Two siblings with Fanconi anemia (FANCQ, ERCC4/XPF) presenting with tumor-mimicking lesions in the brain and acute neurological deterioration.

The complementation Q group (FANCQ) subtype of Fanconi anemia (FA) caused by the ERCC4/XPF mutation is very rare. Two siblings, aged 13 and 10 with Fanconi phenotypic features, presented with right hemiparesis and focal-onset seizures. In both cases, cranial magnetic resonance imaging (MRI) showed mass-like lesions accompanied by peripheral edema and calcification. In one case, oral steroid treatment and surgical excision were performed, while in the other case, the cranial lesion regressed just with steroid treatment and without surgery. Both siblings remained wheelchair-bound due to neurological dysfunction. One case died due to hepatocellular carcinoma. ERCC4/XPF gene mutation was detected in both siblings.

Somatic amplification and addiction profile as risk factors for medication overuse headache with chronic migraine.

INTRODUCTION: Overuse of analgesics can lead to medication-overuse headache (MOH) in chronic migraine (CM) patients, and is often linked to addiction. This study explores the addiction-related characteristics and somatic amplification in patients with, CM with medication overuse headache (CM+MOH), CM, and healthy controls. METHODS: 73 CM patients and 70 CM+MOH, along with 63 healthy controls, participated in the study. Assessments included a Sociodemographic Form, Migraine Disability Assessment Scale (MIDAS), Addiction Profile Index (API), Addiction Profile Index-Clinical Version (API-C), and the Somatosensory Amplification Scale (SSAS). RESULTS: Substance use characteristics, craving, motivation for use, and addiction severity scores were higher in the CM+MOH group than in both the CM and the control group. Specifically, the SSAS scores within the CM+MOH group surpassed those of both the CM and control groups. In the CM+MOH group, SSAS scores were a strong predictor of the amount of analgesic usage. Besides, craving and motivation for substance use scores significantly predicted the number of days analgesic taken per month in the CM+MOH group CONCLUSION: CM patients with MOH exhibit a pronounced association with addiction, and a heightened manifestation of somatic symptoms. Addressing addiction characteristics and psychosomatic amplification is important to ensure comprehensive management.

Effectiveness of Intermittent Theta Burst Stimulation to Enhance Upper Extremity Recovery after Stroke: A Randomized Controlled Study.

OBJECTIVE: To first investigate the effectiveness of modified Constraint-Induced Movement Therapy (mCIMT) in low-functioning patients with stroke (PwS). Second, we aimed to investigate the efficiency of intermittent theta-burst stimulation (iTBS), applied on intermittent days, in addition to the mCIMT in PwS. DESIGN: Randomized, sham-controlled, single-blinded study. SETTING: Outpatient clinic. PARTICIPANTS: Fifteen PwS (age 66.3 ± 9.2 years (mean ± SD); 53% female) who were in the first 1-12 months after the incident were included in the study. INTERVENTIONS: PwS were divided into 3 groups: 1) mCIMT alone, 2) mCIMT + sham iTBS, and 3) mCIMT + iTBS. Each group received fifteen sessions of mCIMT (1 hour/session, 3 sessions/week). iTBS was applied with 600-pulses on impaired M1 prior to mCIMT. MAIN OUTCOME MEASURES: Upper extremity (UE) impairment was assessed with the Fugl-Meyer Test (FMT-UE), while the motor function was evaluated with the Wolf-Motor Function Test (WMFT). Motor Activity Log-28 (MAL-28) was used to evaluate the amount of use (AUS) and how well (HWS) the impaired UE movements. RESULTS: With-in-group analysis revealed that all groups had statistically significant improvements based on the FMT-UE and MAL-28 (p<0.05). However, the performance time and arm strength variables of WMFT were only increased in the mCIMT + iTBS group (p<0.05). The only between-group difference was observed in the intracortical facilitation in favor of the mCIMT + iTBS group (p<0.05). The effect size of iTBS was f=0.18. CONCLUSION: Our findings suggest that mCIMT with and without the application of iTBS has increased the UE motor function in low-functioning PwS. iTBS applied on intermittent days may have additional benefits as an adjunct therapy for facilitating cortical excitability, increasing the speed and strength of the impaired UE as well as decreasing disability.

Inhibition of Monoamine Oxidases by Pyridazinobenzylpiperidine Derivatives.

Monoamine oxidase inhibitors (MAOIs) have been crucial in the search for anti-neurodegenerative medications and continued to be a vital source of molecular and mechanistic diversity. Therefore, the search for selective MAOIs is one of the main areas of current drug development. To increase the effectiveness and safety of treating Parkinson's disease, new scaffolds for reversible MAO-B inhibitors are being developed. A total of 24 pyridazinobenzylpiperidine derivatives were synthesized and evaluated for MAO. Most of the compounds showed a higher inhibition of MAO-B than of MAO-A. Compound S5 most potently inhibited MAO-B with an IC50 value of 0.203 µM, followed by S16 (IC50 = 0.979 µM). In contrast, all compounds showed weak MAO-A inhibition. Among them, S15 most potently inhibited MAO-A with an IC50 value of 3.691 µM, followed by S5 (IC50 = 3.857 µM). Compound S5 had the highest selectivity index (SI) value of 19.04 for MAO-B compared with MAO-A. Compound S5 (3-Cl) showed greater MAO-B inhibition than the other derivatives with substituents of -Cl > -OCH3 > -F > -CN > -CH3 > -Br at the 3-position. However, the 2- and 4-position showed low MAO-B inhibition, except S16 (2-CN). In addition, compounds containing two or more substituents exhibited low MAO-B inhibition. In the kinetic study, the Ki values of S5 and S16 for MAO-B were 0.155 ± 0.050 and 0.721 ± 0.074 µM, respectively, with competitive reversible-type inhibition. Additionally, in the PAMPA, both lead compounds demonstrated blood-brain barrier penetration. Furthermore, stability was demonstrated by the 2V5Z-S5 complex by pi-pi stacking with Tyr398 and Tyr326. These results suggest that S5 and S16 are potent, reversible, selective MAO-B inhibitors that can be used as potential agents for the treatment of neurological disorders.

Tandem high-dose chemotherapy followed by autologous stem cell transplantation: An infant with trilateral retinoblastoma.

BACKGROUND: Retinoblastoma (RB) is the most common intraocular malignancy in childhood. Advanced RB, associated with exceedingly poor prognosis, requires more intensive multiagent chemotherapy than conventional regimens. Rescue of the bone marrow after intensive chemotherapy is achieved with stem cell transplantation. The sequential courses (tandem transplantation) of high-dose chemotherapy followed by autologous stem cell transplantation allow for even greater dose intensity in consolidation with the potential to use different active chemotherapeutics at each transplant and have proven feasible and successful in treating children with recurrent/refractory solid tumors. CASE DESCRIPTION: We report an infant with trilateral high-risk RB who received tandem high-dose chemotherapy (HDC) followed by autologous stem cell transplantation after the conventional chemotherapy. A 5-month-old female patient presented with strabismus, and the ophthalmoscopic examination showed intraocular tumoral lesions in both eyes. Magnetic resonance imaging (MRI) concluded the trilateral retinoblastoma diagnosis due to a tumoral mass in the optic chiasm. The follow-up ophthalmologic examinations and the MRI detected stable disease after six cycles of multiagent chemotherapy. CONCLUSIONS: Rescue with autologous stem cell transplantation after HDC allows for an increase in chemotherapy intensity. Tandem transplantation provides the chance to perform different chemotherapeutics at each transplant and enables an increase in the chemotherapy intensity, thus providing a positive effect on disease-free survival.

Use of dual energy CT urography in evaluation of urinary stone and complex cyst.

BACKGROUND: Dual-energy computed tomography scans can provide significant benefits to the urinary system. The aim of this study is to determine the limitations and benefits of using dual energy CT urography in patients with urinary system stones and cysts. METHODS: In the analysis of the images, the virtual noncontrasted images obtained from the combined nephrogenicexcretory phase and the true noncontrasted images were evaluated. The true noncontrast images were accepted as the gold standard for stone detection. RESULTS: Eighty-three different stones were detected in 26 of the 115 patients included in the study. Sensibilities of virtual noncontrast images in detecting urinary system stones were 66.7% and 65.4% according to the first and second radiologists, respectively. In this study, 32 hyperdense cysts were detected. According to iodine map images, there was no enhancement in 26 of 32 cysts; only 5 cysts showed minimal contrast enhancement. One patient could not decide on contrast enhancement. DISCUSSION: As a result, if CT urography is performed with dual energy, it can provide additional information in patients with urinary system disorder.

A Case Report of Congenital Thrombotic Thrombocytopenic Purpura: The Peripheral Blood Smear Lights the Diagnosis.

We report on a 12-year-old boy with congenital thrombotic thrombocytopenic purpura, on who had an erroneous diagnosis as chronic immune thrombocytopenia. The patient presented with complaints of jaundice and skin rash. Laboratory analysis showed nonimmune hemolytic anemia and severe thrombocytopenia. Peripheral blood smear showed 8% schistocytes, polychromasia, and anisocytosis. The ADAMTS13 antigen and activity were suspected to be lower than 5% with any antibodies against the enzyme. The DNA sequence analyses resulted in compound heterozygosity consisting of c.291_391del in exon 3 and c.4143dupA in exon 29. Schistocyte (fragmented erythrocytes) on the peripheral blood smear is a light that illuminates the diagnosis. Early recognition of the disease can prevent inappropriate treatments and morbidities due to organ damage.

Antifungal Azole Derivatives Featuring Naphthalene Prove Potent and Competitive Cholinesterase Inhibitors with Potential CNS Penetration According to the in Vitro and in Silico Studies.

Cholinesterase inhibition is of great importance in the fight against neurodegenerative disorders such as Alzheimer's disease. Azole antifungals have come under the spotlight with recent discoveries that underline the efficacy and potential of miconazole and its derivatives against cholinesterase enzymes. In this study, we evaluated a library of azoles against acetylcholinesterase and butyrylcholinesterase using in vitro and in silico methods to identify potent inhibitors. Low micromolar IC50 values were obtained for imidazole derivatives, which were further tested and found potent competitive cholinesterase inhibitors via enzyme kinetics study. The active derivatives showed negligible toxicity in in vitro cytotoxicity tests. Molecular modeling studies predicted that these derivatives were druglike, could penetrate blood-brain barrier, and tightly bind to cholinesterase active site making key interactions via the imidazole moiety at protonated state. Thus, current study identifies potent and competitive cholinesterase inhibitor azoles with minor toxicity and potential to pass into the central nervous system.

Development of a Novel Class of Pyridazinone Derivatives as Selective MAO-B Inhibitors.

Sixteen compounds (TR1-TR16) were synthesized and evaluated for their inhibitory activities against monoamine oxidase A and B (MAOs). Most of the derivatives showed potent and highly selective MAO-B inhibition. Compound TR16 was the most potent inhibitor against MAO-B with an IC50 value of 0.17 µM, followed by TR2 (IC50 = 0.27 µM). TR2 and TR16 selectivity index (SI) values for MAO-B versus MAO-A were 84.96 and higher than 235.29, respectively. Compared to the basic structures, the para-chloro substituent in TR2 and TR16 increased the inhibitory activity of MAO-B. TR2 and TR16 were reversible MAO-B inhibitors that were competitive, with Ki values of 0.230 ± 0.004 and 0.149 ± 0.016 µM, respectively. The PAMPA method indicated that compounds TR2 and TR16 had the tendency to traverse the blood-brain barrier. Docking investigations revealed that lead compounds were beneficial for MAO-B inhibition via association with key as well as selective E84 or Y326 residues, but not for MAO-A inhibition via interaction primarily driven by hydrophobic contacts. In conclusion, TR2 and TR16 are therapeutic prospects for the management of multiple neurodegenerative diseases.

Azole derivatives with naphthalene showing potent antifungal effects against planktonic and biofilm forms of Candida spp.: an in vitro and in silico study.

Candida infections pose a serious public health threat due to increasing drug resistance. Azoles are first-line antifungal drugs for fungal infections. In this study, we tested an in-house azole collection incorporating naphthalene ring to find hits against planktonic and biofilm forms of resistant Candida spp. In the collection, potent derivatives were identified against the susceptible strains of Candida with minimum inhibitory concentration (MIC) values lower than those of the reference drug, fluconazole. MIC values of 0.125 µg/ml against C. albicans, 0.0625 µg/ml against C. parapsilosis, and 2 µg/ml against C. krusei, an intrinsically azole-resistant non-albicans Candida, were obtained. Some of the derivatives were highly active against fluconazole-resistant clinical isolate of C. tropicalis. Inhibition of C. albicans biofilms was also observed at 4 µg/ml similar as amphotericin B, the reference drug known for its antibiofilm activity. Through molecular docking studies, affinities and key interactions of the compounds with fungal lanosterol 14α-demethylase (CYP51), the target enzyme of azoles, were predicted. The interactions of imidazole with heme cofactor and of the naphthalene with Tyr118 were highlighted in line with the literature data. As a result, this study proves the importance of naphthalene for the antifungal activity of azoles against Candida spp. in both planktonic and biofilm forms.

Whole Blood miR-210, miR-122, miR-223 Expression Levels and Their Relationship With Iron Status Parameters and Hypercoagulability Indices in Children With Iron Deficiency Anemia.

MicroRNAs have the potential to regulate systemic and cellular iron homeostasis at multiple points. In iron deficiency anemia (IDA), hypoxia, platelet reactivity, and potentially microRNAs play a role in the development of hypercoagulability. A total of 57 children diagnosed with IDA between October 2016 and October 2017 and 48 healthy children were included in this cross-sectional study. Blood count parameters, serum iron, transferrin saturation, ferritin level, maximum clot firmness (MCF), and clot formation time index, which are indicators of hypercoagulability in rotational thromboelastometry test, of the IDA and control groups obtained in our previous study were recorded. miR-210, miR-122, and miR-223 levels were analyzed. There was no difference in the miR-210, miR-122, and miR-223 levels between the IDA and control groups. Patients with hemoglobin (Hb) <8 g/dL had higher miR-210 levels than patients with Hb>8 g/dL (P<0.05). There was a negative correlation between miR-210 and Hb and ferritin levels, a positive correlation between miR-122 and ferritin levels, and a negative correlation between miR-223 and MCF index. In IDA, there is a close relationship between the severity of anemia and miR-210, and miR-210 expression is slightly increased in those with severe anemia. miR-210 and miR-122 collectively play a role in maintaining the iron balance. The correlation between miR-223, a platelet function regulator, and the MCF index, suggested that miR-223 has a role in the development of hypercoagulability in IDA.

Rotational Thromboelastometry Profile in Children With Chronic Spontaneous Urticaria.

The pathogenesis of chronic spontaneous urticaria (CSU) is incompletely understood. There is a growing interest in the role of the coagulation cascade in chronic urticaria. Rotational thromboelastometry (ROTEM) assay enables the global assessment of coagulation status. In the present study, we aimed to test the coagulation profile in children with CSU using ROTEM and correlate these parameters with those of a healthy group. A total of 24 children with active CSU (11 girls and 13 boys) 8 to 17 years of age and age-matched and sex-matched 30 healthy control participants were enrolled in the study. ROTEM assays (intrinsic thromboelastometry and extrinsic thromboelastometry) were used to measure and analyze coagulation time, clot formation time, and maximum clot firmness. The CSU patients and controls did not differ in age, sex, erythrocyte, neutrophil, and platelet counts. Also, ROTEM parameters did not show any difference between the 2 groups. ROTEM is increasingly being used as a tool for monitoring coagulation status. In this study, ROTEM parameters did not show any difference between CSU patients and the healthy group. Further studies are needed to confirm our findings on a larger number of CSU patients.

A Novel Physical Examination Test for Ischiofemoral Impingement: Validation With Magnetic Resonance Imaging Correlation.

OBJECTIVE: The purpose of this study was to propose and validate a novel physical examination test for ischiofemoral impingement with magnetic resonance imaging (MRI) correlation. METHODS: We prospectively studied 24 women with buttock (deep gluteal) pain and 27 asymptomatic women. Each group underwent a 2-stage physical examination test that featured hip adduction-external rotation-extension and knee flexion. Visual analog scale pain scores were noted just before and during test stages on both sides. The MRI findings of the ischiofemoral impingement were evaluated quantitatively and qualitatively. RESULTS: Mean ages were 56.0 and 55.2 years (P = 0.797), and mean body mass indexes were 29.1 and 28.8 kg/m2 (P = 0.817) in symptomatic and asymptomatic groups, respectively. Ischiofemoral spaces were significantly narrower (P < 0.001), ischial angles were wider (P < 0.001, right; P = 0.002, left), and soft tissue edema at the ischiofemoral space was more common (P < 0.001) in the symptomatic group, which also had higher pretest visual analog scale scores (P < 0.001) that increased significantly during both upright standing (P = 0.003, right; P < 0.001, left) and recumbent (P < 0.001 for both sides) stages of the physical examination test. CONCLUSIONS: A novel physical examination test significantly increases symptoms of ischiofemoral impingement with positive MRI correlation.

The effects of 30 Hz, 50 Hz AND 100 Hz continuous theta burst stimulation via transcranial magnetic stimulation on the electrophysiological parameters in healthy individuals.

BACKGROUND AND PURPOSE: Transcranial magnetic stimulation is a non-invasive procedure that uses robust magnetic fields to create an electrical current in the cerebral cortex. Dual stimulation consists of administering subthre-shold conditioning stimulation (CS), then suprathreshold test stimulation (TS). When the interstimulus interval (ISI) is 1-6 msec, the motor evoked potential (MEP) decreases in amplitude; this decrease is termed "short interval intracortical inhibition" (SICI); when the ISI is 7-30 msec, an increase in MEP amplitude occurs, termed "short interval intracortical facilitation" (SICF). Continuous theta burst stimulation (cTBS), often applied at a frequency of 50 Hz, has been shown to decrease cortical excitability. The primary objective is to determine which duration of cTBS achieves better inhibition or excitation. The secondary objective is to compare 50 Hz cTBS to 30 Hz and 100 Hz cTBS. METHODS: The resting motor threshold (rMT), MEP, SICI, and SICF were studied in 30 healthy volunteers. CS and TS were administered at 80%-120% and 70%-140% of rMT at 2 and 3-millisecond (msec) intervals for SICI, and 10- and 12-msec intervals for SICF. Ten individuals in each group received 30, 50, or 100 Hz, followed by administration of rMT, MT-MEP, SICI, SICF immediately and at 30 minutes. RESULTS: Greater inhibition was achieved with 3 msec than 2 msec in SICI, whereas better facilitation occurred at 12 msec than 10 msec in SICF. At 30 Hz, cTBS augmented inhibition and suppressed facilitation, while 50 Hz yielded less inhibition and greater inter-individual variability. At 100 Hz, cTBS provided slight facilitation in MEP amplitudes with less interindividual variability. SICI and SICF did not differ significantly between 50 Hz and 100 Hz cTBS. CONCLUSION: Our results suggest that performing SICI and SICF for 3 and 12 msec, respectively, and CS and TS at 80%-120% of rMT, demonstrate safer inhibition and facilitation. Recently, TBS has been used in the treatment of various neurological diseases, and we recommend preferentially 30 Hz over 50 Hz cTBS for better inhibition with greater safety and less inter-individual variability.

Evaluation of the Coagulation Profile With Rotational Thromboelastometry in Children With Hereditary Spherocytosis.

Hereditary spherocytosis (HS) is a familial hemolytic disorder associated with a variety of mutations that lead to defects in red blood cell (RBC) membrane proteins. There is increasing evidence that hypercoagulability occurs in chronic hemolytic anemia. In this study, changes in the coagulation profile in children with HS were investigated using rotational thromboelastometry. A total of 21 children with HS and 28 healthy children were enrolled in the study between October 2010 and October 2018. Complete blood count, prothrombin time, activated partial thromboplastin time, and fibrinogen level were ascertained, while rotational thromboelastometry assays were used to measure and analyze coagulation time, clot formation time, and maximum clot firmness. There was no difference between the 2 groups in terms of age and sex. The values of hemoglobin and RBC in the patient group were statistically significantly lower than those in the control group (P<0.01, <0.0001, respectively), and the values of platelet count, mean corpuscular hemoglobin concentration, and RBC distribution width were statistically significantly higher than those in the control group (P<0.05, 0.001, <0.0001, respectively). There was no statistically significant difference between the 2 groups in terms of prothrombin time, activated partial thromboplastin time, fibrinogen levels, coagulation time, clot formation time, and maximum clot firmness values. In contrast to other chronic hemolytic anemias, no predisposition to hypercoagulability has been shown in the coagulation profile of children with HS without splenectomy.

Erythrocyte Indices as Differential Diagnostic Biomarkers of Iron Deficiency Anemia and Thalassemia.

INTRODUCTION: The most common causes of microcytic anemia are iron deficiency anemia (IDA) and thalassemia trait (TT). This study investigated the reliability of erythrocyte indices and formulas as screening tests in the differential diagnosis of IDA and TT before performing detailed tests for definitive diagnosis. MATERIALS AND METHODS: In total, 50 children with ß-TT, 31 with α-TT, 50 with IDA were included. For the 8 erythrocyte indices and formulas (red blood cells [RBC], red blood cell distribution width [RDW], red blood cell distribution width index [RDWI], Mentzer index [MI], Shine and Lal index [S&L], England and Fraser [E&F], Green and King index [G&K], Srivastava index) the sensitivity, specificity, positive and negative predictive values (PPVs and NPVs, respectively) were calculated according to the cutoff values in the literature and recalculated revised cutoff values. RESULTS: According to the cutoff values in the literature for the differential diagnosis of IDA and TT, the ranking of sensitivity, specificity, PPVs, and NPVs from the highest to the lowest was RDWI, RBC, E&F, G&K, MI, Srivastava, RDW, S&L. The sensitivity, specificity, PPVs, and NPVs of all the indices according to the revised cutoff values were higher than those according to the cutoff values in the literature. CONCLUSIONS: According to both the cutoff values in the literature and revised cutoff values, the most reliable indices were RBC and RDWI.

Hemotologic Indices for Predicting Internal Organ Involvement in Henoch-Schönlein Purpura (IgA vasculitis).

Henoch-Schönlein purpura is the most common vasculitis of childhood. This study investigated the values of hematologic indices that can help predict internal organ involvement. The study included 112 patients followed up between January 2007 and May 2017 and 81 healthy children. Leukocyte, neutrophil, monocyte, lymphocyte and platelet counts, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) levels were compared between patients with and without internal organ involvement. Overall, 57 (50.8%) patients had internal organ involvement. Leukocyte, neutrophil, and monocyte counts, NLR, and CRP levels were significantly higher in patients with internal organ involvement than in patients without internal organ involvement. There was no difference between the groups in terms of lymphocyte count, platelet count, and PLR. The cutoff values were found to be ≥10.8×10/L [area under the curve (AUC), 0.734] for leukocyte, ≥6.0×10/L (AUC, 0.665) for neutrophil, ≥0.710×10/L (AUC, 0.681) for monocyte, ≥3.95×10/L (AUC, 0.609) for NLR, and 2.41 mg/dL (AUC, 0.635) for CRP. Logistic regression analysis revealed that leukocyte count is a risk factor for internal organ involvement. Leukocyte, neutrophil, monocyte counts, NLR, and CRP levels are useful in predicting internal organ involvement in the acute phase of Henoch-Schönlein purpura. Leukocyte count is an important risk factor for internal organ involvement and its predictive value is more reliable than the other hematologic indices.

Synthesis and biological evaluation of new 3(2H)-pyridazinone derivatives as non-toxic anti-proliferative compounds against human colon carcinoma HCT116 cells.

Novel 3(2H)-pyridazinone derivatives were designed, synthesised in satisfactory yields and evaluated in different experimental assays to assess their preliminary toxicity in vivo and anti-proliferative effects against HCT116 cell lines in vitro. Artemia salina lethality test provided LC50 values >100 µg/mL for all compounds. Successive assays revealed that some compounds were endowed with a promising anti-proliferative effect against HCT116 cells, alone or stimulated by serotonin as a pro-inflammatory factor in order to mimick an inflamed model in vivo of cancer cell microenvironment. Moreover, the kinurenic acid level after treatment with these newly synthesised compounds was monitored as a marker of anti-proliferation in colon carcinoma models. The IC50 values obtained for the best-in-class compounds were comparable to that of daunorubicin as a reference drug. Conversely, these compounds were not able to counteract the spontaneous migration of human cancer HCT116 cell line in the wound healing paradigm.

Antibacterial azole derivatives: Antibacterial activity, cytotoxicity, and in silico mechanistic studies.

Azole antifungal drugs are commonly used in antifungal chemotherapy. Antibacterial effects of some topical antifungals, such as miconazole and econazole, have lately been revealed, which suggests a promising venue in antimicrobial chemotherapy. In this study, we tested an in-house azole collection with antifungal properties for their antibacterial activity to identify dual-acting hits using the broth microdilution method. The in vitro screen yielded a number of potent derivatives against gram-positive bacteria, Enterococcus faecalis and Staphylococcus aureus. Compound 73's minimum inhibitory concentration (MIC) value less than 1 µg/ml against S. aureus; however, none of the compounds showed noteworthy activity against methicillin-resistant S. aureus (MRSA). All the active compounds were found safe at their MIC values against the healthy fibroblast cells in the in vitro cytotoxicity test. Molecular docking studies of the most active compounds using a set of docking programs with flavohemoglobin (flavoHb) structure, the proposed target of the azole antifungals with antibacterial activity, presented striking similarities regarding the binding modes and interactions between the tested compounds and the antifungal drugs with crystallographic data. In addition to being noncytotoxic, the library was predicted to be drug-like and free of pan-assay interference compounds (PAINS). As a result, the current study revealed several potential azole derivatives with both antifungal and antibacterial activities. Inhibition of bacterial flavoHb was suggested as a possible mechanism of action for the title compounds.

Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors.

Twelve pyridazinones (T1-T12) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. T6 was found to be the most potent MAO-B inhibitor with an IC50 value of 0.013 µM, followed by T3 (IC50 = 0.039 µM). Inhibitory potency for MAO-B was more enhanced by meta bromo substitution (T6) than by para bromo substitution (T7). For para substitution, inhibitory potencies for MAO-B were as follows: -Cl (T3) > -N(CH3)2 (T12) > -OCH3 (T9) > Br (T7) > F (T5) > -CH3 (T11) > -H (T1). T6 and T3 efficiently inhibited MAO-A with IC50 values of 1.57 and 4.19 µM and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). T3 and T6 were found to be reversible and competitive inhibitors of MAO-B with Ki values of 0.014 and 0.0071, respectively. Moreover, T6 was less toxic to healthy fibroblast cells (L929) than T3. Molecular docking simulations with MAO binding sites returned higher docking scores for T6 and T3 with MAO-B than with MAO-A. These results suggest that T3 and T6 are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer's disease.