Antileishmanial Activities of (Z)-2-(Nitroimidazolylmethylene)-3(2H)-Benzofuranones: Synthesis, In Vitro Assessment, and Bioactivation by NTR 1 and 2.

The antileishmanial activity of a series of (Z)-2-(heteroarylmethylene)-3(2H)-benzofuranone derivatives, possessing 5-nitroimidazole or 4-nitroimidazole moieties, was investigated against Leishmania major promastigotes and some analogues exhibited prominent activities. Compounds with IC50 values lower than 20 µM were further examined against L. donovani axenic amastigotes. Evaluated analogues in 5-nitroimidazole subgroup demonstrated significantly superior activity (~17-88-folds) against L. donovani in comparison to L. major. (Z)-7-Methoxy-2-(1-methyl-5-nitroimidazole-2-ylmethylene)-3(2H)-benzofuranone (5n) showed the highest L. donovani anti-axenic amastigote activity with IC50 of 0.016 µM. The cytotoxicity of these analogues was determined using PMM peritoneal mouse macrophage and THP-1 human leukemia monocytic cell lines and high selectivity indices of 26 to 431 were obtained for their anti-axenic amastigote effect over the cytotoxicity on PMM cells. Further studies on their mode of action showed that 5-nitroimidazole compounds were bioactivated predominantly by nitroreductase 1 (NTR1) and 4-nitroimidazole analogues by both NTR1 and 2. It is likely that this bioactivation results in the production of nitroso and hydroxylamine metabolites that are cytotoxic for the Leishmania parasite.

Antimalarial Activities of (Z)-2-(Nitroheteroarylmethylene)-3(2H)-Benzofuranone Derivatives: In Vitro and In Vivo Assessment and ß-Hematin Formation Inhibition Activity.

A series of (Z)-2-(nitroheteroarylmethylene)-3(2H)-benzofuranones possessing nitroheteroaryl groups of nitroimidazole, nitrofuran, and nitrothiophene moieties was screened for antiplasmodium activity against a drug-sensitive strain (3D7 strain) and a multidrug-resistant (chloroquine [CQ] and pyrimethamine) strain (K1 strain) of Plasmodium falciparum. 5-Nitroimidazole and 4-nitroimidazole analogs were highly selective and active against resistant parasites, while 5-nitrofuran and 5-nitrothiophene derivatives were more potent against the 3D7 strain than against the K1 strain. Among the synthetic analogues, (Z)-6-chloro-2-(1-methyl-5-nitroimidazol-2-ylmethylene)-3(2H)-benzofuranone (compound 5h) exhibited the highest activity (50% inhibitory concentration [IC50], 0.654 nM) against the K1 strain and (Z)-7-methoxy-2-(5-nitrothiophen-2-ylmethylene)-3(2H)-benzofuranone (10g) showed the highest activity (IC50, 0.28 µM) against the 3D7 strain in comparison with the activities of CQ (IC50s of 3.13 and 206.3 nM against 3D7 and K1 strains, respectively). The more active compounds, with IC50s lower than 5 µg/ml (∼20 µM), were further studied for their cytotoxicity responses using KB cells. From these studies, 5-nitroimidazole, 4-nitroimidazole, and 5-nitrofuran analogues were shown to be cytotoxic against KB cells, while 5-nitrothiophene analogues were shown to have the least cytotoxic effects. To gain some insight into their potential contributing mechanisms of action, three derivatives, 10e, 10g, and 10h (from the nitrothiophene subgroup, possessing 6-methoxy, 7-methoxy, and 6,7-dimethoxy substituents, respectively, on their benzofuranone moieties), showing the least toxicity and highest selectivity indices were assessed for their ß-hematin formation inhibition activity. Compound 10g demonstrated the highest inhibition activity (IC50, 10.78 µM) in comparison with that of CQ (IC50, 2.63 µM) as the reference drug. Finally, these three analogues (10e, 10g, and 10h) were further evaluated for their in vivo activities against the Plasmodium berghei/albino mouse model (Peter's test). The tested analogues were shown to be active, reducing the percentages of erythrocytes that contained parasites by 53.4, 48.8, and 32.4%, respectively.

Internet-Delivered Versus Face-to-Face Cognitive Behavior Therapy for Anxiety Disorders: Systematic Review and Meta-Analysis.

BACKGROUND: Over the last 20 years, internet-delivered cognitive behavior therapy (ICBT) has been tested in a large number of randomized controlled trials, often with positive results. However, it is not widely known about the efficacy of ICBT as compared to face-to-face cognitive behavior therapy (CBT). METHODS: In the present systematic review and meta-analysis, ICBT for treatment of anxiety disorders was directly compared to face- to-face CBT within the same trial. This study aimed to reinvestigate the effect of ICBT compared to face-to-face CBT for anxiety disorders. A total of 8 studies out of the 236 articles screened met all the inclusion criteria. The included studies targeting five different anxiety disorders, social anxiety disorder, adolescent anxiety, panic disorder, spider phobia, and fear of public speaking, had been carried out in Australia, Spain, and Sweden. The total number of participants was 348 in ICBT and 316 in face-to-face conditions. RESULTS: The results of our meta-analysis are interesting both from theoretical and practical standpoints, which showed a pooled effect size posttreatment with Hedges' g = 0.01 (95% CI: -0.16 to 0.18). CONCLUSIONS: ICBT and face-to-face CBT created equivalent overall effects. in treatment of anxiety disorders. Since there have been similar systematic reviews about anxiety disorders so far, and in majority of them, ICBT has not been compared against face-to-face treatment. More research is needed to establish the general equivalence of the two treatment formats. Also, understanding what makes ICBT work is a challenge for future research.

The relationship between social anxiety and online communication among adolescents in the city of isfahan, iran.

BACKGROUND: The internet is a phenomena that changes human, specially the younger generation's, life in the 21(st) century. Online communication is a common way of interacting among adolescents who experience feelings of social anxiety. The aim of this study was to investigate the relationship between social anxiety and online communication in adolescents. METHODS: Three hundred and thirty students aged 13-16 years were selected from eight middle and high schools in Isfahan by multistage cluster sampling. Each of them completed a survey on the amount of time they spent communicating online, the topics they discussed, the partners they engaged with and their purpose for communicating over the internet. They also completed the social anxiety scale of adolescents. Data were analyzed using Pearson correlation and multiple regression. RESULTS: Results of the Pearson analysis showed that online communication has a significant positive relationship with apprehension and fear of negative evaluation (AFNE), and a significant negative relationship with tension and inhibition in social contact (TISC) (P < 0.01). The results of regression analysis showed that the best predictor of online communication is AFNE, TISC. CONCLUSIONS: It is suggested that students from middle school get assessed in terms of the level of social anxiety. Then, the quality and quantity of their online communication should be moderated through group training and consulting and referral to medical centers, if needed. The results of this study may lead to optimal use of online communications and reduce the personal, social and psychological problems of adolescents.

Synthesis, antibacterial activity, and quantitative structure-activity relationships of new (Z)-2-(nitroimidazolylmethylene)-3(2H)-benzofuranone derivatives.

A new series of (Z)-2-(1-methyl-5-nitroimidazole-2-ylmethylene)-3(2H)-benzofuranones (11a-p) and (Z)-2-(1-methyl-4-nitroimidazole-5-ylmethylene)-3(2H)-benzofuranones (12a-m) were synthesized and assayed for their antibacterial activity against Gram-positive and Gram-negative bacteria. Most of the 5-nitroimidazole analogues (11a-p) showed a remarkable inhibition of a wide spectrum of Gram-positive bacteria (Staphylococcus aureus, Streptococcus epidermidis, MRSA, and Bacillus subtilis) and Gram-negative Klebsiella pneumoniae, whereas 4-nitroimidazole analogues (12a-m) were not effective against selected bacteria. The quantitative structure-activity relationship investigations were applied to find out the correlation between the experimentally evaluated activities with various parameters of the compounds studied. The QSAR models built in this work had reasonable predictive power and could be explained by the observed trends in activities.