule exhibits strong inhibitory potential against Lp-PLA2, its drug development prospects face challenges related to solubility and interactions with drug transport proteins.

Evaluation of the Possible Pathways Involved in the Protective Effects of Quercetin, Naringenin, and Rutin at the Gene, Protein and miRNA Levels Using In-Silico Multidimensional Data Analysis.

Flavonoids are secondary metabolites that are non-essential for plant growth or survival, and they also provide numerous health benefits to humans. They are antioxidants that shield plants from the ill effects of ultraviolet light, pests, and diseases. They are beneficial to health for several reasons, including lowering inflammation, boosting cardiovascular health, and lowering cancer risk. This study looked into the physicochemical features of these substances to determine the potential pharmacological pathways involved in their protective actions. Potential targets responsible for the protective effects of quercetin, naringenin, and rutin were identified with SwissADME. The associated biological processes and protein-protein networks were analyzed by using the GeneMANIA, Metascape, and STRING servers. All the flavonoids were predicted to be orally bioavailable, with more than 90% targets as enzymes, including kinases and lyases, and with common targets such as NOS2, CASP3, CASP9, CAT, BCL2, TNF, and HMOX1. TNF was shown to be a major target in over 250 interactions. To extract the "biological meanings" from the MCODE networks' constituent parts, a GO enrichment analysis was performed on each one. The most important transcription factors in gene regulation were RELA, NFKB1, PPARG, and SP1. Treatment with quercetin, naringenin, or rutin increased the expression and interaction of the microRNAs' hsa-miR-34a-5p, hsa-miR-30b-5p, hsa-let-7a-5p, and hsa-miR-26a-1-3p. The anticancer effects of hsa-miR-34a-5p have been experimentally confirmed. It also plays a critical role in controlling other cancer-related processes such as cell proliferation, apoptosis, EMT, and metastasis. This study's findings might lead to a deeper comprehension of the mechanisms responsible for flavonoids' protective effects and could present new avenues for exploration.

In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic.

In continuation of our research programs for the discovery, production, and development of the pharmacological activities of molecules for various disease treatments, Schiff bases and pyrazole scaffold have a broad spectrum of activities in biological applications. In this context, this manuscript aims to evaluate and study Schiff base-pyrazole molecules as a new class of antioxidant (total antioxidant capacity, iron-reducing power, scavenging activity against DPPH, and ABTS radicals), anti-diabetic (α-amylase% inhibition), anti-Alzheimer's (acetylcholinesterase% inhibition), and anti-arthritic (protein denaturation% and proteinase enzyme% inhibitions) therapeutics. Therefore, the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were designed and synthesized for evaluation of their antioxidant, anti-diabetic, anti-Alzheimer's, and anti-arthritic properties. The results for compound 22b demonstrated significant antioxidant, anti-diabetic (α-amylase% inhibition), and anti-Alzheimer's (ACE%) activities, while compound 23a demonstrated significant anti-arthritic activity. Prediction of in silico bioinformatics analysis (physicochemical properties, bioavailability radar, drug-likeness, and medicinal chemistry) of the target derivatives (22a, b and 23a, b) was performed. The molecular lipophilicity potential (MLP) of the derivatives 22a, b and 23a, b was measured to determine which parts of the surface are hydrophobic and which are hydrophilic. In addition, the molecular polar surface area (PSA) was measured to determine the polar surface area and the non-polar surface area of the derivatives 22a, b and 23a, b. This study could be useful to help pharmaceutical researchers discover a new series of potent agents that may act as an antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic.

Development of a New Benzofuran-Pyrazole-Pyridine-Based Molecule for the Management of Osteoarthritis.

Osteoarthritis is a substantial burden for patients with the disease. The known medications for the disease target the mitigation of the disease's symptoms. So, drug development for the management of osteoarthritis represents an important challenge in the medical field. This work is based on the development of a new benzofuran-pyrazole-pyridine-based compound 8 with potential anti-inflammatory and anti-osteoarthritis properties. Microanalytical and spectral data confirmed the chemical structure of compound 8. The biological assays indicated that compound 8 produces multifunctional activity as an anti-osteoarthritic candidate via inhibition of pro-inflammatory mediators, including RANTES, CRP, COMP, CK, and LPO in OA rats. Histopathological and pharmacokinetic studies confirmed the safety profile of the latter molecule. Accordingly, compound 8 is considered a promising anti-osteoarthritis agent and deserves deeper investigation in future trials.

Targeting Transcriptional CDKs 7, 8, and 9 with Anilinopyrimidine Derivatives as Anticancer Agents: Design, Synthesis, Biological Evaluation and In Silico Studies.

Cyclin-dependent kinases (CDKs) are promising targets in chemotherapy. In this study, we report a series of 2-anilinopyrimidine derivatives with CDK inhibitory activity. Twenty-one compounds were synthesized and their CDK inhibitory and cytotoxic activities were evaluated. The representative compounds demonstrate potent antiproliferative activities toward different solid cancer cell lines and provide a promising strategy for the treatment of malignant tumors. Compound 5f was the most potent CDK7 inhibitor (IC50 = 0.479 µM), compound 5d was the most potent CDK8 inhibitor (IC50 = 0.716 µM), and compound 5b was the most potent CDK9 inhibitor (IC50 = 0.059 µM). All the compounds satisfied the Lipinski's rule of five (molecular weight < 500 Da, number of hydrogen bond acceptors <10, and octanol-water partition coefficient and hydrogen bond donor values below 5). Compound 5j is a good candidate for lead optimization because it has a non-hydrogen atom (N) of 23, an acceptable ligand efficiency value of 0.38673, and an acceptable ligand lipophilic efficiency value of 5.5526. The synthesized anilinopyrimidine derivatives have potential as anticancer agents.

New Indazol-Pyrimidine-Based Derivatives as Selective Anticancer Agents: Design, Synthesis, and In Silico Studies.

In this research study, the authors successfully synthesized potent new anticancer agents derived from indazol-pyrimidine. All the prepared compounds were tested for in vitro cell line inhibitory activity against three different cancerous cell lines. Results demonstrated that five of the novel compounds-4f, 4i, 4a, 4g, and 4d-possessed significant cytotoxic inhibitory activity against the MCF-7 cell line, with IC50 values of 1.629, 1.841, 2.958, 4.680, and 4.798 µM, respectively, compared to the reference drug with an IC50 value of 8.029 µM, thus demonstrating promising suppression power. Compounds 4i, 4g, 4e, 4d, and 4a showed effective cytotoxic activity stronger than the standard against Caco2 cells. Moreover, compounds 4a and 4i exhibited potent antiproliferative activity against the A549 cell line that was stronger than the reference drug. The most active products, 4f and 4i, werr e further examined for their mechanism of action. It turns out that they were capable of activating caspase-3/7 and, therefore, inducing apoptosis. However, produced a higher safety profile than the reference drug, towards the normal cells (MCF10a). Furthermore, the dynamic nature, binding interaction, and protein-ligand stability were explored through a Molecular Dynamics (MD) simulation study. Various analysis parameters (RMSD, RMSF, RoG, and SASA) from the MD simulation trajectory have suggested the stability of the compounds during the 20 ns MD simulation study. In silico ADMET results revealed that the synthesized compounds had low toxicity, good solubility, and an absorption profile since they met Lipinski's rule of five and Veber's rule. The present research highlights the potential of derivatives with indazole scaffolds bearing pyrimidine as a lead compound for designing anticancer agents.

Erlotinib-Loaded Dendrimer Nanocomposites as a Targeted Lung Cancer Chemotherapy.

Lung cancer is the main cause of cancer-related mortality globally. Erlotinib is a tyrosine kinase inhibitor, affecting both cancerous cell proliferation and survival. The emergence of oncological nanotechnology has provided a novel drug delivery system for erlotinib. The aims of this current investigation were to formulate two different polyamidoamine (PAMAM) dendrimer generations-generation 4 (G4) and generation 5 (G5) PAMAM dendrimer-to study the impact of two different PAMAM dendrimer formulations on entrapment by drug loading and encapsulation efficiency tests; to assess various characterizations, including particle size distribution, polydispersity index, and zeta potential; and to evaluate in vitro drug release along with assessing in situ human lung adenocarcinoma cell culture. The results showed that the average particle size of G4 and G5 nanocomposites were 200 nm and 224.8 nm, with polydispersity index values of 0.05 and 0.300, zeta potential values of 11.54 and 4.26 mV of G4 and G5 PAMAM dendrimer, respectively. Comparative in situ study showed that cationic G4 erlotinib-loaded dendrimer was more selective and had higher antiproliferation activity against A549 lung cells compared to neutral G5 erlotinib-loaded dendrimers and erlotinib alone. These conclusions highlight the potential effect of cationic G4 dendrimer as a targeting-sustained-release carrier for erlotinib.

Design, synthesis, and carbonic anhydrase inhibition activities of Schiff bases incorporating benzenesulfonamide scaffold: Molecular docking application.

In this study, The inhibitory actions of human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII are being examined using recently synthesized substituted hydroxyl Schiff derivatives based on the quinazoline scaffold 4-22. Quinazolines 2, 3, 4, 5, 7, 10, 15, and 18 reduce the activity of hCA I isoform effectively to a Ki of 87.6-692.3 nM, which is nearly equivalent to or more potent than that of the standard drug AAZ (Ki, 250.0 nM). Similarly, quinazolines 2, 3, and 5 and quinazoline 14 effectively decrease the inhibitory activity of the hCA II isoform to a KI of 16.9-29.7 nM, comparable to that of AAZ (Ki, 12.0 nM). The hCA IX isoform activity is substantially diminished by quinazolines 2-12 and 14-21 (Ki, 8.9-88.3 nM against AAZ (Ki, 25.0 nM). Further, the activity of the hCA XII isoform is markedly inhibited by the quinazolines 3, 5, 7, 14, and 16 (Ki, 5.4-19.5 nM). Significant selectivity levels are demonstrated for inhibiting tumour-associated isoforms hCA IX over hCAI, for sulfonamide derivatives 6-15 (SI; 10.68-186.29), and 17-22 (SI; 12.52-57.65) compared to AAZ (SI; 10.0). Sulfonamide derivatives 4-22 (SI; 0.50-20.77) demonstrated a unique selectivity in the concurrent inhibition of hCA IX over hCA II compared to AAZ (SI; 0.48). Simultaneously, benzenesulfonamide derivative 14 revealed excellent selectivity for inhibiting hCA XII over hCA I (SI; 60.35), whereas compounds 5-8, 12-14, 16, and 18-22 demonstrated remarkable selectivity for hCA XII inhibitory activity over hCA II (SI; 2.09-7.27) compared to AAZ (SI; 43.86 and 2.10, respectively). Molecular docking studies additionally support 8 to hCA IX and XII binding, thus indicating its potential as a lead compound for inhibitor development.

Chitosan loaded RNA polymerase inhibitor nanoparticles increased attenuation in toxin release from Streptococcus pneumonia.

Background: Multidrug-resistant (MDR) bacterial infections have become an emerging health concern around the world. Antibiotics resistance among S. pneumoniae strains increased recently contributing to increase in incidence of pneumococcal infection. This necessitates the discovery of novel antipnemococcal such as compound C3-005 which target the interaction between RNA polymerase and σ factors. Chitosan nanoparticles (CNPs) exhibited antibacterial activity including S. pneumonia. Therefore, the aims of the current investigation were to formulate CNPs loaded with C3-005 and characteristic their antimicrobial properties against S. pneumonia. Methods: The CNPs and C3-005 loaded CNPs were produced utilizing ionic gelation method, and their physicochemical characteristics including particle size, zeta potential, polydispersity index (PDI), encapsulation efficiency (EE%), and in vitro release profile were studied. Both differential scanning calorimetry (DSC) and fourier transform infrared spectroscopy (FTIR) were used for chemical characterization. The synthesized NPs' minimum inhibitory concentration (MIC) was determined using killing assay and broth dilution method, and their impact on bacteria induced hemolysis were also studied. Results: The NPs encapsulating C3-005 were successfully prepared with particle size of 343.5 nm ± 1.3, zeta potential of 29.8 ± 0.37, and PDI of 0.20 ± 0.03. 70 % of C3-005 were encapsulated in CNPs and sustained release pattern of C3-005 from CNPs was revealed by an in vitro release study. CNPs containing C3-005 exhibited higher antipnomcoccal activity with MIC50 of 30 µg/ml when compared with C3-005 and empty CNPs alone. The prepared C3-CNPs showed a reduction of bacterial hemolysis in a concentration-related (dependent) manner and was higher than C3-005 alone. Conclusions: The findings of this study showed the potential for using C3-005 loaded CNPs to treat pneumococcal infection.

Multi-stage structure-based virtual screening approach towards identification of potential SARS-CoV-2 NSP13 helicase inhibitors.

On account of its crucial role in the virus life cycle, SARS-COV-2 NSP13 helicase enzyme was exploited as a promising target to identify a novel potential inhibitor using multi-stage structure-based drug discovery approaches. Firstly, a 3D pharmacophore was generated based on the collected data from a protein-ligand interaction fingerprint (PLIF) study using key interactions between co-crystallised fragments and the NSP13 helicase active site. The ZINC database was screened through the generated 3D-pharmacophore retrieving 13 potential hits. All the retrieved hits exceeded the benchmark score of the co-crystallised fragments at the molecular docking step and the best five-hit compounds were selected for further analysis. Finally, a combination between molecular dynamics simulations and MM-PBSA based binding free energy calculations was conducted on the best hit (compound FWM-1) bound to NSP13 helicase enzyme, which identified FWM-1 as a potential potent NSP13 helicase inhibitor with binding free energy equals -328.6 ± 9.2 kcal/mol.

Targeting VEGFR-2 by new quinoxaline derivatives: Design, synthesis, antiproliferative assay, apoptosis induction, and in silico studies.

Twelve new triazolo[4,3-a]quinoxaline-based compounds are reported as anticancer agents with potential effects against vascular endothelial growth factor receptor-2 (VEGFR-2), using sorafenib as a reference molecule. With sorafenib as the positive control, the antiproliferative effects of the synthesized compounds against MCF-7 and HepG2 cells, as well as their VEGFR-2-inhibitory activities, were assessed. The most powerful VEGFR-2 inhibitor was compound 14a, which had an IC50 value of 3.2 nM, which is very close to that of sorafenib (IC50 = 3.12 nM). Furthermore, compounds 14c and 15d showed potential inhibitory activity against VEGFR-2, with IC50 values of 4.8 and 5.4 nM, respectively. Compound 14a caused apoptosis in HepG2 cells and stopped the cell cycle at the G2/M phase. In HepG2 cells, it also increased the levels of the proteases caspase-3 and caspase-9, as well as the Bax/Bcl-2 ratio. In silico ADMET (absorption, distribution, metabolism, excretion, and toxicity) and toxicity experiments revealed that the synthesized agents had acceptable drug-likeness.

Carbonic Anhydrase Inhibition Activities of Schiff's Bases Based on Quinazoline-Linked Benzenesulfonamide.

Human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII were investigated for their inhibitory activity with a series of new Schiff's bases based on quinazoline scaffold 4-27. The hCA I isoform was efficiently inhibited by Schiff's bases 4-6, 10-19, 22-27 and had an inhibition constant (Ki) value of 52.8-991.7 nM compared with AAZ (Ki, 250 nM). Amongst the quinazoline derivatives, the compounds 2, 3, 4, 10, 11, 16, 18, 24, 26, and 27 were proven to be effective hCA II inhibitors, with Ki values of 10.8-52.6 nM, measuring up to AAZ (Ki, 12 nM). Compounds 2-27 revealed compelling hCA IX inhibitory interest with Ki values of 10.5-99.6 nM, rivaling AAZ (Ki, 25.0 nM). Quinazoline derivatives 3, 10, 11, 13, 15-19, and 24 possessed potent hCA XII inhibitory activities with KI values of 5.4-25.5 nM vs. 5.7 nM of AAZ. Schiff's bases 7, 8, 9, and 21 represented attractive antitumor hCA IX carbonic anhydrase inhibitors (CAIs) with KI rates (22.0, 34.8, 49.2, and 45.3 nM, respectively). Compounds 5, 7, 8, 9, 14, 18, 19, and 21 showed hCA I inhibitors on hCA IX with a selectivity index of 22.46-107, while derivatives 12, 14, and 18 showed selective hCA I inhibitors on hCA XII with a selectivity profile of 45.04-58.58, in contrast to AAZ (SI, 10.0 and 43.86). Compounds 2, 5, 7-14, 19-23, and 25 showed a selectivity profile for hCA II inhibitors over hCA IX with a selectivity index of 2.02-19.67, whereas derivatives 5, 7, 8, 13, 14, 15, 17, 20, 21, and 22 showed selective hCA II inhibitors on hCA XII with a selectivity profile of 4.84-26.60 balanced to AAZ (SI, 0.48 and 2.10).

Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors.

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcriptional elongation, through which short-lived antiapoptotic proteins are overexpressed and make cancer cells resistant to apoptosis. Therefore, CDK9 inhibition depletes antiapoptotic proteins, which in turn leads to the reinstatement of apoptosis in cancer cells. Twenty-seven compounds were synthesized, and their CDK9 inhibitory and cytotoxic activities were evaluated. Compounds 7, 9, and 25 were the most potent CDK9 inhibitors, with IC50 values of 0.115, 0.131, and 0.142 µM, respectively. The binding modes of these molecules were studied via molecular docking, which shows that they occupy the adenosine triphosphate binding site of CDK9. Of these three molecules, compound 25 shows good drug-like properties, as it does not violate Lipinski's rule of five. In addition, this molecule shows promising ligand and lipophilic efficiency values and is an ideal candidate for further optimization.

Preparation and characterization of Meta-bromo-thiolactone calcium alginate nanoparticles.

Recently, the focus has been shifting toward Quorum sensing inhibitors which reduce Pseudomonas aeruginosa virulence factors, alleviating infections. In this work, me-ta-bromo-thiolactone (mBTL), a potent quorum and virulence inhibitor for the Pseudomonas aeruginosa strains, were formulated in calcium alginate nanoparticles (CANPs). Alginate is used as nutrients and as backbone virulence aspect for Pseudomonas and therefore was chosen. mBTL-loaded-CANPs were characterized for particle size, polydispersity index, zeta potential, morphology visualized by Transmission Electron Microscopy (TEM) and drug release profile. Chemical and physical analysis of formulated mBTL-loaded-CANPs were evaluated using Fourier transform infrared Spectroscopy (FTIR) and differential scanning calorimetry (DSC) and Physical stability of mBTL-loaded-CANPs assessed at various temperature 25 ± 1 °C, 4 ± 0.5 °C and -30° ± 1 °C over a period of 4 and 9 months. Synthesized CANPs showed nano-size particles ranging from 140 to 200 nm with spherical particles for plain CANPS and irregular shape for mBTL-loaded-CANPs with a sustainable release profile over 48hrs. FTIR showed stable structure of loaded-mBTL and DSC displayed no interaction between mBTL and polymer. State of released mBTL from CANPs kept at 25 °C, 4 °C and -30 °C over 4 and 9 months showed stable formula at room temperature which kept as a goal of nanoparticles storage. The findings of this study revealed successful preparation of mBTL-loaded-CANPs.