Synthesis and biological evaluation of substituted aurone derivatives as potential tyrosinase inhibitors: in vitro, kinetic, QSAR, docking and drug-likeness studies.

Tyrosinase enzyme plays an essential role in melanin biosynthesis and enzymatic browning of fruits and vegetables. To discover potent tyrosinase inhibitors, the present studies were undertaken. In this context, synthetic aurone derivatives 26-50 were designed, synthesized, and structurally elucidated by various spectroscopic techniques including IR, UV, 1H- & 13C-NMR and mass spectrometry. The target compounds 26-50 were screened for their anti-tyrosinase inhibitory potential, and thus kinetic mechanism was analyzed by Lineweaver-Burk plots. All target compounds exhibited good to excellent IC50 values in the range of 7.12 ± 0.32 µM to 66.82 ± 2.44 µM. These synthesized aurone derivatives were found as potent tyrosinase inhibitors relative to the standard kojic acid (IC50 = 16.69 ± 2.81 µM) and the compound 39 inhibited tyrosinase non-competitively (Ki = 11.8 µM) by forming an enzyme-inhibitor complex. The binding modes of these molecules were ascribed through molecular docking studies against tyrosinase protein (PDB ID: 2Y9X). The quantitative structure-activity relationship studies displayed a good correlation between 26-50 structures and their anti-tyrosinase activity (IC50) with a correlation coefficient (R2) of 0.9926. The computational studies were coherent with experimental results and these ligands exhibited good binding values against tyrosinase and interacted with core residues of target protein. Moreover, the drug-likeness analysis also showed that some compounds have a linear correlation with Lipinski's rule of five, indicating good drug-likeness and bioactivity scores for pharmacological targets.Communicated by Ramaswamy H. Sarma.

Synthesis of Novel Benzimidazole-Based Thiazole Derivatives as Multipotent Inhibitors of α-Amylase and α-Glucosidase: In Vitro Evaluation along with Molecular Docking Study.

In this study, hybrid analogs of benzimidazole containing a thiazole moiety (1-17) were afforded and then tested for their ability to inhibit α-amylase and α-glucosidase when compared to acarbose as a standard drug. The recently available analogs showed a wide variety of inhibitory potentials that ranged between 1.31 ± 0.05 and 38.60 ± 0.70 µM (against α-amylase) and between 2.71 ± 0.10 and 42.31 ± 0.70 µM (against α-glucosidase) under the positive control of acarbose (IC50 = 10.30 ± 0.20 µM against α-amylase) (IC50 = 9.80 ± 0.20 µM against α-glucosidase). A structure-activity relationship (SAR) study was carried out for all analogs based on substitution patterns around both rings B and C respectively. It was concluded from the SAR study that analogs bearing either substituent(s) of smaller size (-F and Cl) or substituent(s) capable of forming hydrogen bonding (-OH) with the catalytic residues of targeted enzymes enhanced the inhibitory potentials. Therefore, analogs 2 (bearing meta-fluoro substitution), 3 (having para-fluoro substitution) and 4 (with ortho-fluoro group) showed enhanced potency when evaluated against standard acarbose drug with IC50 values of 4.10 ± 0.10, 1.30 ± 0.05 and 1.90 ± 0.10 (against α-amylase) and 5.60 ± 0.10, 2.70 ± 0.10 and 2.90 ± 0.10 µM (against α-glucosidase), correspondingly. On the other hand, analogs bearing substituent(s) of either a bulky nature (-Br) or that are incapable of forming hydrogen bonds (-CH3) were found to lower the inhibitory potentials. In order to investigate the binding sites for synthetic analogs and how they interact with the active areas of both targeted enzymes, molecular docking studies were also conducted on the potent analogs. The results showed that these analogs adopted many important interactions with the active areas of enzymes. The precise structure of the newly synthesized compounds was confirmed using several spectroscopic techniques as NMR and HREI-MS.

New Triazinoindole Bearing Benzimidazole/Benzoxazole Hybrids Analogs as Potent Inhibitors of Urease: Synthesis, In Vitro Analysis and Molecular Docking Studies.

Twenty-four analogs based on triazinoindole bearing benzimidazole/benzoxazole moieties (1-25) were synthesized. Utilizing a variety of spectroscopic methods, including 1H-, 13C-NMR, and HREI-MS, the newly afforded compounds (1-25) were analyzed. The synthesized analogs were tested against urease enzyme (in vitro) as compared to the standard thiourea drug. All triazinoindole-based benzimidazole/benzoxazole analogs (1-25) exhibited moderate to excellent inhibition profiles, having IC50 values of 0.20 ± 0.01 to 36.20 ± 0.70 µM when evaluated under the positive control of thiourea as a standard drug. To better understand the structure-activity relationship, the synthesized compounds were split into two groups, "A" and "B." Among category "A" analogs, analogs 8 (bearing tri-hydroxy substitutions at the 2,4,6-position of aryl ring C) and 5 (bearing di-hydroxy substitutions at the 3,4-position of aryl ring C) emerged as the most potent inhibitors of urease enzyme and displayed many times more potency than a standard thiourea drug. Besides that, analog 22 (which holds di-hydroxy substitutions at the 2,3-position of the aryl ring) and analog 23 (bearing ortho-fluoro substitution) showed ten-fold-enhanced inhibitory potential compared to standard thiourea among category "B" analogs. Molecular docking studies on the active analogs of each category were performed; the results obtained revealed that the presence of hydroxy and fluoro-substitutions on different positions of aryl ring C play a pivotal role in binding interactions with the active site of the targeted urease enzyme.