Izabel C.P.P. Frugulhetti

Anti-HSV-1 and anti-HIV-1 activity of gallic acid and pentyl gallate

The synthetic n-alkyl esters of gallic acid (GA), also known as gallates, especially propyl, octyl and dodecyl gallates, are widely employed as antioxidants by food and pharmaceutical industries. The inhibitory effects of GA and 15 gallates on Herpes Simplex Virus type 1 (HSV-1) and Human Immunodeficiency Virus (HIV-1) replication were investigated here. After a preliminary screening of these compounds, GA and pentyl gallate (PG) seemed to be the most active compounds against HSV-1 replication and their mode of action was characterized through a set of assays, which attempted to localize the step of the viral multiplication cycle where impairment occurred. The detected anti-HSV-1 activity was mediated by the inhibition of virus attachment to and penetration into cells, and by virucidal properties. Furthermore, an anti-HIV-1 activity was also found, to different degrees. In summary, our results suggest that both compounds could be regarded as promising candidates for the development of topical anti-HSV-1 agents, and further studies concerning the anti-HIV-1 activity of this group of molecules are merited.

Antibacterial profile against drug-resistant Staphylococcus epidermidis clinical strain and structure-activity relationship studies of 1H-pyrazolo(3,4-b)pyridine and thieno(2,3-b)pyridine derivatives

Antibacterial resistance is a complex problem that contributes to health and economic losses worldwide. The Staphylococcus epidermidis is an important nosocomial pathogen that affects immunocompromised patients or those with indwelling devices. Currently, there are several resistant strains including S. epidermidis that became an important medical issue mainly in hospital environment. In this work, we report the biological and theoretical evaluations of a 4-(arylamino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acids series (1, 1a-m) and the comparison with a new isosteric ring nucleus series, 4-(arylamino)thieno[2,3-b]pyridine-5-carboxylic acids derivatives (2, 2a-m). Our results revealed the 1H-pyrazolo[3,4-b]pyridine derivatives significant antibacterial activity against a drug-resistant S. epidermidis clinical strain in contrast to the thieno[2,3-b]pyridine series. The minimal inhibitory concentration (MIC) of the most active derivatives (1a, 1c, 1e, and 1f) against S. epidermidis was similar to that of oxacillin and twofold better than chloramphenicol. Interestingly, the position of the functional groups has a great impact on the activity as observed in our structure-activity relationship (SAR) study. The SAR of 1H-pyrazolo[3,4-b]pyridine derivatives shows that the highest inhibitory activity is observed when the meta position is occupied by electronegative substituents. The molecular modeling analysis of frontier molecular orbitals revealed that the LUMO density is less intense in meta than in ortho and para positions for both series (1 and 2), whereas HOMO density is overconcentrated in 1H-pyrazolo[3,4-b]pyridine ring nucleus compared to the thieno[2,3-b]pyridine system. The most active derivatives of series 1 were submitted to in silico ADMET screening, which confirmed these compounds as potential antibacterial candidates.

Human papillomavirus infection and cervical cancer in Brazil: a retrospective study

Two hundred and thirty paraffin-embedded biopsies obtained from female cervical lesions were tested for the presence of human papillomavirus (HPV) types 6/11, 16/18 and 31/33/35 DNA using non-isotopic in situ hybridization. Specimens were classified according to the Bethesda System in low grade squamous intraepithelial lesion (LSIL), high grade SIL (HSIL) and squamous cell carcinoma (SCC). HPV prevalence ranged from 92.5% in LSIL to 68.5% in SCC. Benign types were prevalent in LSILs while oncogenic types infected predominantly HSILs and SCC. HPV infection showed to be age-dependent, but no significant relation to race has been detected. Patients were analyzed through a five-year period: 20.7% of the lesions spontaneously regressed while 48.9% persisted and 30.4% progressed to carcinoma. Patients submitted to treatment showed a 19.4% recurrence rate. High risk types were present in 78.6% (CrudeOR 13.8, P = 0.0003) of the progressive lesions, and in 73.7% of the recurrent SILs (COR 19.3, P = 0.0000001). Possible co-factors have also been evaluated: history of other sexually transmitted diseases showed to be positively related either to progression (Adjusted OR 13.0, P = 0.0002) or to recurrence (AOR 17.2, P = 0.0002) while oral contraceptive use and tobacco smoking were not significantly related to them (P > 0.1). Association of two or more co-factors also proved to be related to both progression and recurrence, indicating that they may interact with HPV infection in order to increase the risk of developing malignant lesions.

Synthesis and antiviral activities of new pyrazolo[4,3-c]quinolin-3-ones and their ribonucleoside derivatives.

Several new pyrazolo[4,3‐c]quinolin‐3‐one ribonucleosides (5a–g) and their corresponding heterocycle moieties (3a–g) were synthesized and evaluated against vaccinia virus (VV) and herpes simplex virus type 1 (HSV‐1). The derivatives 3c and 3d showed modest inhibitory activity against vaccinia virus reaching 70% at a concentration of 100 µM. All heterocyclic compounds (3a–f) showed a modest inhibition against HSV‐1, reaching the maximal inhibitory effect around 20–30%. The antiviral effects of most of the pyrazolo[4,3‐c]quinolin‐3‐one ribonucleosides (5a–f) on VV and HSV were not impressive.

Synthesis of novel nucleosides of 4‐oxoquinoline‐3‐carboxylic acid analogues

A series of new ribonucleosides 1a–d having 4-oxoquinoline-3-carboxylic acid substituted with a chloro or bromo atom in the aromatic ring, as the nitrogen base, was synthesized and examined for anti-HIV activity. Compounds 1a and 1c showed a modest inhibition activity on HIV-1 reverse transcriptase, inhibiting 10% of the enzyme activity at the concentration of 100 μM.

Prevalence of human papillomavirus DNA in female cervical lesions from Rio de Janeiro, Brazil

A hundred-sixty paraffin-embedded specimens from female cervical lesions were examined for human papillomavirus (HPV) types 6, 11, 16 and 18 infections by non-isotopic in situ hybridization. The data were compared with histologic diagnosis. Eighty-eight (55%) biopsies contained HPV DNA sequences. In low grade cervical intraepithelial neoplasias (CIN I), HPV infection was detected in 78.7% of the cases, the benign HPV 6 was the most prevalent type. HPV DNA was detected in 58% of CIN II and CIN III cases and in 41.8% of squamous cell carcinomas (SCC). Histologically normal women presented 20% of HPV infection. Oncogenic HPV was found in 10% of these cases, what may indicate a higher risk of developing CINs and cancer. Twenty-five percent of the infected tissues contained mixed infections. HPV 16 was the most common type infecting the cervix and its prevalence raised significantly with the severity of the lesions, pointing its role in cancer pathogenesis. White women presented twice the cervical lesions of mulatto and African origin women, although HPV infection rates were nearly the same for the three groups (approximately 50%). Our results showed that HPV typing by in situ hybridization is a useful tool for distinguishing between low and high risk cervical lesions. Further studies are required to elucidate risk factors associated with HPV infection and progression to malignancy in Brazilian population.

Dictyota dolabellana sp. nov. (Dictyotaceae, Phaeophyceae) based on morphological and chemical data

Abstract Dictyota dolabellana De Paula, Yoneshigue-Valentin et Teixeira is a new species of Dictyotaceae from the South Atlantic Ocean and the first denticulate species in which dolabellane diterpenes have been found. The major compound found in this species is the 4-hydroxy-7,8-epoxy-2-dolabellene. Until now, all populations of thalli containing dolabellane diterpenes had smooth margins and all species with denticulate margins produced prenylated guaiane and xeniane diterpenes. In addition, Dictyota dolabellana differs from other species by the presence of an inconspicuous denticulation irregularly located in the central to upper portions of the frond. Morphological and chemical data and comparison with type materials of other species clearly indicate the presence of a new species.

The chloroxoquinolinic derivative 6-chloro-1,4-dihydro-4-oxo-1-(β-D-ribofuranosyl) quinoline-3-carboxylic acid inhibits HSV-1 adsorption by impairing its adsorption on HVEM

SummaryIn this paper, we describe that the oxoquinolinic acid derivative (compound A) inhibited HSV-1 adsorption on Vero cells. This effect was achieved with an EC50 value of 10 ± 2.0 µM and with low cytotoxicity, since the CC50 value for compound A was >1000 µM. Moreover, we demonstrate for the first time that adsorption inhibition was due to the blockage of the interactions between HSV-1 and the cellular receptor herpes virus entry mediator (HVEM). These results show that compound A can prevent HSV-1 infection in Vero cells, encouraging further studies to determine at what level compound A inhibits HSV-1-HVEM interactions.

Determinação de autoanticorpos para antígenos da mielina no soro de pacientes HLA - DQB1*0602 com esclerose múltipla

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the human central nervous system (CNS) mediated by autoimmune Th1 lymphocytes. We determined the serum levels of autoantibodies for myelin basic protein (MBP), proteolipid (PLP) and myelin oligodendrocyte glycoprotein sequence MOG 92-106 in a group of 54 healthy individuals and 26 MS patients expressing or not HLA-DQB1*0602. Regardless expression of the susceptibility allele DQB1*0602, MS patients presented marked (p<0.0001) IgG antibody production for MBP and MOG92-106. Yet, significant (p<0.0001) IgA antibody levels were mainly observed for PLP and MOG antigens. Our results suggest that other HLA class II alleles may be conferring susceptibility to MS in this population and influencing the pattern of immune recognition of encephalitogen antigens. Furthermore, distinct IgG and/or IgA autoantibody production may be contributing to the control or maintenance of the CNS inflammatory reaction.

SYNTHESIS AND ANTIVIRAL EVALUATION OF ISATIN RIBONUCLEOSIDES

ABSTRACT A series of novel substituted isatin ribonucleosides 3b–3f were synthesized in good yields by a TMSOTf catalysed coupling reaction between the silylated nitrogenated base (1b–1f) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (2). Isatin nucleoside 3a previously reported was also prepared using this method giving high yield. From the compounds tested, ribonucleoside 3f proved to be the most active one when assayed for antiviral activitiy on HSV-1 infected cells, leading to 66% of inhibition of virus yield. All the isatin derivatives tested did not inhibit HIV-1 Reverse Transcriptase (RT) activity.