Expanding cyclodextrin use in normal phase and super/subcritical fluid chromatographic modes for the chiral separation of 1,4-dihydropyridines.

Cyclodextrin-based stationary phases are important chiral selectors in liquid chromatography. These chiral selectors are most commonly used in the reversed-phase mode because native cyclodextrin assumes a torus conformation with a hydrophobic cavity, facilitating inclusion complexation in aqueous environments. However, the value of native and aliphatic-derivatized cyclodextrins in other modes, such as the normal phase liquid chromatography (NPLC) or super/subcritical fluid chromatography (SFC), remains unexplored. In this work, we report chiral separations of pharmaceutically relevant compounds with the 1,4-dihydropyridine (DHP) scaffold on a 2-hydroxypropyl-ß-cyclodextrin (CD-RSP) stationary phase in NPLC and SFC modes. Although CD-RSP is conventionally considered only effective in the reversed-phase mode, we show that these compounds tend to separate better in other modes. This is particularly apparent for analytes with hydrogen-bonding moieties. We propose that the separation mechanism primarily depends on external adsorption rather than inclusion complexation. The negligible impact of a complexation-competitive additive on retention in non-aqueous modes further supports this claim. Additionally, van Deemter analysis demonstrated the efficiency and environmental benefit of using this stationary phase in the SFC mode, further highlighting the promise of aliphatic derivatized cyclodextrin stationary phases for greener separations.

Novel 1,2,4-triazole derivatives containing the naphthalene moiety as selective butyrylcholinesterase inhibitors: Design, synthesis, and biological evaluation.

Butyrylcholinesterase (BChE) is considered a promising therapeutic target for treating Alzheimer's disease due to the increase in the levels and activity of BChE in the late stage of the disease. In this study, a series of novel 1,2,4-triazole derivatives bearing the naphthalene moiety linked to the benzothiazole, thiazole, and phenyl scaffolds via amid chain were designed and synthesized as potential and selective BChE inhibitors. The results of the inhibitory activity studies revealed that most of these compounds exhibited significant inhibitor potency on BChE. Compounds 35a (0.025 ± 0.01 µM) and 37a (0.035 ± 0.01 µM) displayed the most potent inhibitory activity, with excellent selectivity against BChE over acetylcholinesterase (SIBChE, 23,686 and 16,936, respectively) among the target compounds. The kinetics studies revealed that these compounds behaved with noncompetitive BChE inhibitors. Molecular docking studies indicated that 35a and 37a fit well into the active side of BChE. In addition, 35a and 37a also had the lowest cytotoxicity for human neuroblastoma cells (SH-SY5Y), potential antioxidant capacity, moderate inhibition potency on amyloid-ß1-42 aggregation, and significant neuroprotective effect against SH-SY5Y cell injury induced by H2O2 and amyloid-ß1-42. All results suggest that these compounds might be considered as promising new lead compounds in the drug discovery process for the treatment of late-stage Alzheimer's disease.

Isoniazid Linked to Sulfonate Esters via Hydrazone Functionality: Design, Synthesis, and Evaluation of Antitubercular Activity.

Isoniazid (INH) is one of the key molecules employed in the treatment of tuberculosis (TB), the most deadly infectious disease worldwide. However, the efficacy of this cornerstone drug has seriously decreased due to emerging INH-resistant strains of Mycobacterium tuberculosis (Mtb). In the present study, we aimed to chemically tailor INH to overcome this resistance. We obtained thirteen novel compounds by linking INH to in-house synthesized sulfonate esters via a hydrazone bridge (SIH1-SIH13). Following structural characterization by FTIR, 1H NMR, 13C NMR, and HRMS, all compounds were screened for their antitubercular activity against Mtb H37Rv strain and INH-resistant clinical isolates carrying katG and inhA mutations. Additionally, the cytotoxic effects of SIH1-SIH13 were assessed on three different healthy host cell lines; HEK293, IMR-90, and BEAS-2B. Based on the obtained data, the synthesized compounds appeared as attractive antimycobacterial drug candidates with low cytotoxicity. Moreover, the stability of the hydrazone moiety in the chemical structure of the final compounds was confirmed by using UV/Vis spectroscopy in both aqueous medium and DMSO. Subsequently, the compounds were tested for their inhibitory activities against enoyl acyl carrier protein reductase (InhA), the primary target enzyme of INH. Although most of the synthesized compounds are hosted by the InhA binding pocket, SIH1-SIH13 do not primarily show their antitubercular activities by direct InhA inhibition. Finally, in silico determination of important physicochemical parameters of the molecules showed that SIH1-SIH13 adhered to Lipinski's rule of five. Overall, our study revealed a new strategy for modifying INH to cope with the emerging drug-resistant strains of Mtb.

Azoles containing naphthalene with activity against Gram-positive bacteria: in vitro studies and in silico predictions for flavohemoglobin inhibition.

Azoles are first-line drugs used in fungal infections. Topical antifungals, such as miconazole and econazole, are known to be active against Gram-positive bacteria, which was reported to result from bacterial flavohemoglobin (flavoHb) inhibition. Dual antibacterial/antifungal action is believed to have benefits for antimicrobial chemotherapy. In this study, we tested antibacterial effects of an in-house library of naphthalene-bearing azoles, some of which were reported as potent antifungals, in an attempt to find dual-acting hits. Several potent derivatives were obtained against the Gram-positive bacteria, Enterococcus faecalis and Staphylococcus aureus. 9 was active at a minimum inhibitor concentration (MIC) less than 1 µg/ml against E. faecalis and S. aureus, and 10 against S. aureus. 16 was also potent against E. faecalis and S. aureus (MIC = 1 and 2 µg/ml, respectively). Six more were active against S. aureus with MIC ≤ 4 µg/ml. In vitro cytotoxicity studies showed that the active compounds were safe for healthy cells within their MIC ranges. According to the calculated descriptors, the library was found within the drug-like chemical space and free of pan-assay interference compounds (PAINS). Molecular docking studies suggested that the compounds might be bacterial flavohemoglobin (flavoHb) inhibitors and the azole and naphthalene rings were important pharmacophores, which was further supported by pharmacophore modeling study. As a result, the current study presents several non-toxic azole derivatives with antibacterial effects. In addition to their previously reported antifungal properties, they could set a promising starting point for the future design of dual acting antimicrobials. Communicated by Ramaswamy H. Sarma.

Potential of nafimidone derivatives against co-morbidities of epilepsy: In vitro, in vivo, and in silico investigations.

Nafimidone is known for its clinical antiepileptic effects and alcohol derivatives of nafimidone were reported be potent anticonvulsants. These compounds are structurally similar to miconazole, which is known to inhibit cholinesterases, protect neurons, and ameliorate cognitive decline. Herein, we aimed to reveal the potential of three nafimidone alcohol esters (5 g, 5i, and 5 k), which were previously reported for their anticonvulsant effects, against co-morbidities of epilepsy such as inflammatory and neuropathic pain, cognitive and behavioral deficits, and neuron death, and understand their roles in related pathways such as γ-butyric acid type A (GABAA ) receptor and cholinesterases using in vitro, in vivo and in silico methods. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test was used for cytotoxicity evaluation, hippocampal slice culture assay for neuroprotection, formalin test for acute and inflammatory pain, sciatic ligation for neuropathic pain, Morris water maze and open field locomotor tasks for cognitive and behavioral deficits, radioligand binding for GABAA receptor affinity, spectrophotometric methods for cholinesterase inhibition in vitro, and molecular docking in silico. The compounds were non-toxic to fibroblast cells. 5 k was neuroprotective against kainic acid-induced neuron death. 5i reduced pain response of mice in both the acute and the inflammatory phases. 5i improved survival upon status epilepticus. The compounds showed no affinity to GABAA receptor but inhibited acetylcholinesterase, 5 k also inhibited butyrylcholinesterase. The compounds were predicted to interact mainly with the peripheric anionic site of cholinesterase enzymes. The title compounds showed neuroprotective, analgesic, and cholinesterase inhibitory effects, thus they bear promise against certain co-morbidities of epilepsy with neurological insults.

In silico Repurposing of Drugs for pan-HDAC and pan-SIRT Inhibitors: Consensus Structure-based Virtual Screening and Pharmacophore Modeling Investigations.

OBJECTIVES: Drug repurposing is a highly popular approach to find new indications for drugs, which greatly reduces time and costs for drug design and discovery. Non-selective inhibitors of histone deacetylase (HDAC) isoforms including sirtuins (SIRTs) are effective against conditions like cancer. In this study, we used molecular docking to screen Food and Drug Administration (FDA)-approved drugs to identify a number of drugs with a potential to be repurposed for pan-HDAC and pan-SIRT inhibitor activity. MATERIALS AND METHODS: The library of FDA-approved drugs was optimized using MacroModel. The crystal structures of HDAC1-4, 6-8, SIRT1-3, 5, 6 were prepared before the library was docked to each structure using Glide, FRED, and AutoDock Vina/PyRx. Consensus scores were derived from the docking scores obtained from each software. Pharmacophore modeling was performed using Phase. RESULTS: Based on the consensus scores, belinostat, bexarotene, and cianidanol emerged as top virtual pan-HDAC inhibitors whereas alosetron, cinacalcet, and indacaterol emerged as virtual pan-SIRT inhibitors. Pharmacophore hypotheses for these virtual inhibitors were also suggested through pharmacophore modeling in agreement with the molecular docking models. CONCLUSION: The consensus approach enabled selection of the best performing drug molecules according to different software, and good scores against isoforms (virtual pan-HDAC and pan-SIRT inhibitors). The study not only proposes potential drugs to be repurposed for HDAC and SIRT-related diseases but also provides insights for designing potent de novo derivatives.

List of leaf beetles (Coleoptera: Chrysomelidae) from Lagodekhi reserve with new records for Transcaucasia and Georgia.

Leaf beetles of Lagodekhi National Park have been studied for the first time. Thirty two species were recorded from the area of which 14 are new for Georgia, 1 genus and 8 species are new to Transcaucasus. Together with the additional 16 species that were already known from literature, a total of 48 chrysomelid species for Lagodekhi reserve is listed here with notes on the specimens examined and general distributions. Some insights into the elevational pattern of leaf beetle diversity in Lagodekhi National Park are also provided.

Sociodemographic and clinical features of postpartum depression among Turkish women: a prospective study.

BACKGROUND: Postpartum depression (PPD) is moderate to severe depression in a woman after she has given birth. Findings from several well-designed studies reflect great variability in rates, from 10 to 22%, and also in risk factors for PPD. This variability may reflect geographical location. The incidence and risk factors for PPD among Turkish women are not well documented. It is, however, important to understand the risk factors to develop preventive intervention strategies. This study aims to examine the prevalence of PPD and associated risk factors among a sample of women receiving services at a tertiary obstetrics hospital in Ankara, Turkey. METHODS: A sample of 671 women, between 36 and 40 gestational weeks, were enrolled and screened for depressive symptomatology using the Hospital Depression Inventory. Sociodemographic and clinical data were also collected. At a subsequent postpartum evaluation, 6-8 weeks post-delivery, 540 of the 671 were screened using the Edinburgh Postnatal Depression Scale (EPDS) for PPD. RESULTS: Eighty-three (15.4%) of the 540 women had scores above the cutoff point (>13) on the EPDS. Statistically significant correlations were found between antenatal, prenatal and postpartum depression scores (r = 0.24). Women reporting suicidal thoughts during pregnancy (OR: 6.99), history of past PPD (OR: 6.64), physical violence during pregnancy (OR: 6.20) or during the postpartum period (OR: 5.87), previous psychiatric history (OR: 4.16), depressive symptoms during pregnancy (OR: 1.70), subjectively lower level of satisfaction with the pregnancy (OR:0. 69), a history of premenstrual syndrome (PMS) (OR: 2.05), and unplanned pregnancy (OR: 1.69) had higher odds for developing PPD. CONCLUSION: One in six mothers screened as positive for PPD. Women who had previously been diagnosed with PPD, reported suicidal thoughts during pregnancy, or had been exposed to physical violence were at especially high risk for postpartum depression. To prevent and treat postpartum depression, special attention should be paid to women reporting these characteristics.

Ghrelin and motilin levels in hyperemesis gravidarum.

PURPOSE: Ghrelin, an endogenous ligand for the growth hormone secratogogue receptor, and its receptors are found in the reproductive organs and placenta. Motilin is produced from the endocrine cells of the duodeno jejunal mucosa and considered to be a regulator of interdigestive migrating contractions. Aim of this study is to investigate ghrelin and motilin levels in patients with hyperemesis gravidarum. METHODS: A total of 56 patients with singleton pregnancies in the first trimester were recruited in the study, 39 with hyperemezis gravidarum and 17 normal pregnant women. Patients with medical complications and body mass index <18 or >25 were excluded. Fasting plasma ghrelin and motilin concentrations were measured. Fasting blood glucose, liver enzymes, blood urea nitrogen, creatinin, estradiol, progesterone, human chorionic gonadotropin, and thyroid function tests were also investigated. RESULTS: Ghrelin levels were significantly higher in patients with hyperemesis group than the normal pregnant women (p = 0.025). Serum estradiol levels were also higher in the hyperemesis group (p = 0.001). No significant difference was observed in plasma motilin levels between the two groups. In correlation analyses, maternal ghrelin was positively correlated with estradiol (r = 0.29, p = 0.029) in the whole cohort. CONCLUSION: There are a few studies about the course of circulating ghrelin levels during human pregnancy. Ghrelin administration increases food intake through central mechanisms but its effects on appetite in relation to human pregnancy is unknown. The increased levels of ghrelin in hyperemesis gravidarum might be a compensatory mechanism to restore the energy metabolism of the pregnant women.

Single intrastromal corneal ring segment implantation using the femtosecond laser after radial keratotomy in a keratoconic patient.

A 33-year-old woman with irregular astigmatism 6 years after radial keratotomy (RK) for keratoconus was treated with implantation of a single intrastromal corneal ring segment (Keraring) using the femtosecond laser. The segment (0.150 mm thick with a 160-degree arc) was inserted in the steepest area (inferior) with no intraoperative or postoperative complications. Six months postoperatively, the uncorrected visual acuity had improved from 20/40 to 20/25 and the best spectacle-corrected visual acuity, from 20/32 to 20/20. The mean manifest astigmatic correction decreased from -2.50 diopters (D) to -0.75 D, and corneal topography showed improved inferior steepening and less irregular astigmatism. Although the results are encouraging, the long-term effect of this approach in post-RK patients is not known.

Intrastromal corneal ring segment implantation with the femtosecond laser in a post-keratoplasty patient with recurrent keratoconus.

A 50-year-old woman had implantation of intrastromal corneal ring segments for recurrent keratoconus 15 years after penetrating keratoplasty. Two segments (0.15 mm and 0.25 mm) were inserted without any intraoperative or postoperative complications, using the femtosecond laser to create the tunnels (superior and inferior). Ten months after the procedure, the uncorrected visual acuity was 20/100, compared with counting fingers preoperatively, and the best spectacle-corrected visual acuity improved from 20/63 to 20/32. Although the results are encouraging, the long-term effect of this approach for the management of post-keratoplasty patients with recurrent keratoconus is not known.