Evaluation of new thiadiazoles and benzothiazoles as potential radioprotectors: Free radical scavenging activity in vitro and theoretical studies (QSAR,DFT)

Thiol and aminothiol compounds are among the most efficient chemical radioprotectors. To increase their efficiency, we synthesized two new classes of thiol and aminothiol compounds derived from benzothiazole (T1, T2, AM1, AM2) and thiadiazole (T3, T4, AM3) structures. We examined them for their ability to scavenge free radicals (DPPH^·, ABTS^·+, ^·OH). Thiol derivatives with a thiadiazole structure are the most active compounds scavenging DPPH^· and ABTS^·+ free radicals, with an IC₅₀ of 0.053 ± 0.006 and 0.023 ± 0.002 mM, respectively, for the derivative T3. Moreover, compounds T1, T2, and T3 at 60 μM gave 83% protection against 2-deoxyribose degradation by ^·OH. The ability of these compounds to protect DNA against ^·OH produced by a Fenton reaction and γ-irradiation (15 Gy)-induced strand breaks was also evaluated on pBR322 plasmid DNA. In both tests thiol derivatives were the most efficient compounds. Derivatives T2 and T3 totally inhibit DNA strand breaks at the concentration of 50 μM. The protection afforded by these derivatives was comparatively higher than that of the radioprotectors WR-2721 and WR-1065. Our data indicate that these two compounds are free radical scavengers and potential antioxidant agents. Finally, DFT and QSAR studies were performed to support the experimental observations.     

Synthesis and antioxidant properties of a new lipophilic ascorbic acid analogue

4-(4-Hydroxyphenyl)-5-(4-hydroxyphenylmethyl)-2-hydroxyfurane-2-one 1 was prepared by an acidic dimerisation of 4-hydroxyphenylpyruvic acid and some of its antioxidant and spectroscopic properties have been measured and compared to that of ascorbic acid. 1 is as good an antioxidant as ascorbic acid in the DPPH (2,2-diphenyl-1-picryl hydrazyl radical) test and the inhibition of hydroxyl radical and a powerful inhibitor of the Cu(2+) or AAPH (2,2'-azobis-(2-amidinopropane) dihydrochloride) induced oxidation of human LDL. 1 gives a stable radical characterised by its ESR spectrum similarly to ascorbic acid but in lower concentration and with a different reactivity towards nitroxides. Theoretical calculations allow us to propose the structure for the radical formed from 1, to explain its lower stability than ascorbyl radical and to evaluate the lipophilicity of 1.     

Synthesis,radioprotective activity and pharmacokinetics characteristic of a new stable nitronyl nitroxyl radical-NIT2011

A new stable nitronyl nitroxyl radical NIT2011 was synthesized and characterized. The radioprotective effect and pharmacokinetics profiles of NIT2011 were investigated. The results showed that when irradiation exposure dose was 6.5 Gy gama radiation, the survival rate in the irradiation-only group was 20% on 30th day. The survival rate was 70%, 80%, and 90% on 30th day when mice were pretreated with 0.25, 0.5 and 1.0 mmol/kg NIT2011, respectively. The pretreatment of NIT2011 increased number of spleen colonies, the numbers of bone marrow cells and protein level in bone marrow cells. Pretreatment with NIT2011 prior to radiation exposure increased the plasma SOD (superoxide dismutase) activity. 24 h after irradiation exposure, level of plasma MDA (malondialdehyde) in irradiation-only mice was 14.8 ± 2.8 nmol/mL, level of plasma MDA in NIT2011 (1 mmol/kg) pretreated mice was 9.8 ± 2.0 nmol/mL. Three days after irradiation exposure, the micronucleus ratio in irradiation-only mice is 40.2 ± 3.6, the micronucleus ratio in NIT2011 (1 mmol/kg) pretreated mice was 11.7 ± 1.2. NIT2011 was easily absorbed in mice after it was oral administrated. Compared with the intraperitoneal injection, the relative oral bioavailability of the NIT2011 was 27.5% in mice. The LD₅₀ of NIT2011 was 1510 mg/kg in mice by oral administration. Thus, NIT2011 has potential in being developed as an oral dosage form, safe and effective radioprotective agent.     

Luplatex and its radioprotective properties

In experimental conditions the radioprotective properties of the placental complex Luplatex created in Scientific production complex "Biotechindustry" was studied. In experiments on mice F1(CBA x C57Bl) it was shown that Luplatex injected intraperitoneally in dose 0.5 ml 5-10 min before or after whole body gamma-irradiation with 8 Gy (LD80/30) increased the survival up to 40% as compared to the control group. In white mice protected by oral administration of Luplatex 30 min before exposure to 7.5 Gy, which is absolute minimal lethal dose for this type of mice (LD100/30), the effect was 48.3%.     

Synthesis and antioxidant properties of dendritic polyphenols

Three dendritic polyphenols (generation 1) were synthesized: a syringaldehyde-based dendrimer (1), a vanillin-based dendrimer (2), and an iodinated vanillin-based dendrimer (3). They all showed strong antioxidant activity according to the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical assay. The syringaldehyde dendrimer was twice and 10 times stronger than quercetin and Trolox, respectively. The vanillin-based dendrimer and its more hydrophobic iodinated derivative were also more potent antioxidants than quercetin and Trolox. The DPPH order of potency was 1 > 2, 3 > quercetin > Trolox. All three dendrimers also protected human LDL from free radical attack in a dose-dependent manner. Their order of free radical scavenging was 1 > 3 > 2 > quercetin > Trolox. The increased hydrophobic nature of the iodinated derivative may have contributed to its better LDL protection than 2. Protection of linoleic acid oxidation was studied by the β-carotene–linoleate assay. Dendrimer 1 was clearly superior to the other antioxidants in protecting the fatty acid. In case of DNA protection against free radical damage, the order of activity was 1 > quercetin > 2 > 3, Trolox. Pro-oxidant effect on copper-induced DNA oxidation showed the following order: quercetin, Trolox > 1 > 2 > 3. Results of the study show that dendritic antioxidants, even at the generation 1 level, provide promising antioxidant properties for their potential use as drug candidates for diseases associated with oxidative stress.     

Synthesis and antioxidant properties of pulvinic acids analogues

The synthesis of three types of pulvinic acid analogues, using a diversity-oriented strategy starting from a single compound, dimethyl l-tartrate, is described. Lacey-Dieckmann condensation, alcohol dehydration and Suzuki-Miyaura cross-couplings were employed in the course of the analogues syntheses. The evaluation of the antioxidant properties of the 28 synthesized analogues was carried out using antioxidant capacity assays (protection of thymidine and β-carotene) and free radical scavenging assays (DPPH radical and ABTS radical cation). This allowed to assess the relative influence of the groups bonded to the tetronic ring and to the exocyclic double bond on the activity, as well as the importance of this exocyclic double bond. It was shown that the presence of an electron-donating group on the 3-position of the tetronic ring had a beneficial effect. It was shown in several assays that the presence of the exocyclic bond was not crucial to the activity.     

Synthesis and antioxidant properties of novel benzimidazole derivatives

Some novel benzimidazole derivatives carrying thiosemicarbazide and triazole moieties at the N1 position were synthesized and their in vitro effects on rat liver microsomal NADPH-dependent lipid peroxidation (LP) levels determined by measuring the formation of 2-thiobarbituric acid reactive substance. The free radical scavenging properties of the compounds were also examined in vitro by determining the capacity to scavenge superoxide anion formation and the interaction with the stable free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). The compounds showed a significant effect in the above tests except to scavenge superoxide anion formation.     

Synthesis and antioxidant activity of new lipophilic dihydropyridines

Dihydropyridines (DHPs) obtained from Hantzsch multicomponent reactions are an important pharmaceutical class of compounds marketed as antihypertensive (e.g., nifedipine, nitrendipine, and amlodipine) drugs. This study synthesized new symmetrical and unsymmetrical long-chain fatty DHPs using multicomponent reactions under metal-free conditions with sulfamic acid as a catalyst. The DHPs were tested for antioxidant activity using three different methods. The insertion of a long chain into the DHP core contributed to antioxidant potential, and compounds derived from nitro aldehydes have better antioxidant potential than the antihypertensive drug nifedipine. In addition, fatty analogs to nifedipine derived from palmitic and oleic chains showed similar antioxidant activity to the common standards butylated hydroxytoluene and vitamin E. These results showed that our new synthesized products may find novel applications as antioxidant additives or for tools for use in drug discovery.     

Synthesis,molecular docking,and antioxidant activity of new fluorescent tetrafluoroterphenyl analogues

Nucleophilic aromatic substitution (S_NAr) chemistry has been applied to develop many functionalized pentafluorobenzene derivatives. Those compounds are highly specific at the para position of the fluorinated ring. Therefore, they are typical adducts for the preparation of antioxidant molecular systems. In this context, we report the use of S_NAr chemistry as a suitable and simple approach for the synthesis of fluorescent antioxidant perfluorinated materials bearing ether bonds in various para-substituted alkoxy chains and with high purity and excellent yields. The fluoroterphenyl core was prepared via alkylation, Cu(I)-assisted decarboxylation, and cross-coupling using the potassium salt of fluorobenzoate, followed by the reaction with different alcohols. The structures of the synthesized fluoroterphenyl adducts were investigated using FT-IR, ¹H NMR, ¹³C NMR, and ¹⁹F NMR spectroscopy. The emission spectra and absorption spectra showed solvatochromism. The newly prepared tetrafluoroterphenyl analogues were investigated by antioxidant examination using the 2,2-diphenyl-1-picrylhydrazyl assay. Results were compared with ascorbic acid and butylated hydroxytoluene as references, and revealed that the tetrafluoroterphenyl analogues containing a decyl chain had the highest activity, with an IC₅₀ value of 22.36 ± 0.19 g/ml. The produced tetrafluoroterphenyl analogues were used in molecular docking strategies with a Protein Data Bank protein ID 5IKQ. The antioxidant investigations and docking results were convergent.     

A new multifunctional hydroxytyrosol-clofibrate with hypolipidemic,antioxidant, and hepatoprotective effects

Oxidative stress has been regarded as the leading mechanism of the hepatotoxicity of clofibrate (CF). To achieve multifunctional novel hypolipidemic agents with hypolipidemia, antioxidant, and ameliorating liver injury, clofibric acid derivative hydroxytyrosol-clofibrate (CF-HT) was synthesized by molecular hybridization. CF-HT exhibited significant hypolipidemia, reducing serum triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 30%, 33%, and 29% in hyperlipidemic mice induced by Triton WR 1339. CF-HT also shown hepatoprotective effect, a significant decrease in hepatic indices toxicity was observed, i.e. aspartate and lactate transaminases (AST and ALT) activities, alkalines phosphatases (ALP), and total bilirubin (TBIL) levels. The liver weight and liver coefficient were also ameliorated. Serum superoxide dismutase (SOD) was significantly elevated, and serum catalase (CAT) and malondialdehyde (MDA) content were remarkably restored. The hepatic glutathione (GSH) content was obviously increased and hepatic oxidized glutathione (GSSG) content was reduced dramatically by CF-HT, as compared to the CF treated mice (p?<?0.05). Moreover, the histopathological damage that hepatocyte hyperplasia and hypertrophy was also significantly ameliorated by treatment with CF-HT. Therefore, the results indicated that CF-HT exerted more potent hypolipidemic activity and definite hepatoprotective effect which may mainly be associated with its antioxidative property in mice.     

Synthesis and properties of 11-(3,5-di-tert-butyl-2-hydroxyphenylcarbamoyl)undecanoic acid,a new amphiphilic antioxidant

Based on the membrane addressing concept, designing and synthesis of 11-(3,5-di-tert-butyl-2-hydroxyphenylcarbamoyl)undecanoic acid have been carried out. Antioxidant properties of the prepared compound were investigated in comparison with its non-amphiphilic analogues.     

Synthesis of new morpholine-connected pyrazolidine derivatives and their antimicrobial,antioxidant, and cytotoxic activities

A simple and convenient one-pot four-component synthesis of morpholine-connected pyrazolidine derivatives 2a–f and 4a–f was developed using direct metal-free catalysis, with the identities of the synthesized compounds confirmed by IR, NMR (¹H and ¹³C), mass spectrometry, and elemental analysis. The prepared compounds were inspected for antimicrobial, antioxidant, and cytotoxic activities.Antimicrobial and antifungal activities against five bacterial and four fungal pathogens, respectively, were investigated using the disc diffusion technique. In antibacterial activity, compounds 2d and 2f (MIC = 2 μg/mL) exhibited significantly higher activity than the standard ciprofloxacin. The results of antifungal assay showed that the activity of compound 4a (MIC = 0.5 μg/mL) was significantly higher than the standard clotrimazole. Antioxidant activity was screened based on ABTS⁺ radical scavenging and linoleic acid peroxidation performance. Compound 4a showed substantial antioxidant (91.3%) activities, as compared with the Trolox standard. Cytotoxicity was evaluated using HepG2 (liver), HeLa (cervical), and MCF-7 (breast) cancer cell lines, with high toxicities observed for 2b (GI₅₀ = 12.2 μm) and 4a (GI₅₀ = 07.8 μm).     

Synthesis and radioprotective effects of novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opening derivatives

As the potential risk of radiation exposure is increasing, radioprotectors studies are gaining importance. In this study, novel hybrid compounds containing edaravone analogue and 3-n-butylphthalide ring-opening derivatives were synthesized, and their radioprotective effects were evaluated. Among these, compound 10a displayed the highest radioprotective activity in IEC-6 and HFL-1 cells. Its oral administration increased the survival rates of irradiated mice and alleviated total body irradiation (TBI)-induced hematopoietic damage by mitigating myelosuppression and improving hematopoietic stem/progenitor cell frequencies. Furthermore, 10a treatment prevented abdominal irradiation (ABI)-induced structural damage to the small intestine. Experiment results demonstrated that 10a increased the number of Lgr5⁺ intestinal stem cells, lysozyme⁺ Paneth cells and Ki67⁺ transient amplifying cells, and reduced apoptosis of the intestinal epithelium cells in irradiated mice. Moreover, in vitro and in vivo studies demonstrated that the radioprotective activity of 10a is associated to the reduction of oxidative stress and the inhibition of DNA damage. Furthermore, compound 10a downregulated the expressions of p53, Bax, caspase-9 and caspase-3, and upregulated the expression of Bcl-2, suggesting that it could prevent irradiation-induced intestinal damage through the p53-dependent apoptotic pathway. Collectively, these findings demonstrate that 10a is beneficial for the prevention of radiation damage and has the potential to be a radioprotector.     

Hemopoiesis stimulating and radioprotective effects of carboxymethylglucan.

Carboxymethylglucan, a novel soluble derivative of beta-1,3-glucan, was found to enhance hemopoietic recovery in sublethally gamma-irradiated mice and to increase survival in lethally irradiated animals when given 24 hours prior to irradiation. Postirradiation treatment with carboxymethylglucan also induced favourable effects in terms of survival when used in combination with preirradiation cystamine administration.     

Synthesis and pharmacochemical study of novel polyfunctional molecules combining anti-inflammatory, antioxidant, and hypocholesterolemic properties

We have designed and synthesized a series of novel molecules having a residue of a classical NSAID and an antioxidant moiety, both attached through amide bonds to a known nootropic structure, an L-proline, trans-4-hydroxy-L-proline or DL-pipecolinic acid residue. The compounds were found to retain anti-inflammatory and antioxidant activities, to acquire hypocholesterolemic action, and to possess a greatly reduced gastrointestinal toxicity. The novel molecules could find useful applications, among others, in slowing the progression or delaying the onset of neurodegenerative diseases.     

Synthesis and antioxidant properties of substituted 2-phenyl-1H-indoles

In this study, we report the design, synthesis and antioxidant activity of a series of substituted 2-(4-aminophenyl)-1H-indoles and 2-(methoxyphenyl)-1H-indoles. The new compounds are structurally related to the known indole-based antioxidant lead compound melatonin (MLT), and the antitumour 2-(4-aminophenyl)benzothiazole and 2-(3,4-dimethoxyphenyl)benzothiazole series. Efficient access to the target 2-phenylindoles was achieved via Fischer indole synthesis between substituted phenylhydrazines and acetophenones. 2-(4-Aminophenyl)indoles (such as the 6-fluoro analogue 3b) in particular showed potent antioxidant activity in the DPPH and superoxide radical scavenging assays (80% and 81% inhibition at 1 mM concentration of 3b, respectively), at a level comparable with the reference standard MLT (98% and 75% at 1 mM).     

New silibinin glyco-conjugates: Synthesis and evaluation of antioxidant properties

New silibinin glyco-conjugates have been synthesized by efficient method and in short time. Exploiting our solution phase strategy, several structurally diverse silibinin glyco-conjugates (gluco, manno, galacto, and lacto-) were successfully realized in very good yields and in short time. In preliminary study to evaluate their antioxidant and neuroprotective activities new derivatives were subjected to DPPH free radical scavenging assay and the Xanthine oxidase (XO) inhibition models assay. Irrespective of the sugar moiety examined, new glyco-conjugates are more than 50 times water-soluble of silibinin. In the other hand they exhibit a radical scavenging activities slightly higher than to silibinin and XO inhibition at least as silibinin.