N‐Substituted isatoic anhydrides were used as starting materials for the synthesis of compounds 5–16 through alkali hydrolysis, Schiff base reactions, and oxidation. Compounds 18–23 were obtained by thionation of their oxo isosteres using Lawesson's reagent. Cyclocondesation of anthranilic acid with thiourea afforded compounds 25–27, which were S‐alkylated to afford compounds 28–30, which were thionated using Lawesson's reagent to afford 31–33. The compounds were tested for their in vitro inhibitory activity against the phosphodiesterase 7A (PDE7A) enzyme compared with the selective PDE7 inhibitor BRL50481. All the compounds showed the inhibitory activity on the enzyme at micromolar levels. Compounds 9 and 25 showed the highest inhibitory activity on the enzyme: IC50 = 0.096 and 0.074 μM, respectively, comparable to BRL50481 (IC50 = 0.072 μM). The binding mode and binding affinity of the target compounds at the enzyme PDE7A‐binding site were studied through molecular docking. Compounds 9 and 25 showed good recognition at the enzyme‐binding site and were capable of binding in an inhibitory mode similar to the reference compound BRL50481, forming the necessary interactions with the key amino acids. Docking studies and enzyme assay were in agreement.

No abstract

Novel 6(3-1H-1,2,4-triazol-1-yl)-3-phenylquinazoline-2,4(1H,3H)-diones (7a–e) were synthesized from different enaminones (6a–e) with 6-hydrazinyl-3-phenylquinazoline-2,4(1H,3H)-dione. 2,6(4-2-Substituted-1,3,5-triazin-1(2H)-yl)-3-phenylquinazoline-2,4(1H,3H)-diones (8a–k) were synthesized from the reaction of 1-(2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinazolin-6-yl)thiourea, urea, or guanidine (3a–c) with enaminones (6a–e), and a series from 3-substituted-2-imino-1,3,5-triazin-1(2H)-yl-sulfonyl-phenyl-1-methylquinazoline-2,4(1H,3H)-dione (12a–j) were obtained from the reaction of N-(diaminomethylene)-4-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)benzenesulfonamide (11) with the enaminone (6a–j). The antitumor activity of the synthesized compounds was evaluated against two human cell lines: human colon carcinoma HCT116 and human hepatocellular carcinoma HEP-G2. Some of the tested compounds showed significant potency compared to the reference drug staurosporin.

The increasing incidence of erythromycin and erythromycin-induced resistance to clindamycin among Staphylococcus aureus (S. aureus) is a serious problem. Patients infected with inducible resistance phenotypes may fail to respond to clindamycin. This study aimed to identify the prevalence of erythromycin and erythromycin-induced resistance and assess for potential inhibitors. A total of 99 isolates were purified from various clinical sources. Phenotypic detection of macrolide-lincosamide-streptogramin B (MLSB)-resistance phenotypes was performed by D-test. MLSB-resistance genes were identified using PCR. Different compounds were tested for their effects on erythromycin and inducible clindamycin resistance by broth microdilution and checkerboard microdilution methods. The obtained data were evaluated using docking analysis. Ninety-one isolates were S. aureus. The prevalence of constitutive MLSB, inducible MLSB, and macrolide-streptogramin (MS) phenotypes was 39.6%, 14.3%, and 2.2%, respectively. Genes including ermC, ermA, ermB, msrA, msrB, lnuA, and mphC were found in 82.6%, 5.8%, 7.7%, 3.8%, 3.8%, 13.5%, and 3.8% of isolates, respectively. Erythromycin resistance was significantly reduced by doxorubicin, neomycin, and omeprazole. Quinine, ketoprofen, and fosfomycin combated and reversed erythromycin/clindamycin-induced resistance. This study highlighted the significance of managing antibiotic resistance and overcoming clindamycin treatment failure. Doxorubicin, neomycin, omeprazole, quinine, ketoprofen, and fosfomycin could be potential inhibitors of erythromycin and inducible clindamycin resistance.

Novel series of aminopyrimidines bearing a biologically active cyclohexenone 3a–f and oxo-selaneylidene moiety 4 , besides selenadiazolopyrimidines ( 5a–e and 7 ), were synthesised using 5,6-diaminouracils as starting materials. Compound 3a exhibited strong anti-proliferative activity against three cell lines: HepG-2 (IC 50 14.31 ± 0.83 µM), A-549 (IC 50 30.74 ± 0.76 µM), and MCF-7 (IC 50 27.14 ± 1.91 µM). Also, it was four times more selectively cytotoxic against WI-38 cell lines than doxorubicin. Furthermore, Topoisomerase II (IC 50 4.48 ± 0.65 µM) and HSP90 (IC 50 1.78 ± 0.11 µM) were both strongly inhibited in vitro by 3a . The cell cycle was halted at the G1-S phase, and total apoptotic cells were 65 times more than control Hep-G2 cells. Besides, it increased caspase-3 gene expression, triggering mitochondrial cell death. Molecular docking study indicated that it could bind to Topoisomerase II and HSP90 binding sites in an inhibitory mode. Its geometric properties were investigated using the density functional theory (DFT). Furthermore, compound 3a demonstrated in silico good oral bioavailability.

P HOSPHODIESTERASE 7A enzyme is one of the most recent targets for designing potent anti-inflammatory agents with minimal side effects. Quinazolinones are unique building blocks of wide biological activities. Different quinazolinones were reported to act as Phosphodiesterase 7A inhibitors anti-inflammatory particularly against chronic inflammation and autoimmune disease. Ultrasound is a green convenient method for synthesis of different heterocyclic ring system that is advantageous in terms of yield and reaction time. Ultrasound was used for one pot synthesis of 3-substituted 6-aryldihydroisoindolo[2,1-a] quinazolin-5,11diones and 3-arylquinazolin-2,4(1H,3H)-diones. Seventeen compounds were synthesized in good yields. The synthesized compounds were inspected for in vitro inhibitory activity against phosphodiesterase7A enzyme. Molecular docking was used to study the mode of interaction of all the synthesized compounds into the enzyme phosphodiesterase 7A binding site. Five compounds showed high inhibitory activity of enzyme Phosphodiesterase 7A at micro-molar level compared to reference drug. The compounds showed good recognition at the enzyme binding site in the molecular docking. There was a good agreement between the molecular docking and the biological screening results.

No abstract

Nanotechnology-based strategies can overcome the limitations of conventional cancer therapies. Hence, novel series of pyrimidine Schiff bases ( 4–9 ) were employed in the synthesis of selenium nanoparticle forms ( 4NPs–9NPs ). All selenium nano-sized forms exerted greater inhibitions than normal-sized compounds, far exceeding 5-fluorouracil activity. Compound 4 showed effective anti-proliferative activity against MCF-7(IC 50 3.14 ± 0.04 µM), HepG-2(IC 50 1.07 ± 0.03 µM), and A549(IC 50 1.53 ± 0.01 µM) cell lines, while its selenium nanoform 4NPs showed excellent inhibitory effects, with efficacy increased by 96.52%, 96.45%, and 93.86%, respectively. Additionally, 4NPs outperformed 4 in selectivity against the Vero cell line by 4.5-fold. Furthermore, 4NPs exhibited strong inhibition of CDK1(IC 50 0.47 ± 0.3 µM) and tubulin polymerase(IC 50 0.61 ± 0.04 µM), outperforming 4 and being comparable to roscovitine (IC 50 0.27 ± 0.03 µM) and combretastatin-A4(IC 50 0.25 ± 0.01 µM), respectively. Moreover, both 4 and 4NPs arrested the cell cycle at G0/G1 phase and significantly forced the cells towards apoptosis. Molecular docking demonstrated that 4 and 4NPs were able to inhibit CDK1 and tubulin polymerase binding sites.