RESUMO
In keeping with our investigation, a simple and practical synthesis of novel heterocyclic compounds with a sulfamoyl moiety that can be employed as insecticidal agents was reported. The compound 2-hydrazinyl-N-(4-sulfamoylphenyl)-2-thioxoacetamide 1 was coupled smoothly with triethylorthoformate or a variety of halo compounds, namely phenacyl chloride, chloroacetyl chloride, chloroacetaldehyde, chloroacetone, 1,3-dichloropropane, 1,2-dichloroethane, ethyl chloroformate, 2,3-dichloro-1,4-naphthoquinone, and chloroanil respectively, which afforded the 1,3,4-thiadiazole and 1,3,4-thiadiazine derivatives. The new products structure was determined using elemental and spectral analysis. Under laboratory conditions, the biological and toxicological effects of the synthetic compounds were also evaluated as insecticides against Spodoptera littoralis (Boisd.). Compounds 3 and 5 had LC50 values of 6.42 and 6.90 mg/L, respectively. The investigated compounds (from 2 to 11) had been undergoing molecular docking investigation for prediction of the optimal arrangement and strength of binding between the ligand (herein, the investigated compounds (from 2 to 11)) and a receptor (herein, the 2CH5) molecule. The binding affinity within docking score (S, kcal/mol) ranged between -8.23 (for compound 5), -8.12 (for compound 3) and -8.03 (for compound 9) to -6.01 (for compound 8). These compounds were shown to have a variety of binding interactions within the 2CH5 active site, as evidenced by protein-ligand docking configurations. This study gives evidence that those compounds have 2CH5-inhibitory capabilities and hence may be used for 2CH5-targeting development. Furthermore, the three top-ranked compounds (5, 3, and 9) and the standard buprofezin were subjected to density functional theory (DFT) analysis. The highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy difference (ΔE) of compounds 5, 3, and 9 was found to be comparable to that of buprofezin. These findings highlighted the potential and relevance of charge transfer at the molecular level.
Assuntos
Desenho de Fármacos , Inseticidas , Simulação de Acoplamento Molecular , Spodoptera , Tiadiazinas , Tiadiazóis , Animais , Inseticidas/química , Inseticidas/síntese química , Inseticidas/farmacologia , Spodoptera/efeitos dos fármacos , Tiadiazóis/química , Tiadiazóis/farmacologia , Tiadiazóis/síntese química , Tiadiazinas/química , Tiadiazinas/farmacologia , Tiadiazinas/síntese química , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/síntese química , Proteínas de Insetos/química , Benzenossulfonamidas , Estrutura Molecular , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica II/químicaRESUMO
The carbonic anhydrase (CA) inhibitory activity of newly synthesized compounds 4-21 against the human CA (hCA) isoforms I, II, IX, and XII was measured and compared to that of standard sulfonamide inhibitors, acetazolamide (AAZ) and SLC-0111. Among this series; benzensulfonamides 6-11 gave the best potent hCA inhibitors with inhibition constants (KIs) ranging from 81.9 to 456.6â¯nM (AAZ and SLC-0111: KIs, 250.0 and 5080â¯nM, respectively). Compounds 6-11 proved to be effective hCA II inhibitors (KIs, 8.9-51.5â¯nM); they were almost equally potent to AAZ (KI, 12.0â¯nM) and had superior potency to SLC-0111 (KI, 960.0â¯nM). For hCA IX inhibition, compounds 6-11 proved to be potent inhibitors, with KI values of 3.9-36.0â¯nM, which were greater than or equal to that of AAZ and greater than that of SLC-0111 (KIs, 25.0 and 45.0â¯nM, respectively). For hCA XII inhibitory activity, compounds 6-11 displayed effective inhibition with KI values ranging from 4.6 to 86.3â¯nM and were therefore comparable to AAZ and SLC-0111 (KIs, 5.7 and 4.5â¯nM, respectively). Molecular docking studies of compounds 6, 7, 10, and 11 were conducted using the crystal structures of hCA isozymes I, II, IX, and XII to study their binding interactions for further lead optimization.
Assuntos
Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Derivados de Benzeno/síntese química , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Anidrase Carbônica IX/antagonistas & inibidores , Anidrase Carbônica IX/metabolismo , Inibidores da Anidrase Carbônica/síntese química , Anidrases Carbônicas/metabolismo , Humanos , Simulação de Acoplamento Molecular , Sulfonamidas/síntese químicaRESUMO
A library of twenty-five derivatives of 2-substituted quinazolin-4(3H)-ones 1-25 was synthesized and evaluated against phosphodiesterase-I (PDE) and carbonic anhydrase-II (CA). Compounds 17 (IC50 = 210.7 ± 2.62 µM), 16 (IC50 = 301.6 ± 1.18 µM), and 13 (IC50 = 458.13 ± 3.60 µM), selectively exhibited PDE inhibition while compounds 22 (IC50 = 61.33 ± 2.38 µM), 1 (IC50 = 108.30 ± 0.93 µM), and 21 (IC50 = 191.93 ± 2.72 µM), discriminatingly exhibited CA inhibition as compared to standards EDTA (IC50 = 277.69 ± 2.52 µM) and acetazolamide (IC50 = 0.12 ± 0.03 µM), for PDE and CA inhibitions, respectively. However, compound 15 was found to be active against both enzymes with the IC50 values 344.33 ± 4.32 µM and 20.94 ± 0.58 µM, for PDE and CA inhibitions, respectively. Remaining compounds were found to be inactive against both the enzymes. Structure-activity relationship studies are discussed herein.