Synthesis, Biological Evaluation, and Molecular Modeling Studies of New 8-methyl-4-oxo-1,4-dihydroquinoline-3-carbohydrazides as Potential Anti-HIV Agents.

Background: The development of a highly safe and potent scaffold is a significant challenge in anti-HIV drug discovery. Objectives: This study aimed at developing a novel series of anti-HIV agents based on HIV integrase inhibitor pharmacophores. Methods: A novel series of 8-methyl-4-oxo-1,4-dihydroquinoline-3-carbohydrazide derivatives featuring various substituted benzoyl and N-phenyl carboxamide and carbothioamide moieties were designed and synthesized. Results: According to the biological evaluation, all the developed compounds were effective against HIV at concentrations lower than 150 µM, associated with no significant cytotoxicity (CC50 > 500 µM). Conclusions: Compound 8b, possessing a 4-fluorobenzoyl group, was the most potent compound, with an EC50 of 75 µM. Docking studies revealed that the binding modes of designed compounds are similar to the known HIV integrase inhibitors.

4-(1-Benzyl-1H-benzo[d]imidazol-2-yl)-4-oxo-2-butenoic Acid Derivatives: Design, Synthesis and Anti-HIV-1 Activity.

Acquired immunodeficiency syndrome (AIDS) is still an incurable disease with increasing mortality rate. Despite the development of effective FDA-approved anti-HIV drugs, there are some problems due to the growing of resistant viral strands. Therefore, discovery of novel anti-HIV agents is so needed. Integrase, targeted in highly active antiretroviral therapy (HAART), is a crucial enzyme in viral replication. In this study, new benzimidazolyl diketo acid derivatives were designed according to required features for inhibitors of HIV-1 integrase. Designed compounds were synthesized and evaluated for anti-HIV-1 effects. According to the cell-based biological assay's results, most of the tested compounds demonstrated good anti-HIV-1 activity, ranging from 40-90 µM concentration with no severe cytotoxicity. The most potent compound was 13g with EC50 value of 40 µM and CC50 value of 550 µM. Docking analysis of compound 13g in integrase active site was in good agreement with well-known integrase inhibitors, proposing that anti-HIV-1 potency of compounds may be via integrase inhibition.

Proteasome Inhibition by Carfilzomib Induced Apotosis and Autophagy in a T-cell Acute Lymphoblastic Leukemia Cell Line.

T-cell acute lymphoblastic leukemia is an aggressive hematologic malignancy which is usually associated with unfavorable prognosis particularly in patients with refractory/relapsed disease. Therefore, development of novel therapeutic strategies is highly required for improving the outcome of these patients. Although there are several studies evaluating the efficacy of proteasome inhibitors on acute lymphoblastic leukemia of B-cell lineage, the data are still limited regarding T-cell acute lymphoblastic leukemia. Here, we tried to investigate the effects of the proteasome inhibition by carfilzomib on the induction of apoptosis and autophagy in Molt4 cells. The effect of carfilzomib in combination with dexamethasone in Molt4, as a glucocorticoid-resistant T-cell acute lymphoblastic leukemia cell line, was also assessed. Our data showed that carfilzomib can induce both apoptosis and autophagy in Molt4 cells. Furthermore, we found that carfilzomib is a potent inducer of reactive oxygen species production and also induces G2/M phase cell cycle arrest in Molt4 cells. Concomitant treatment with carfilzomib and dexamethasone demonstrated that carfilzomib can synergistically enhance the cytotoxic effect of dexamethasone on Molt4 cells. Furthermore, co-treatment of the cells with carfilzomib and dexamethasone increased the induction of autophagy as compared with each drug alone. In conclusion, our results are suggestive of the effectiveness of carfilzomib on Molt4 cells as a model of GC-resistant T-cell acute lymphoblastic leukemia.

The prevalence of Human Papilloma Virus (HPV) infection in the oligospermic and azoospermic men.

BACKGROUND: Human papilloma virus (HPV) infection is one of the most common sexually transmitted diseases that affects men like women and infected cutaneous and mucosal squamous epithelium. The aim of the present study was to determine the prevalence of HPV in the semen of oligospermic, azoospermic and normal patients. METHODS: From June 2012 to June 2013, a total of 90 individuals were enrolled in this cross sectional comparative study. The participants were classified into three groups (oligospermia, azoosprmia and normal). This classification was based on a new WHO reference values for human semen characteristics published on 2010. After extraction of DNA from specimens L1 gene of HPV was amplified by nested polymerase chain reaction (Nested-PCR) and the PCR products of positive specimens were genotyped using INNO-LiPA HPV Genotyping Extra assay. RESULTS: Among 50 confirmed oligospermic male, 15 were HPV DNA positive (30%). In azoospemic group we had 8 HPV DNA positive (40%) and in normal group just 3 of 20(15%) samples were positive. Statistical assessment was done with SPSS v.15. Chi-square test showed no significant relationship between 3 groups results. Based on independent samples t-test, we found statistical significant relationship for sperm count (p<0.05) and sperm motility (slow) (p<0.05) in oligospermic group positive samples compared with negative. In the present study, 13 HPV genotypes were detected among positive samples. HPV genotypes 16, 45 in the high risk group and 6,11,42 in the low risk group were more frequent than the others. CONCLUSION: The current study shows that HPV infection can affect on sperm count and motility and decrease count of sperm cell and decrease motility capability of these cells.