Sulfonyl thiourea derivatives from 2-aminodiarylpyrimidines: In vitro and in silico evaluation as potential carbonic anhydrase I, II, IX, and XII inhibitors.

A series of synthesized sulfonyl thiourea derivatives (7a-o) of substituted 2-amino-4,6-diarylpyrimidines (4a-o) exhibited the remarkable inhibitory activity against some the human carbonic anhydrases (hCAs), including hCA I, II, IX, and XII isoforms. The inhibitory efficacy of synthesized sulfonyl thiourea derivatives were experimentally validated by in vitro enzymatic assays. 7a (KI = 46.14 nM), 7j (KI = 48.92 nM), and 7m (KI = 62.59 nM) (for isoform hCA I); 7f (KI = 42.72 nM), 7i (KI = 40.98 nM), and 7j (KI = 33.40 nM) (for isoform hCA II); 7j (KI = 228.5 nM), 7m (KI = 195.4 nM), and 7n (KI = 210.1 nM) (for isoform hCA IX); 7l (KI = 116.9 nM), 7m (KI = 118.8 nM), and 7n (KI = 147.2 nM) (for isoform hCA XII) in comparison with KI values of 452.1, 327.3, 437.2, and 338.9 nM, respectively, of the standard drug AAZ. These compounds also had significantly more potent inhibitory action against cytosolic isoform hCA I and tumor-associated isoforms hCA IX and hCA XII. Furthermore, the potential inhibitory compounds were subjected to in silico screening for molecular docking and molecular dynamics simulations. The results of in vitro and in silico studies revealed that compounds 7a, 7j, and 7m were the most promising derivatives in this series due to their significant effects on studied hCA I, II, IX, and XII isoforms, respectively. The results showed that the sulfonyl thiourea moiety was accommodated deeply in the active site and interacted with the zinc ion in the receptors.

Thiourea derivatives containing 4-arylthiazoles and d-glucose moiety: design, synthesis, antimicrobial activity evaluation, and molecular docking/dynamics simulations.

Some substituted glucose-conjugated thioureas containing 1,3-thiazole ring, 4a-h, were synthesized by the reaction of the corresponding substituted 2-amino-4-phenyl-1,3-thiazoles 2a-h with 2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl isocyanate. The antibacterial and antifungal activities of these thiazole-containing thioureas were estimated using a minimum inhibitory concentration protocol. Among these compounds, 4c, 4g, and 4h were better inhibitors with MIC = 0.78-3.125 µg mL-1. These three compounds were also tested for their ability to inhibit S. aureus enzymes, including DNA gyrase, DNA topoisomerase IV (Topo IV), and dihydrofolate reductase, and compound 4h was found to be a strong inhibitor with IC50 = 1.25 ± 0.12, 67.28 ± 1.21, and 0.13 ± 0.05 µM, respectively. Induced-fit docking and MM-GBSA calculations were performed to observe the binding efficiencies and steric interactions of these compounds. The obtained results showed that compound 4h is compatible with the active site of S. aureus DNA gyrase 2XCS with four H-bond interactions with residues Ala1118, Met1121, and F:DC11 and also three interactions with F:DG10 (two interactions) and F:DC11 (one interaction). Molecular dynamics simulation in a water solvent system showed that ligand 4h had active interactions with enzyme 2XCS through residues Ala1083, Glu1088, Ala1118, Gly1117, and Met1121.

1H-1,2,3-Triazole-4H-chromene-D-glucose hybrid compounds: Synthesis and inhibitory activity against Mycobacterium tuberculosis protein tyrosine phosphatase B.

A series of 1H-1,2,3-triazole-4H-chromene-D-glucose hybrid compounds 7a-w were synthesized using click chemistry of 2-amino-7-propargyloxy-4H-chromene-3-carbonitriles 5a-w. CuNPs@montmorillonite was used as a catalyst in the presence of DIPEA as an additive for this chemistry. All synthesized 1H-1,2,3-triazoles were examined for in vitro inhibition against Mycobacterium tuberculosis protein tyrosine phosphatase B (MtbPtpB). Nine 1H-1,2,3-triazoles, including 7c-e, 7h, 7i, and 7r-t, displayed remarkable inhibitory activity against MtbPtpB with IC50 < 10 µM; compound 7t exhibited the most potent inhibition in vitro with an IC50 value of 0.61 µM. Kinetic studies of the three most active compounds, 7c,h,t, showed their competitive inhibition toward the MtbPtpB enzyme. Induced-fit docking and MM-GBSA studies on the enzyme (PDB: 2OZ5) revealed that the most active compound 7t was more effective against MtbPtpB. Residues Arg64, Arg136, Ash165, Arg166, and Arg63 in the binding pocket were identified as potential ligand-binding hot-spot residues for ligand 7t. The binding free energy calculation by the MM-GBSA approach for ligand 7t indicated that Coulomb, lipophilic, and van der Waals energy terms are major contributors to the inhibitor binding. Furthermore, the stability of the ligand-protein complex and the structural insights into the mode of binding were confirmed by 300-ns molecular dynamics simulation of 7t/2OZ5.

Design, Synthesis, α-Amylase/α-Glucosidase Inhibition Assay, Induced Fit Docking Study of New Hybrid Compounds Containing 4H-Pyrano[2,3-d]pyrimidine, 1H-1,2,3-Triazole and D-Glucose Components.

In this study, the click chemistry between N-propargyl derivatives of substituted 4H-pyrano[2,3-d]pyrimidines and tetra-O-acetyl-α-d-glucopyranosyl azide carried out under catalytic conditions using catalyst CuI@Montmorillonite and additive N,N-diisopropylethylamine (DIPEA). The yields of obtained hybrid compounds having 4H-pyrano[2,3-d]pyrimidine connected to 1H-1,2,3-triazole rings were about 85-94 %. All these synthesized hybrid compounds were examined for in vitro α-amylase (with IC50 values in the range of 103.63±1.13 µM to 295.45±1.11 µM) and α-glucosidase (with IC50 values in the range of 45.63±1.14 µM to 184.52±1.15) inhibitory activity. Amongst this series, ethyl ester 8m showed the best inhibitory activity against α-amylase with IC50 of 103.63±1.13 µM, while ethyl ester 8t exhibited the highest activity against α-glucosidase with IC50 of 45.63±1.14 µM. The kinetics of the inhibition of compound 8t showed the competitive α-glucosidase inhibitor property of this compound. Furthermore, the most potent compounds had any cytotoxicity against human normal cells. Induced fit docking and molecular dynamics simulation calculations indicated that the inhibition potential compounds 8m and 8t had the active interactions with the residues in receptors of corresponding tested enzymes. The calculated binding free energy from MM-GBSA approach showed that the major energy components contributed to the active binding of these studied inhibitors, including Coulomb, lipophilic and van der Waals energy. Further, 300 ns MD simulation showed that studied ligand-protein complexes were stable and indicated the structural observations into mode of binding in these complexes.

Synthesis and evaluation of in vivo antioxidant, in vitro antibacterial, MRSA and antifungal activity of novel substituted isatin N-(2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl)thiosemicarbazones.

Some new isatin N-(2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl)thiosemicarbazones 4a-t with different substituents at 1-, 5- and 7-positions of isatin ring have been synthesized by reaction of N-(2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl)thiosemicarbazide 2 with corresponding isatins 3a-t. Compounds 4a-t were evaluated in vivo for antioxidant activity and in vitro for anti-microorganism activities. The MIC values were found for Gram positive bacteria (MIC = 1.56-6.25 µM), for Gram negative bacteria (MIC = 12.5 µM), and for fungi Aspergillus niger (MIC = 3.12-12.5 µM), Fusarium oxysporum (MIC = 6.25-12.5 µM) and Saccharomyces cerevisiae (MIC = 6.25-12.5 µM). Regarding the antioxidant activity, the SOD, GHS-Px and catalase activities of 4c-i and 4m-r were MIC = 10.57-10.85, 0.27-0.93 and 345.45-399.75 unit/mg protein, respectively. Compounds 4e-h had MIC values of 0.78, 1.56, and 3.12 µM for three clinical MRSA isolates. Compound 4e showed the selective cytotoxic effects against some cancer (LU-1, HepG2, MCF7, P338, SW480, KB) cell lines and normal fibroblast cell line NIH/3T3.