Design, synthesis, and biological evaluation of some novel naphthoquinone-glycine/ß-alanine anilide derivatives as noncovalent proteasome inhibitors.

A series of novel noncovalent glycine/ß-alanine anilide derivatives possessing 2-chloronaphthoquinone structure as a pharmacophoric unit were designed, synthesized, and evaluated for their antiproliferative and antiproteasomal activities against MCF-7 cell line, in vitro. According to biological activity results, all the target compounds showed antiproliferative activity in the range of IC50  = 7.10 ± 0.10-41.08 ± 0.14 µM and most of them exhibited inhibitory efficacy with varying ratios against the three catalytic subunits (ß1, ß2, and ß5) presenting caspase-like (C-L), trypsin-like (T-L) and chymotrypsin-like (ChT-L) activities of proteasome. The antiproteasomal activity evaluations revealed that compounds preferentially inhibited the ß5 subunit compared with ß1 and ß2 subunits of the proteasome. Among the compounds, compounds 7 and 9 showed the highest antiproliferative activity with an IC50 value of 7.10 ± 0.10 and 7.43 ± 0.25 µM, respectively. Additionally, compound 7 displayed comparable potency to PI-083 lead compound in terms of ß5 antiproteasomal activity with an inhibition percentage of 34.67 at 10 µM. This compound showed an IC50 value of 32.30 ± 0.45 µM against ß5 subunit. Furthermore, molecular modeling studies of the most active compound 7 revealed key interactions with ß5 subunit. The results suggest that this class of compounds may be beneficial for the development of new potent proteasome inhibitors.

Design, synthesis and biological evaluation of novel naphthoquinone-4-aminobenzensulfonamide/carboxamide derivatives as proteasome inhibitors.

A series of novel 4-aminobenzensulfonamide/carboxamide derivatives bearing naphthoquinone pharmacophore were designed, sythesized and evaluated for their proteasome inhibitory and antiproliferative activities against human breast cancer cell line (MCF-7). The structures of the synthesized compounds were confirmed by spectral and elemental analyses. The proteasome inhibitory activity studies were carried out using cell-based assay. The antiproteasomal activity results revealed that most of the compounds exhibited inhibitory activity with different percentages against the caspase-like (C-L, ß1 subunit), trypsin-like (T-L, ß2 subunit) and chymotrypsin-like (ChT-L, ß5 subunit) activities of proteasome. Among the tested compounds, compound 14 bearing 5-chloro-2-pyridyl ring on the nitrogen atom of sulfonamide group is the most active compound in the series and displayed higher inhibition with IC50 values of 9.90 ± 0.61, 44.83 ± 4.23 and 22.27 ± 0.15 µM against ChT-L, C-L and T-L activities of proteasome compared to the lead compound PI-083 (IC50 = 12.47 ± 0.21, 53.12 ± 2.56 and 26.37 ± 0.5 µM), respectively. The antiproliferative activity was also determined by MTT (3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay in vitro. According to the antiproliferative activity results, all of the compounds exhibited cell growth inhibitory activity in a range of IC50 = 1.72 ± 0.14-20.8 ± 0.5 µM and compounds 13 and 28 were found to be the most active compounds with IC50 values of 1.79 ± 0.21 and 1.72 ± 0.14 µM, respectively. Furthermore, molecular modeling studies were carried out for the compounds 13, 14 and 28 to investigate the ligand-enzyme binding interactions.

A novel hemostatic scaffold material and the importance of scaffold formation on ending hemorrhage: An experimental rat study.

BACKGROUND: Different pharmacological agents are developed to control bleeding. However, it is critical for these agents to induce thrombin formation and have an effect on vasoconstriction, coagulation, and scaffold. In this study, we aimed to demonstrate the agents' ability to stop bleeding properties on minor and major open bleedings after skin clefts, extracorporal injuries, traumatic cuts, spontaneous or surgical intervention besides scaffold properties. For this purpose, a new and authentic hemostatic agent, processed diatomite (PD) and the most preferred chitosan in the medical area were used to test blood stopping and scaffold effects in a rat femoral bleeding model. The samples were examined by scanning electron microscopy (SEM), and the results on blood stopping were shared. METHODS: The current experimental study was conducted on rats. The effects of hemostatic agents on our femoral bleeding model were determined. In this study, 22 male Wistar albino rats weighing 158-215 g, were used. The rats were assigned randomly to three groups: control group (n=6), chitosan group (n=8), and PD group (n=8). Bleeding time, scaffold formation, weight differences, histopathological effect and scanning electron microscope (SEM) analyses were performed. RESULTS: In our experimental model, weight loss was 5.0±1.3 g for the control group, 2.9±1.1 g for the chitosan group, and 2.7±1.0 g for the PD group, respectively. When weighed before and after the experiment, there was a significant change in weights of rats in chitosan, and PD groups regarding scaffold formation: it was complete for six rats (75%) and weak for two (25%) rats in chitosan group; however, it was complete for seven rats (87.5%) and weak for one (12.5%) rat in the PD group. Scaffold formation was significant for the chitosan and PD groups versus the control group (p=0.002). CONCLUSION: In our study, the scaffold formed by PD exerts appropriate porousness and contributes to fibrin formation and prevent re-bleeding. PD had a strong and significant scaffold effect. The effectiveness of PD to stop bleeding was equal to chitosan. Besides being natural, hemostatic agents should not induce cellular damage. We histopathologically demonstrated that PD was harmless for the natural structure of cells and vessels in the femoral site.

Crystal structure and theoretical study of N,N-bis-[(5-chloro-2-oxo-2,3-di-hydro-benzo[d]oxazol-3-yl)meth-yl]-2-phenyl-ethanamine.

In the mol-ecular structure of the title compound, C24H19Cl2N3O4, the three C atoms of the central N,N-di-methyl-methanamine moiety are bonded to the N atoms of the two 5-chloro-1,3-benzoxazol-2(3H)-one groups and to the methyl C atom of the methyl-benzene group. One of the nine-membered 2,3-di-hydro-1,3-benzoxazole rings and the phenyl ring are almost parallel to each other, making a dihedral angle of 5.30 (18)°, but they are almost normal to the mean plane of the other nine-membered 2,3-di-hydro-1,3-benzoxazole ring, subtending dihedral angles of 89.29 (16) and 85.41 (18)°, respectively. The crystal structure features C-H⋯O hydrogen bonds and π-π stacking inter-actions [centroid-to-centroid distances = 3.5788 (19) Å, slippage = 0.438 and 3.7773 (16) Å, and slippage = 0.716 Å].

Synthesis, biological evaluation, and docking studies of some 5-chloro-2(3H)-benzoxazolone Mannich bases derivatives as cholinesterase inhibitors.

A series of N-substituted-5-chloro-2(3H)-benzoxazolone derivatives were synthesized and evaluated for their acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) inhibitory, and antioxidant activities. The structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The free radical scavenging activity was also determined by in vitro ABTS (2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)) assay. The biological activity results revealed that all of the title compounds displayed higher AChE inhibitory activity than the reference compound, rivastigmine, and were selective for AChE. Among the tested compounds, compound 7 exhibited the highest inhibition against AChE (IC50 = 7.53 ± 0.17 µM), while compound 11 was found to be the most active compound against BuChE (IC50 = 17.50 ± 0.29 µM). The molecular docking study of compound 7 showed that this compound can interact with the catalytic active site (CAS) of AChE and also has potential metal chelating ability and a proper log P value. On the other hand, compound 2 bearing a methyl substituent at the ortho position on the phenyl ring showed better radical scavenging activity (IC50 = 1.04 ± 0.04 mM) than Trolox (IC50 = 1.50 ± 0.05 mM).

Synthesis and molecular docking studies of some 4-phthalimidobenzenesulfonamide derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors.

A series of 4-phthalimidobenzenesulfonamide derivatives were designed, synthesized and evaluated for the inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Structures of the title compounds were confirmed by spectral and elemental analyses. The cholinesterase (ChE) inhibitory activity studies were carried out using Ellman's colorimetric method. The biological activity results revealed that all of the title compounds (except for compound 8) displayed high selectivity against AChE. Among the tested compounds, compound 7 was found to be the most potent against AChE (IC50= 1.35 ± 0.08 µM), while compound 3 exhibited the highest inhibition against BuChE (IC50= 13.41 ± 0.62 µM). Molecular docking studies of the most active compound 7 in AChE showed that this compound can interact with both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.

3-Anilinomethyl-5-chloro-1,3--benzoxazol-2(3H)-one.

In the title compound, C(14)H(11)ClN(2)O(2), the 2,3-dihydro-1,3-benzoxazole ring system is essentially planar [maximum deviation = 0.009 (2) Å] and makes a dihedral angle of 79.15 (7)° with the phenyl ring. Inter-molecular N-H⋯O and weak C-H⋯Cl hydrogen bonds occur in the crystal structure.

Synthesis and screening of cyclooxygenase inhibitory activity of some 1,3-dioxoisoindoline derivatives.

In this study, 15 compounds bearing N,N-phthaloylacetamide structure designed by the molecular simplification approach based on thalidomide structure were synthesized and evaluated for inhibitory potencies against cyclooxgenase (COX) isoenzymes, namely COX-1 and COX-2. The results suggested that the N,N-phthaloylacetamide structure, as a primary amide, has inhibitory activity against cyclooxygenase isoenzymes with a higher COX-1 selectivity. The conversion of the primary amide to secondary or tertiary derivatives lowered the potency but favored the COX-2 selectivity thus yielding the compounds with stronger COX-2 inhibiting activity.

Synthesis of some 2(3H)-benzoxazolone derivatives and their in-vitro effects on human leukocyte myeloperoxidase activity.

Myeloperoxidase (MPO), a heme protein expressed by polymorphonuclear leukocytes, generates potent oxidants which are proposed to contribute to tissue damage during inflammation and certain pathogenesis such as neurodegenerative disorders. In this study, twenty omega-[2-oxo-3H-benzoxazol-3-yl]-N-phenylacetamide and propionamide derivatives having substituents of different lipophilic and electronic nature on the N-phenyl ring were synthesized to evaluate the inhibitory effects on in vitro leukocyte MPO chlorinating activity. The most active compounds in the series were the derivatives bearing 2-methyl and 4-nitro substituent on the N-phenyl ring.

Synthesis and anticonvulsant activity of some omega-(1H-imidazol-1-yl)-N-phenylacetamide and propionamide derivatives.

In this study, eight new omega-(1H-imidazol-1-yl)-N-phenylacetamide and propionamide derivatives having 2,6-dimethyl, 2,6-dichloro, 2-chloro-6-methyl and 2-isopropyl substitutions on N-phenyl ring were synthesized to evaluate anticonvulsant activity against maximal electroshock test. The most active compounds in the series were the derivatives bearing 2-isopropyl and 2,6-dimethyl substituents on N-phenyl ring.

The synthesis and anticonvulsant activity of some omega-phthalimido-N-phenylacetamide and propionamide derivatives.

In this study, by combining anilide and N', N'-phthaloylglycinamide pharmacophores which are known to produce potent anticonvulsant compounds, sixteen omega-phthalimido-N-phenylacetamide and propionamide derivatives bearing substituents at positions 2 or 2, 6 on N-phenyl ring have been synthesized. The structural confirmation of the title compounds was achieved by interpretation of spectral and analytical data. The anticonvulsant activity of the title compounds was determined against maximal electroshock seizure at 100 mg/kg dose level in mice. The preliminary screening results indicated that omega-phthalimido-N-phenylacetamide and propionamide nuclei have pronounced anticonvulsant activity against maximal electroshock seizure.