Novel synthesis of nitro-quinoxalinone derivatives as aldose reductase inhibitors

A novel, non-acid series of nitroquinoxalinone derivatives was synthesized and tested for their inhibitory activity against aldose reductase as targeting enzyme. All active compounds displayed an 8-nitro group, and showed significant activity in IC₅₀ values ranging from 1.54 to 18.17 μM. Among them 6,7-dichloro-5,8-dinitro-3-phenoxyquinoxalin-2(1H)-one (7e), exhibited the strongest aldose reductase activity with an IC₅₀ value of 1.54 μM and a good SAR (structure–activity relationship) profile.     

Synthesis and structure–activity relationship studies of phenolic hydroxyl derivatives based on quinoxalinone as aldose reductase inhibitors with antioxidant activity

To enhance aldose reductase (ALR2) inhibition and add antioxidant ability, phenolic hydroxyl was introduced both to the quinoxalinone core and C3 side chain, resulting in a series of derivatives as ALR2 inhibitors. Biological activity tests suggested that most of the derivatives were potent and selective inhibitors with IC₅₀ values ranging from 0.059 to 6.825 μM, and 2-(3-(4-hydroxystyryl)-7-methoxy-2-oxoquinoxalin-1(2H)-yl)acetic acid (6b) was the most active. Particularly, it was encouraging to find that some derivatives endowed with obvious antioxidant activity, and among them the phenolic 3,4-dihydroxyl compound 6f with 7-hydroxyl in the quinoxalinone core showed the most potent activity, even comparable with the well-known antioxidant Trolox. Structure-activity relationship and docking studies highlighted the importance of phenolic hydroxyl both in C3 side chain and the core structure for constructing potent ALR2 inhibitors with antioxidant activity.     

Synthesis and evaluation of triazole linked glycosylated 18β-glycyrrhetinic acid derivatives as anticancer agents

A series of glycosyl triazol linked 18β-glycyrrhetinic acid (GA) derivatives have been synthesized using 1,3-dipolar cycloaddition reaction of per-O-acetylated glycosyl azide derivatives (4a–h) with propargyl ester of 18β-glycyrrhetinic acid (GA) (2 and 3) following the concept of ‘Click chemistry’. The synthesized triazole derivatives were de-O-acetylated to furnish compounds (7a–h and 8a–c) with free hydroxyl groups in the carbohydrate moieties, which were evaluated for their anticancer potential against human cervical cancer cells (HeLa) and normal kidney epithelial (NKE) cells. GA (1), compound 7d, compound 7g and compound 8c showed promising anticancer activities.     

Designing of acyl sulphonamide based quinoxalinones as multifunctional aldose reductase inhibitors

A series of quinoxalinone scaffold-based acyl sulfonamides were designed as aldose reductase inhibitors and evaluated for aldose reductase (ALR2)/aldehyde reductase (ALR1) inhibition and antioxidation. Compounds 9b-g containing styryl side chains at C3-side exhibited good ALR2 inhibitory activity and selectivity. Of them, 9g demonstrated the most potent inhibitory activity with an IC₅₀ value of 0.100?μM, and also exhibited excellent antioxidant activity, even comparable to the typical antioxidant Trolox. Compounds 9 had higher lipid-water partition coefficients relative to the carboxylic acid compounds 8, indicating that they may have better lipophilicity and membrane permeability. Structure-activity relationship (SAR) studies found that acyl trifluoromethanesulfonamide group at N1 and the C3-dihydroxystyryl side chain were the key structure for improving the aldose reductase inhibitory activity and antioxidant activity.     

Dual action spirobicycloimidazolidine-2,4-diones: Antidiabetic agents and inhibitors of aldose reductase-an enzyme involved in diabetic complications

The desired 3-(arylsulfonyl)spiroimidazolidine-2,4-diones were synthesized by reacting spiroiminoimidazolidine-2,4-dione with arylsulfonyl chlorides. Spiroimidazolidine-2,4-dione was in turn synthesized from norcamphor. Structures of the synthesized molecules were established by modern spectroscopic techniques. The synthesized compounds were screened for in vivo antidiabetic activity and aldose reductase inhibition. Compounds 2a, 2b and 2g exhibited excellent dual activity, compound 2a being most prominent. These results reveal that the synthesized compounds may serve as the molecule of choice to treat diabetes and diabetic complications using a single medication.     

Aldose reductase inhibition of a saponin-rich fraction and new furostanol saponin derivatives from Balanites aegyptiaca

BackgroundBalanites aegyptiaca Del. (Zygophyllaceae) fruits are used to treat hyperglycemia in Egyptian folk medicine and are sold by herbalists in the Egyptian open market for this purpose. Nevertheless, the fruits have not yet been incorporated into pharmaceutical dosage forms. The identity of the bioactive compounds and their possible mechanisms of action were not well understood until now.PurposeAldose reductase inhibitors are considered vital therapeutic and preventive agents to address complications caused by hyperglycemia. The present study was carried out to identify the primary compounds responsible for the aldose reductase inhibitory activity of Balanites aegyptiaca fruits.Study designThe 70% ethanolic extract of Balanites aegyptiaca fruit mesocarp and its fractions were screened for inhibition of the aldose reductase enzyme. Bio-guided fractionation of the active butanol fraction was performed and the primary compounds present in the saponin-rich fraction (D), which were responsible for the inhibitory activity, were characterized. HPLC chromatographic profiles were established for the different fractions, using the isolated compounds as biomarkers.MethodsAldose reductase inhibition was tested in vitro on rat liver homogenate. The butanol fraction of the 70% ethanolic extract was fractionated using vacuum liquid chromatography (VLC, RP-18 column). The most active sub-fraction D, which was eluted with 75% methanol, was subjected to preparative HPLC to isolate the bioactive compounds.ResultsThe butanol fraction displayed inhibitory activity against the aldose reductase enzyme (IC₅₀ = 55.0 ± 6 µg/ml). Sub-fraction D exhibited the highest inhibitory activity (IC₅₀ = 12.8 ± 1 µg/ml). Five new steroidal saponin derivatives were isolated from this fraction. The isolated compounds were identified as compound 1a/b, a 7:3 mixture of the 25R:25S epimers of 26-O-β-D-glucopyranosyl-furost-5-ene-3,22,26-triol 3-O-[α-L-rhamnopyranosyl-(1→3)- β-D-glucopyranosyl-(1→2)]- α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranoside; compound 2, 26-O-β-D-glucopyranosyl-(25R)-furost-5-ene-3,22,26-triol 3-O-[ β-D-glucopyranosyl-(1→2)]- α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranoside; compound 3, 26-O-β-D-glucopyranosyl-(25R)-furost-5,20-diene-3,26-diol 3-O-[α-L-rhamnopyranosyl-(1→3)- β-D-glucopyranosyl-(1→2)]- α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranoside; compound 4, 26-O-β-D-glucopyranosyl-(25R)-furost-5,20-diene-3,26-diol 3-O-[ β-D-glucopyranosyl-(1→2)]- α-L-rhamnopyranosyl-(1→4)-β-D-glucopyranoside; and compound 5, which is the 25S epimer of compound 4, by using various spectroscopic methods [MS,1D and 2D NMR (HSQC, HMBC, DQF-COSY, HSQC-TOCSY)]. Compounds 1a/b, 2, 3, 4, 5 exhibited highly significant aldose reductase inhibitory activities (IC₅₀ values were 1.9 ± 0.2, 1.3 ± 0.5, 5.6 ± 0.2, 5.1 ± 0.4, 5.1 ± 0.6 µM, respectively) as compared to the activity of the reference standard quercetin (IC₅₀ = 6.6 ± 0.3 µM).ConclusionThe aldose reductase inhibitory activity of Balanites fruits is due to the steroidal saponins present. HPLC chromatographic profiles of the crude butanol fraction and its 4 sub-fractions showed that the most highly bioactive fraction D contained the highest amount of steroidal saponins (75%) as compared to the 21% present in the original butanol fraction. The isolated furostanol saponins proved to be highly active in an in vitro assay.     

Novel 2-aminopyridine liganded Pd(II) N-heterocyclic carbene complexes: Synthesis,characterization, crystal structure and bioactivity properties

In this work, the synthesis, crystal structure, characterization, and enzyme inhibition effects of the novel a series of 2-aminopyridine liganded Pd(II) N-heterocyclic carbene (NHC) complexes were examined. These complexes of the Pd-based were synthesized from PEPPSI complexes and 2-aminopyridine. The novel complexes were characterized by using ¹³C NMR, ¹H NMR, elemental analysis, and FTIR spectroscopy techniques. Also, crystal structures of the two compounds were recorded by using single-crystal X-ray diffraction assay. Also, these complexes were tested toward some metabolic enzymes like α-glycosidase, aldose reductase, butyrylcholinesterase, acetylcholinesterase enzymes, and carbonic anhydrase I, and II isoforms. The novel 2-aminopyridine liganded (NHC)PdI₂(2-aminopyridine) complexes (1a-i) showed Ki values of in range of 5.78 ± 0.33–22.51 ± 8.59 nM against hCA I, 13.77 ± 2.21–30.81 ± 4.87 nM against hCA II, 0.44 ± 0.08–1.87 ± 0.11 nM against AChE and 3.25 ± 0.34–12.89 ± 4.77 nM against BChE. Additionally, we studied the inhibition effect of these derivatives on aldose reductase and α-glycosidase enzymes. For these compounds, compound 1d showed maximum inhibition effect against AR with a Ki value of 360.37 ± 55.82 nM. Finally, all compounds were tested for the inhibition of α-glycosidase enzyme, which recorded efficient inhibition profiles with Ki values in the range of 4.44 ± 0.65–12.67 ± 2.50 nM against α-glycosidase.     

Synthesis of pyrrolomorphinan derivatives as κ opioid agonists

We synthesized pyrrolomorphinan derivatives 6, 7, and 9 to examine whether the pyrrole ring would be an accessory site in the κ opioid receptor selective antagonist, nor-binaltorphimine. Derivative 6 had an α,β-unsaturated ketone substituent that strongly bound to the κ receptor. The compound with the highest κ receptor selectivity, 6e, produced a dose-dependent antinociceptive effect in the mouse acetic acid writhing test. However, derivatives 7 and 9, which did not have α,β-unsaturated ketone substituents, showed less κ receptor selectivity than compound 6. Based on structure–activity relationships, we proposed that these compounds adopted active structures for κ selective agonist activity. The pyrrole ring would not function as an accessory site, but the ability of the side chain on the pyrrole ring to localize above the C-ring appeared to confer κ selective agonist activity. These results will promote the design of novel κ agonists.     

Synthesis and preliminary biological assay of uridine glycoconjugate derivatives containing amide and/or 1,2,3-triazole linkers

A series of UDP-sugar analogues was synthesized and their preliminary biological activity was evaluated. Glycoconjugates of uridine 1 and 2 were synthesized by condensation of uridine-5′-carboxylic acid and 1-amino sugars derivatives of d-glucose and d-galactose, glycoconjugates 3 and 4 were synthesized by azide-alkyne 1,3-dipolar cycloaddition (CuAAC) of 1-azido sugars and propargylamide derivatives of uridine while glycoconjugates 5 and 6 were synthesized by CuAAC of propargyl β-O-glycosides and 5′-azido uridine. Evaluation of inhibitory activity of compounds 1–6 against commercially available β-1,4-galactosyltransferase I (β4GalT) show that compound 5 inhibited the enzyme in µmolar range. Additionally, the antitumor activity of the obtained glycoconjugates 1–6 were tested using MTT assay.     

Synthesis of novel 5-amino-1,3,4-thiadiazole-2-sulfonamide containing acridine sulfonamide/carboxamide compounds and investigation of their inhibition effects on human carbonic anhydrase I,II, IV and VII

Herein, we report that acridine intermediates 5 were obtained from the reduction of nitro acridine derivatives 4, which were synthesized via condensation of dimedone, p-nitrobenzaldehyde with 4-amino-N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)benzamide, respectively. Then acridine sulfonamide/carboxamide (7a–i) compounds were synthesized by reaction of amino acridine 5 with sulfonyl chlorides and carbamoyl chlorides. The new compounds were characterized by melting points, FT-IR, ¹H NMR, ¹³C NMR and HRMS analyzes. The evaluation of in vitro test of the synthesized compounds against hCA I, II, IV and VII showed that some of them are potent inhibitors. Among them, compound 7e showed the most potent activity against hCA II with a K_I of 7.9 nM.     

Synthesis and biological evaluation of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thioglycosides

In the present study, the synthesis of 1, 3, 4-thiadiazole-based thioglycosides were accomplished in good yields with employing a convergent synthetic route. The starting material 5-amino-1, 3, 4-thiadiazole-2-thiol and followed by a series of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thiols (4a–4j) were synthesized with different fatty acid chlorides. The glycosylation of compounds 4a–4j were achieved with trichloroacetimidate methodology. Antimicrobial and cytotoxicity activities of title compounds were evaluated. Among the entire compounds lauric acid and myristic acid derivatives showed good and moderate antimicrobial activity. In case of cytotoxicity results of compounds 8a–8j and 9a–9j, the acetate protected short chain (C6:0, C8:0, C10:0) compounds and the free hydroxyl long chain saturated (C16:0, C18:0) and unsaturated (C18:1, C22:1) compounds exhibited good activity against different cancer cell lines. Further, the free hydroxyl compounds 9a, 9c–9j did not show any toxicity towards normal CHO-K1 cell line whereas acylated compounds 8a–8j exhibited toxicity.     

Design,synthesis and pharmacological evaluation of (E)-3,4-dihydroxy styryl sulfonamides derivatives as multifunctional neuroprotective agents against oxidative and inflammatory injury

A novel class of (E)-3,4-dihydroxy styryl sulfonamides and their 3,4-diacetylated derivatives as caffeic acid phenethyl ester (CAPE) analogs was designed and prepared for improving stability and solubility of the lead compound. Their neuroprotective properties were assessed by several models. The results showed that target compounds displayed positive free radical quenching abilities, superior to that of CAPE. Compounds 6j–k and 7j–k demonstrated remarkable protection effects against damage induced by hydrogen peroxide which were apparently stronger than that of CAPE. Most of target compounds could inhibit nitric oxide production. Additionally, target compounds showed high blood–brain barrier permeability.     

An investigation on 4-thiazolidinone derivatives as dual inhibitors of aldose reductase and protein tyrosine phosphatase 1B,in the search for potential agents for the treatment of type 2 diabetes mellitus and its complications

Designed multiple ligands (DMLs), developed to modulate simultaneously a number of selected targets involved in etiopathogenetic mechanisms of a multifactorial disease, such as diabetes mellitus (DM), are considered a promising alternative to combinations of drugs, when monotherapy results to be unsatisfactory. In this work, compounds 1–17 were synthesized and in vitro evaluated as DMLs directed to aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two key enzymes involved in different events which are critical for the onset and progression of type 2 DM and related pathologies. Out of the tested 4-thiazolidinone derivatives, compounds 12 and 16, which exhibited potent AR inhibitory effects along with interesting inhibition of PTP1B, can be assumed as lead compounds to further optimize and balance the dual inhibitory profile. Moreover, several structural portions were identified as features that could be useful to achieve simultaneous inhibition of both human AR and PTP1B through binding to non-catalytic regions of both target enzymes.     

Rational design and synthesis of topoisomerase I and II inhibitors based on oleanolic acid moiety for new anti-cancer drugs

Semisynthetic reactions were conducted on oleanolic acid, a common plant-derived oleanane-type triterpene. Ten rationally designed derivatives of oleanolic acid were synthesized based on docking studies and tested for their topoisomerase I and IIα inhibitory activity. Semisynthetic reactions targeted C-3, C-12, C-13, and C-17. Nine of the synthesized compounds were identified as new compounds. The structures of these compounds were confirmed by spectroscopic methods (1D, 2D NMR and MS). Five oleanolic acid analogues (S2, S3, S5, S7 and S9) showed higher activity than camptothecin (CPT) in the topoisomerase I DNA relaxation assay. Four oleanolic acid analogues (S2, S3, S5 and S6) showed higher activity than etoposide in a topoisomerase II assay. The results indicated that the C12–C13 double bond of the oleanolic acid skeleton is important for the inhibitory activity against both types of topoisomerases, while insertion of a longer chain at either position 3 or 17 increases the activity against topoisomerases by various degrees. Some of the synthesized compounds act as dual inhibitors for both topoisomerase I and IIα.     

Synthesis and biological evaluation of novel pazopanib derivatives as antitumor agents

A series of novel pazopanib derivatives, 7a–m, were designed and synthesized by modification of terminal benzene and indazole rings in pazopanib. The structures of all the synthesized compounds were confirmed by ¹H NMR and MS. Their inhibitory activity against VEGFR-2, PDGFR-α and c-kit tyrosine kinases were evaluated. All the compounds exhibited definite kinase inhibition, in which compound 7l was most potent with IC₅₀ values of 12 nM against VEGFR-2. Furthermore, compounds 7c, 7d and 7m demonstrated comparable inhibitory activity against three tyrosine kinases to pazopanib, and compound 7f showed superior inhibitory effects than that of pazopanib.     

Design,synthesis, and evaluation of 2-piperidone derivatives for the inhibition of β-amyloid aggregation and inflammation mediated neurotoxicity

A series of novel multipotent 2-piperidone derivatives were designed, synthesized and biologically evaluated as chemical agents for the treatment of Alzheimer’s disease (AD). The results showed that most of the target compounds displayed significant potency to inhibit Aβ_1–42 self-aggregation. Among them, compound 7q exhibited the best inhibition of Aβ_1–42 self-aggregation (59.11% at 20 μM) in a concentration-dependent manner. Additionally, the compounds 6b, 7p and 7q as representatives were found to present anti-inflammation properties in lipopolysaccharide (LPS)-induced microglial BV-2 cells. They could effectively suppress the production of pro-inflammatory cytokines such as TNF-α, IL-1β and IL-6. Meanwhile, compound 7q could prevent the neuronal cell SH-SY5Y death by LPS-stimulated microglia cell activation mediated neurotoxicity. The molecular modeling studies demonstrated that compounds matched the pharmacophore well and had good predicted physicochemical properties and estimated IC₅₀ values. Moreover, compound 7q exerted a good binding to the active site of myeloid differentiation factor 88 (MyD88) through the docking analysis and could interfere with its homodimerization or heterodimerization. Consequently, these compounds emerged as promising candidates for further development of novel multifunctional agents for AD treatment.     

Solvent free synthesis,anti-inflammatory and anticancer activity evaluation of tricyclic and tetracyclic benzimidazole derivatives

Heterocyclic benzimidazole derivatives 3a–h, 5a–c and 7a–d have been synthesized by condensation of succinic acid (1) homophthalic acid (4) and 2,3-pyrazinedicarboxlic acid (6) with various substituted diamines under microwave irradiation in good yields. Structures assigned to 3a–h, 5a–c and 7a–d are fully supported by spectral data. All these compounds were screened for anti-inflammatory and anticancer activities. At a dose of 50 mg/kg po compounds 3b (39.4%) and 3c (39.2%) exhibited anti-inflammatory activity, comparable to standard ibuprofen which showed 39% activity at 50 mg/kg po and compound 7c exhibit good anticancer activity against ovary (IGR-OV-1), breast (MCF-7) and CNS(SF-295) human cancer cell lines.     

Design and synthesis of biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety as novel antibacterial agents against Gram-positive bacteria

Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed, synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a?6b. The preliminary study showed that compounds 7, 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125?µg/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA, MSSA, VRE and LREF with MIC values in the range of 0.125–0.5?µg/mL, and the potency of 10e against clinical isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an IC₅₀ value of 91.04?μM against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for further investigation.     

Quinazolinone-based rhodanine-3-acetic acids as potent aldose reductase inhibitors: Synthesis,functional evaluation and molecular modeling study

A series of quinazolinone-based rhodanine-3-acetic acids was synthesized and tested for in vitro aldose reductase inhibitory activity. All the target compounds displayed nanomolar activity against the target enzyme. Compounds 3a, 3b, and 3e exhibited almost 3-fold higher activity as compared to the only marketed reference drug epalrestat. Structure-activity relationship studies indicated that bulky substituents at the 3-phenyl ring of the quinazolinone moiety are generally not tolerated in the active site of the enzyme. Insertion of a methoxy group on the central benzylidene ring was found to have a variable effect on ALR-2 activity depending on the nature of peripheral quinazolinone ring substituents. Removal of the acetic acid moiety led to inactive or weakly active target compounds. Docking and molecular dynamic simulations of the most active rhodanine-3-acetic acid derivatives were also carried out, to provide the basis for further structure-guided design of novel inhibitors.     

In vitro anti-hyperglycemic activity of 4-hydroxyisoleucine derivatives

The nonproteinogenic amino acid, 4-hydroxyisoleucine (1) has been isolated in large quantities from the fenugreek (T. foenum-graecum) seeds. Few novel derivatives (3–11 and 13–18) were prepared from the naturally occurring 4-hydroxyisoleucine (1) and screened for their in vitro glucose uptake stimulatory effect in L-6 skeletal muscle cells. The derivatives 6, 7, 8, 10 and 11 exhibited better glucose uptake stimulatory activity than parent compound, 4-hydroxyisoleucine at 5 and 10 µM concentrations and compounds 7 and 11 enhanced translocation of insulin sensitive glucose transporters-4 in skeletal muscle cells.