Design, Synthesis, Docking Studies, and Biological Evaluation of Novel 2-Hydroxyacetophenone Derivatives as Anti-HIV-1 Agents.

BACKGROUND: The persistence of HIV mutations and the existence of multidrug resistance have produced an opportunity for an array of innovative anti-HIV medicines with a variety of structures that target HIV key enzymes. OBJECTIVE: The goal of this work was to find a new class of anti-HIV drugs founded on HIV integrase inhibitor pharmacophores. METHODS: A novel class of 2-hydroxy acetophenone analogs featuring substituted benzamide or N-phenylthiourea groups was designed and synthesized based on the general pharmacophore of HIV-1 integrase inhibitors (INs). RESULTS: Most of the synthesized analogs were found to be moderately active against the virus, with EC50 values ranging from 40 to 140 µM. Additionally, it was found that most of the compounds presented no considerable cytotoxicity (CC50 > 500 µΜ). The most potent compounds substituting with 4-fluorobenzamide (compound 7) and 4-methylbenzamide (compound 9) rings inhibited the HIV-1 replication by EC50 values of 40 and 45 µΜ, respectively. Docking studies using the crystallographic data available for PFV IN indicated that the Mg2+ coordination might be the possible mechanism of the anti-viral activity. CONCLUSION: Our findings proved that the synthesized analogs may suggest a very good basis for the development of new anti-HIV-1 agents.

Design, Synthesis, and Docking Studies of Thioimidazolyl Diketoacid Derivatives Targeting HIV-1 Integrase.

BACKGROUND: Integrase enzyme is a validated drug target to discover novel structures as anti-HIV-1 agents. OBJECTIVE: This study aimed at developing a novel series of thioimidazolyl diketoacid derivatives characterizing various substituents at N-1 and 2-thio positions of the central ring as HIV-1integrase inhibitors. METHODS: In this study, eighteen novel thioimidazolyl DKA derivatives were synthesized in a fivestep parallel procedure and tested in vitro for the inhibition of both IN ST reaction and the singlecycle HIV-1 replication in HeLa cell culture. RESULTS: The obtained molecules were evaluated using the enzyme assay, displaying promising integrase inhibitory activity with IC50 values ranging from 0.9 to 7.7 mM. The synthesized compounds were also tested for antiviral activity and cytotoxicity using HeLa cells infected by the single-cycle replicable HIV-1 NL4-3. CONCLUSION: The most potent compound was found to be 18i with EC50 = 19 µM, IC50 = 0.9 µM, and SI = 10.5. Docking studies indicated that the binding mode of the active molecule is well aligned with the known HIV-1integrase inhibitor.

Induction of Strong and Specific Humoral and T-helper 1 Cellular Responses by HBsAg Entrapped in the Methanobrevibacter smithii Archaeosomes.

BACKGROUND: Application of adjuvants with microbial origins is a recently highlighted approach in the vaccinology trials. Archaeosomes are among these microbial compounds with both adjuvant and liposomal activities and features. METHODS: In the present study, recombinant HBsAg encapsulated into Methanobrevibacter smithii (M. smithii) archaeosomes. Balb/c mice immunized with this compound and humoral and cytokine secretion pattern of immunized models analyzed. RESULTS: Frequency of IFN-γ secreting cells in the HBsAg-containing archaeosomes group was significantly higher than HBsAg and HBsAg(+)C/IFA groups (p≤0.05). IgG2a titer in the sera of HBsAg-containing archaeosomes group was also significantly higher than this subclass titer in the other groups (p≤ 0.05). CONCLUSION: Analysis of induced responses revealed the immunopotentiating characteristics of M. smithii archaeosomes in the induction of T-helper 1 responses according to the dominance of IgG2a subtype and IFN-γ secreting splenocytes of immunized mice.

Evaluation of human papillomavirus infections in prostatic disease: a cross-sectional study in Iran.

BACKGROUND: The role of inflammation in prostate diseases is suggested by the presence of inflammatory cells within the prostate in benign prostatic hyperplasia (BPH) and prostate cancer (PCa) patients. In addition, bacterial and viral infection may lead to chronic and recurrent inflammation of the prostate. The human papillomaviruses (HPVs) are a family of sexually transmitted viruses which have been implicated in the aetiology of cervical cancer and several other malignancies. This study evaluated the frequency of HPV infection in individuals with prostatic disease in Iran. MATERIALS AND METHODS: The study included formalin fixed paraffin- embedded tissue samples of 196 primary prostate cases, including 29 PCa and 167 BPH samples. HPV DNA was purified and amplified through MY09/MY11 and GP5+/GP6+ primers with nested PCR. All patients were interviewed using a questionnaire to collect demographic information. RESULTS: Nested PCR showed that HPV DNA was found in 17.2 percent of PCa samples and 4.8 percent of BPH samples (not significant). CONCLUSIONS: Our data do not support a significant role of HPV infection in prostatic disease in Iranian patients, but demographic data indicated a probable association between presence of HPV DNA and risk of inflammation in prostate tissue which might lead to prostate carcinoma. Further studies are required to elucidate any roles of HPV infection in prostatic disease.

Detection of rtN236T mutation associated with adefovir dipivoxil resistance in Hepatitis B infected patients with YMDD mutations in Tehran.

BACKGROUND OBJECTIVES: The risk of adefovir dipivoxil resistance emergence has increased in lamivudine-resistant hepatitis B infected patients. The mutations known as causing adefovir resistance, rtN236T and rtA181V/T, are detected within the D and B functional domain of the HBV polymerase, respectively. In this study, we intended to determine the pre-existing adefovir-resistance mutations in patients infected with LAM resistant mutants prior to starting adefovir therapy. MATERIAL AND METHODS: The study included 30 patients with chronic hepatitis B with lamivudine resistance mutations in the YMDD motif that experienced viral breakthrough. RESULTS: After alignment of protein coding sequences, the rtN236T mutation was observed in two (6.6%) patients, while twenty-eight others had neither rtN236T, nor rtA181V/T mutation. All 30 patients were infected with genotype D of hepatitis B virus. CONCLUSIONS: The early detection of LAM-resistance mutations may allow a timely chance of therapy to avoid hepatitis flare-up. This data suggests that monitoring of ADV-resistance mutations in ADV naïve patients can be considered in selecting the appropriate anti-viral regimen.