Design, synthesis, molecular docking and biological evaluation of 1,3,5-trisubstituted-1H-pyrazole derivatives as anticancer agents with cell cycle arrest, ERK and RIPK3- kinase activities.

The need for new ERK and RIPK3 kinase modulators arises from their central roles in cellular processes, especially in diseases like cancer. This research focused on a ligand-based strategy, incorporating previously documented 1,3,5-trisubstituted-1H-pyrazole derivatives, to craft innovative inhibitors specifically targeting ERK and RIPK3 kinases. Compounds 6, 7, 10a, 10c, and 10d exhibited significant cytotoxicity against PC-3 and MCF-7 cancer cell lines, with IC50 values ranging from 21.9 to 28.6 µM and 3.90-35.5 µM, respectively values surpassing those of the reference compound Doxorubicin. Additionally, cell cycle analysis revealed intriguing results, particularly with 10d inducing cell cycle arrest at the S phase in treated PC-3 cells, indicating potential DNA replication phase inhibition. Moreover, compounds 6, 10a, and 10d exhibited promising results in the in vitro kinase assay supported by molecular docking studies. The core scaffold of these compounds established interactions with vital amino acids within the active pockets of ERK and RIPK3 kinases, thereby securely anchoring them in place. These findings underscore the development of promising modulators for ERK and RIPK3 kinases, suggesting their potential for future contributions to cancer treatments.

Synthesis of the chromone-thiosemicarbazone scaffold as promising α-glucosidase inhibitors: An in vitro and in silico approach toward antidiabetic drug design.

Diabetes is a serious metabolic disorder affecting individuals of all age groups and prevails globally due to the failure of previous treatments. This study aims to address the most prevalent form of type 2 diabetes mellitus (T2DM) by reporting on the design, synthesis, and in vitro as well as in silico evaluation of chromone-based thiosemicarbazones as potential α-glucosidase inhibitors. In vitro experiments showed that the tested compounds were significantly more potent than the standard acarbose, with the lead compound 3n exhibiting an IC50 value of 0.40 ± 0.02 µM, ~2183-fold higher than acarbose having an IC50 of 873.34 ± 1.67 µM. A kinetic mechanism analysis demonstrated that compound 3n exhibited reversible inhibition of α-glucosidase. To gain deeper insights, in silico molecular docking, pharmacokinetics, and molecular dynamics simulations were conducted for the investigation of the interactions, orientation, stability, and conformation of the synthesized compounds within the active pocket of α-glucosidase.

Discovery of Quinazoline-2,4(1H,3H)-Dione Derivatives as Potential Antibacterial Agent: Design, Synthesis, and Their Antibacterial Activity.

In this paper, we report on the design and synthesis of a novel series of quinazoline-2,4(1H,3H)-dione derivatives as fluoroquinolone-like inhibitors of bacterial gyrase and DNA topoisomerase IV to identify and develop antimicrobial agents to prevent bacterial resistance problems. Their structures were confirmed using spectroscopic analyses (IR, NMR, and EI-MS). The novel quinazoline-2,4(1H,3H)-dione derivatives were evaluated for their antimicrobial activities against Gram-positive and Gram-negative bacterial strains using the Agar well diffusion method to study the antimicrobial activities and compared them with the standard drugs. Most compounds displayed moderate activity. Among the tested compounds, the most promising compounds 13 and 15 provided broad bioactive spectrum against Gram-positive and Gram-negative strains compared to the standard drugs.

Potent, Selective Agonists for the Cannabinoid-like Orphan G Protein-Coupled Receptor GPR18: A Promising Drug Target for Cancer and Immunity.

The human orphan G protein-coupled receptor GPR18, activated by Δ9-tetrahydrocannabinol (THC), constitutes a promising drug target in immunology and cancer. However, studies on GPR18 are hampered by the lack of suitable tool compounds. In the present study, potent and selective GPR18 agonists were developed showing low nanomolar potency at human and mouse GPR18, determined in ß-arrestin recruitment assays. Structure-activity relationships were analyzed, and selectivity versus cannabinoid (CB) and CB-like receptors was assessed. Compound 51 (PSB-KK1415, EC50 19.1 nM) was the most potent GPR18 agonist showing at least 25-fold selectivity versus CB receptors. The most selective GPR18 agonist 50 (PSB-KK1445, EC50 45.4 nM) displayed >200-fold selectivity versus both CB receptor subtypes, GPR55, and GPR183. The new GPR18 agonists showed minimal species differences, while THC acted as a weak partial agonist at the mouse receptor. The newly discovered compounds represent the most potent and selective GPR18 agonists reported to date.

Synthesis, biological evaluation, and molecular modelling of substituted thiazolyl thiourea derivatives: A new class of prolyl oligopeptidase inhibitors.

Prolyl oligopeptidase (POP) is a compelling therapeutic target associated with aging and neurodegenerative disorders due to its pivotal role in neuropeptide processing. Despite initial promise demonstrated by early-stage POP inhibitors, their progress in clinical trials has been halted at Phase I or II. This impediment has prompted the pursuit of novel inhibitors. The current study seeks to contribute to the identification of efficacious POP inhibitors through the design, synthesis, and comprehensive evaluation (both in vitro and in silico) of thiazolyl thiourea derivatives (5a-r). In vitro experimentation exhibited that the compounds displayed significant higher potency as POP inhibitors. Compound 5e demonstrated an IC50 value of 16.47 ±â€¯0.54 µM, representing a remarkable potency. A meticulous examination of the structure-activity relationship indicated that halogen and methoxy substituents were the most efficacious. In silico investigations delved into induced fit docking, pharmacokinetics, and molecular dynamics simulations to elucidate the intricate interactions, orientation, and conformational changes of these compounds within the active site of the enzyme. Moreover, our pharmacokinetic assessments confirmed that the majority of the synthesized compounds possess attributes conducive to potential drug development.

Discovery of potent nucleotide pyrophosphatase/phosphodiesterase3 (NPP3) inhibitors with ancillary carbonic anhydrase inhibition for cancer (immuno)therapy.

Nucleotide pyrophosphatase/phosphodiesterase3 (NPP3) catalyzes the hydrolysis of extracellular nucleotides. It is expressed by immune cells and some carcinomas, e.g. of kidney and colon. Together with ecto-5'-nucleotidase (CD73), NPP3 produces immunosuppressive, cancer-promoting adenosine, and has therefore been proposed as a target for cancer therapy. Here we report on the discovery of 4-[(4-methylphthalazin-1-yl)amino]benzenesulfonamide (1) as an inhibitor of human NPP3 identified by compound library screening. Subsequent structure-activity relationship (SAR) studies led to the potent competitive NPP3 inhibitor 2-methyl-5-{4-[(4-sulfamoylphenyl)amino]phthalazin-1-yl}benzenesulfonamide (23, K i 53.7 nM versus the natural substrate ATP). Docking studies predicted its binding pose and interactions. While 23 displayed high selectivity versus other ecto-nucleotidases, it showed ancillary inhibition of two proposed anti-cancer targets, the carbonic anhydrases CA-II (Ki 74.7 nM) and CA-IX (Ki 20.3 nM). Thus, 23 may act as multi-target anti-cancer drug. SARs for NPP3 were steeper than for CAs leading to the identification of potent dual CA-II/CA-IX (e.g. 34) as well as selective CA-IX inhibitors (e.g. 31).

Stereoselective formation of triphenylene ketals.

The oxidative trimerization of catechol ketals by MoCl(5) or MoCl(5)/TiCl(4) mixtures leads preferentially to the all-syn stereoisomer of the corresponding triphenylene ketal. The concomitant metal salts of the oxidative coupling most probably form a multinuclear template that directs the diastereoselectivity in a subsequent isomerization step under electrophilic conditions. Several functionalities can serve as coordination sites for the multinuclear metal chloro clusters. Suitable functional groups have to be stable towards the strong electrophilic and oxidizing conditions. Therefore, esters, nitriles, nitro derivatives, triazoles, and pyridines are successfully employed. Based on the flexibility and size of the substrate, different reagent mixtures lead to the stereoselective formation of the all-syn derivatives.

Rapid and efficient synthesis of 4-substituted pyrazol-5-one under microwave irradiation in solvent-free conditions.

New heterocyclic compounds containing pyrazol-5-one coupled with benzimidazole, benzothiazole, benzoxazole, quinoline, naphthyridin, and pyrazole were synthesized. Comparative investigations to synthesize these interesting classes of heterocyclic compounds through conventional heating or under microwave-irradiation conditions were presented. Synthesized compounds 1a, 2a, 4k, 3a, c, 5a, b, 6b, 7a, b, d, 8a, and 9a were evaluated for their antitumor activity. Some of these compounds exhibited promising antitumor activity.