Synthesis and biological evaluation of new quinoline-4-carboxylic acid-chalcone hybrids as dihydroorotate dehydrogenase inhibitors.

Fourteen novel quinoline-4-carboxylic acid-chalcone hybrids were obtained via Claisen-Schmidt condensation and evaluated as potential human dihydroorotate dehydrogenase (hDHODH) inhibitors. The ketone precursor 2 was synthesized by the Pfitzinger reaction and used for further derivatization at position 3 of the quinoline ring for the first time. Six compounds showed better hDHODH inhibitory activity than the reference drug leflunomide, with IC50 values ranging from 0.12 to 0.58 µM. The bioactive conformations of the compounds within hDHODH were resolved by means of molecular docking, revealing their tendency to occupy the narrow tunnel of hDHODH within the N-terminus and to prevent ubiquinone as the second cofactor from easily approaching the flavin mononucleotide as a cofactor for the redox reaction within the redox site. The results of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that 4d and 4h demonstrated the highest cytotoxic activity against the A375 cell line, with IC50 values of 5.0 and 6.8 µM, respectively. The lipophilicity of the synthesized hybrids was obtained experimentally and expressed as logD7.4 values at physiologicalpH while the solubility assay was conducted to define physicochemical characteristics influencing the ADMET properties.

Intergeneration Transmission of Violence in Forensic Patients With a Diagnosis of Schizophrenia and Psychosis: Was Parental Alcoholic Abuse a Significant Factor?

Background: Child abuse during childhood and the presence of parental alcohol abuse increase the risk of developing mental illness in children, as well as the risk of violent behavior in adulthood. The association of these factors has not been sufficiently investigated when it comes to forensic mental patients. In this study, we examined the impact of traumatic events in childhood and the presence of mental illness and alcohol abuse of parents in subjects with psychosis and schizophrenia who committed serious crimes. Methods: One-hundred and forty-three respondents were included in the current study. Information on childhood abuse was collected by Childhood Trauma Questionnaire (CTQ). The sample included participants diagnosed with psychotic disorders and schizophrenia with a history of violent behavior (PSCH-V, n = 20), patients diagnosed with psychotic disorders and schizophrenia without a history of violent behavior (Non-V-PSCH, n = 51), and healthy control patients (HC, n = 72). Participants were diagnosed according to the ICD 10 classification system. MINI and CAINS scales were used to confirm the diagnosis. Data on sociodemographic and clinical characteristics were collected. Differences between groups in terms of traumatic events in childhood as well as parental alcohol abuse are presented and analyzed, using descriptive statistical values and nonparametric techniques of inferential statistics. Results: Statistically significant differences were obtained for total scores (χ2 = 28.522, p < 0.001) as well as for (1) major upheaval between the parents (χ2 = 20.739, p < 0.001), (2) being victim of violence-other than sexual (χ2 = 12.701, p < 0.01), and (3) other major upheaval that may have shaped life or personality significantly (χ2 = 30.920, p < 0.001). PSCH-V, compared to HC, had greater exposure to all of the three domains of childhood trauma (U = 396.500, 436.500, and 376.000, respectively; p < 0.001). Similar results were obtained when Non V-PSCH were compared with HC (U = 1,223.000, 1,535.000, and 999.000, respectively; p < 0.001). The results indicated statistically insignificant differences between PSCH-V and Non-V-PSCH in having a family history of mental illness. On the other hand, family history of mental illness was less present in HC compared to PSCH-V (χ2 = 24.238, p < 0.001) and Non V-PSCH (χ2 = 14.456, p < 0.001). The presence of parental alcohol abuse was predominantly present in the PSCH-V group (60%) while a significantly lower presence was found in the Non-V PSCH group (35%) and HC (5.5%). Conclusion: Both PSCH-V and Non-V-PSCH groups had a high degree of exposure to traumatic events in childhood compared to the HC. In PSCH-V, the presence of parental alcohol abuse compared to Non-V-PSCH was dominant. Mental illness coupled with a history of violent behavior represents a factor of polyvictimization, which may increase the likelihood of violent behavior of offspring.

Low cytotoxic quinoline-4-carboxylic acids derived from vanillin precursors as potential human dihydroorotate dehydrogenase inhibitors.

Twenty novel 2-substituted quinoline-4-carboxylic acids bearing amide moiety were designed and synthesized by Doebner reaction. Human dihydroorotate dehydrogenase (hDHODH) was recognized as a biological target and all compounds were screened as potential hDHODH inhibitors in an enzyme inhibition assay. The prepared heterocycles were also evaluated for their cytotoxic effects on the healthy HaCaT cell line while lipophilic properties were considered on the basis of experimentally determined logD values at physiological pH. The most promising compound 5j, with chlorine at para-position of terminal phenyl ring, showed good hDHODH inhibitory activity, low cytotoxicity, and optimal lipophilicity. The bioactive conformation of 5j on the hDHODH, determined by means of molecular docking, revealed the compound's pharmacology and provide guidelines for further lead optimization.

The prevalence of 30 HPV genotypes detected by EUROArray HPV in cervical samples among unvaccinated women from Vojvodina province, Serbia.

This study evaluates the pre-vaccination prevalence of HPV infection in women from Vojvodina, Serbia, according to age and cytological status. A total of 1,495 women, ranging from 18 to 65 years of age, with different cytological results were enrolled. The HPV genotyping assay was performed using the EUROArray HPV test in order to detect thirty genitally relevant HPV subtypes. In our study, the most prevalent genotypeswere HPV 16, 31, 51, and 53. Among these, HPV 16 was consistently present in all cytological subgroups. Twelve HPV genotypes classified as carcinogenic to humans (Group 1) were detected in 77.8.0% of HSIL/ASCH and 55.0% of NILM with abnormal colposcopy findings. Six possible carcinogens-HRs (group 2B) were often found in women with normal cytology (14.8%) and mild abnormalities (ASCUS and LSIL), but with lower frequence in HSIL/ASCH lesions (7.1%). HPVs 6 and 11(Group 3) were not found in the cases of HSIL/ASCH. Unclassified HPV types were equally distributed in all cytology groups: 20.7%, 19.1%, 16.3% and 13% of NILM, ASCUS, LSIL and HSIL/ASCH, respectively. Our findings highlight that majority of abnormal Pap test results are caused by Group 1 HPVs among women from our region. Low frequency HPVs of group 2A/2B, especially HSIL/ASCH, supports the conclusion that individual genotypes require consideration of each type as an individual agent. We expect a positive impact of HPV vaccine in reducing HPV-associated cervical lesions among women from Vojvodina province, after establishing vaccination programs in our country.

Potent human dihydroorotate dehydrogenase inhibitory activity of new quinoline-4-carboxylic acids derived from phenolic aldehydes: Synthesis, cytotoxicity, lipophilicity and molecular docking studies.

A series of novel 2-substituted quinoline-4-carboxylic acids was synthesized by Doebner reaction starting from freely available protocatechuic aldehyde and vanillin precursors. Human dihydroorotate dehydrogenase (hDHODH) was recognised as a clear molecular target for these heterocycles. All compounds were also tested for their antiproliferative potential against three cancer cells (MCF-7, A549, A375) and one normal cell line (HaCaT) to evaluate the selective cytotoxicity. Quinoline derivatives 3f and 3g were identified as potent hDHODH inhibitors while 3k and 3l demonstrated high cytotoxic activity against MCF-7 and A375 cells and good selectivity. In addition, the logD7.4 values obtained by the experimental method were found to be in the range from -1.15 to 1.69. The chemical structures of all compounds were confirmed by IR, NMR and elemental analysis. The compounds pharmacology on the molecular level was revealed by means of molecular docking, highlighting the structural differences that distinguish highly active from medium and low active hDHODH inhibitors.

Micro-elimination of HCV as a possible therapeutic strategy: our experience and a review of literature.

BACKGROUND: Serbia has an intermediate estimated prevalence of chronic hepatitis C (CHC) infection, approximately 1.13%, with hepatitis C remaining one of the leading causes of liver-related morbidity and mortality in Serbia with impaired quality of life and overwhelming cost of treating its complications As the availability of new treatment options and resources for screening remains limited, micro-elimination of CHC becomes a top priority. METHODS: Review of the available published data related to the clinical and epidemiological situation of the hepatitis C infection in Serbia, including the unpublished data from the databases of four major reference centres in Serbia (Clinical Center Serbia, Clinical Center Nis, Clinical Center Vojvodina and Clinical Center Kragujevac). RESULTS: Currently in Serbia, micro-elimination appears to be realistic in the patients with haemophilia, who represent a small, well-defined subpopulation, under constant monitoring by the healthcare system. Other feasible targets for micro-elimination of CHC infection in Serbia are patients on hemodialysis, prisoners and people who inject drugs. CONCLUSIONS: Micro-elimination is feasible in Serbia, especially in the subpopulation of patients with haemophilia. This may represent an initial step towards achieving the WHO objective to eliminate hepatitis C infection by 2030.

The impact of object weight, reach distance, discomfort and muscle activation on the location of preferred critical boundary during a seated reaching task.

Successful performance of a goal-directed action requires the prospective actor to perceive the environment relative to their action capabilities and tailor their movements accordingly. The current study examined the roles of reach distance, object (power drill) weight, gender, discomfort, and muscle activation (anterior deltoid, upper trapezius, biceps, ventral and dorsal forearm) in determining the location of the transition between an arm-only and an arm-and-torso reach (preferred critical boundary) during a seated reach task in which participants had to direct a power drill toward a target. Generalized Estimating Equations (GEE) used extrinsic (independent of the participant) and intrinsic measures (relative to the biodynamic properties of the participant) of reach distance and drill weight, discomfort judgments, and EMG integral recordings for the five muscles to identify factors that best predicted the type of reach used. GEE revealed that intrinsic measures of reach distance and drill weight were superior predictors compared to extrinsic measures. Discomfort judgment and upper trapezius activity were also significant predictors of the location of the preferred critical boundary.