Insecticidal effect of new synthesized chalcone derivatives on Caribbean fruit fly, Anastrepha suspensa.

In this present study, new chalcone derivatives were synthesized from 4-aminoacetophenone, which were confirmed by spectroscopic methods. The toxic risks of chalcones to humans and the environment were investigated by a web-based platform called ADMETlab. With this program, the possible toxic effects of the compounds on liver, respiratory system, and eyes were evaluated. For the topical insecticidal activity, adult female Caribbean fruit fly, Anastrepha suspensa, was targeted. Results of the toxicity tests showed that chalcone derivatives are effective against female A. suspensa. Among the synthesized chalcones, 1-(4-cinnamoylphenyl)-3-(p-tolyl)urea (2) exhibited the greatest insecticidal activity, resulting in 73 % mortality at 100 µg/fly after 24 h, whereas other derivatives showed less than 30 % mortality. Our results demonstrate that insecticidal activity may be modulated by the presence of a certain phenyl ring in the structure of derivative 2 and, therefore, has potential for design of efficient chemicals for tephritid fruit fly management.

Synthesis, biological evaluation and molecular docking studies of novel 1,3,4-thiadiazoles as potential anticancer agents and human carbonic anhydrase inhibitors.

Thiosemicarbazide and also 1,3,4-thiadiazole derivatives have been garnering substantial attention from researchers worldwide due to their expansive range of biological activities, encompassing antimicrobial, anti-inflammatory, and anticancer properties. Herein, we embarked on a comprehensive investigation in this study, introducing a novel series of thiosemicarbazides (3a-3i) and their corresponding 1,3,4-thiadiazole (4a-4i) derivatives. The compounds were meticulously designed, synthesized, and subjected to meticulous characterization using various spectroscopic methods such as FT-IR, 1H-NMR, 13C-NMR, and elemental analysis. Afterward, their potential anti-proliferative effectiveness was assessed using MTT assay against two cancer cell lines (U87 and HeLa) and normal fibroblast cells (L929). Among the compounds, 4d showed the highest cytotoxic activity against U87 and 4i against HeLa. Compound 3b exhibited selective cytotoxic activity against both cancer cells. Among the molecules with selective activity against the U87 cell line; 3a, 3b, 4d and 4e were further evaluated by caspase-3 activity levels, Bax and Bcl-2 protein expression, and total oxidant status assay. Besides, carbonic anhydrase IX activity studies were also performed in order to understand the underlying mechanism of action. The results indicated that compound 4e showed higher efficacy than standard acetazolamide (IC50 = 0.58 ± 0.02 µM) with an IC50 value of 0.03 ± 0.01 µM. Furthermore, molecular docking studies were carried out using carbonic anhydrase IX crystals to determine the compound's interactions with the enzyme's active sites. This comprehensive investigation sheds light on the intricate interplay between molecular structure and biological activity, providing valuable insights into the therapeutic potential of these compounds.

Morphological and electrophysiological evaluation of median and ulnar nerve in complex regional pain syndrome type 1.

OBJECTIVE: Complex regional pain syndrome (CRPS) can be distinguished as type I without and type II with electrophysiological evidence of major nerve lesion. The pathophysiology of both subgroups is still under investigation. The aim of this research is to demonstrate the nerve morphology and electrophysiology in CRPS type I patients. MATERIALS AND METHODS: Bilateral median and ulnar nerve cross-sectional areas were evaluated with ultrasound and also median and ulnar nerve conduction studies of both hands were performed. Cross-sectional areas of median and ulnar nerves and nerve conduction studies in healthy controls were also obtained and compared with the patients. RESULTS: Twenty-five male patients and 11 healthy male controls were enrolled in the study. The mean age of the patients was 24.08 ± 5.50 years and controls was 23.18 ± 5.09 (p > 0.05). Compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes of the diseased side were found significantly lower than the healthy side (p < 0.05). Both median and ulnar nerve distal motor latency values were significantly higher in the patient group (p < 0.05). There was no significant difference in the median and ulnar nerve cross-sectional area when compared with the opposite extremity and healthy volunteers. CONCLUSION: The lower SNAP and CMAP amplitudes of the median and ulnar nerves compared to the healthy side and the prolongation of the affected side median and ulnar nerve distal motor latencies of the affected individuals may indicate axonal involvement in patients with CRPS type 1. Decreased CMAP amplitudes may also indicate muscle atrophy due to a decrease in the number of functional motor units.

Synthesis of Phthalimide Derivatives and Their Insecticidal Activity against Caribbean Fruit Fly, Anastrepha suspensa (Loew).

In this study, thirteen phthalimide derivatives were designed and synthesized. All synthesized compounds were evaluated to determine their potential for inhibitory activities against females of the Caribbean fruit fly, Anastrepha suspensa (Loew) (Diptera: Tephritidae). These efforts led to the discovery of three compounds 4a, 4c, and 4d with potent insecticidal activity (LD50 range from 0.70 to 1.91 µg/fly). Among these compounds, 4a exhibited the highest inhibitory potency with 0.70 µg/fly. In addition, in silico models indicated that compound 4a is less toxic than phthalimide and other precursors. Therefore, our results suggest that 4a has strong potential as a candidate component for developing a novel environmentally friendly insecticide for control of pest fruit flies.

Synthesis and Biological Evaluation of Some Hydrazide-Hydrazone Derivatives as Anticancer Agents.

In this study, a series of hydrazide-hydrazone derivatives (3a-3u) were synthesized and evaluated for their anticancer activities against prostate cancer cell line (PC-3), breast cancer cell line (MCF-7), colon cancer cell line (HT-29) and human umbilical vein endothelial cells (HUVEC) using MTT assay. In particular, compound 3h having a pyrrole ring was found to be the most potent derivative with IC50 = 1.32, 2.99, 1.71 µM against PC-3, MCF-7, HT-29 cancer cell lines respectively using paclitaxel as a standard compound. Furthermore, compound 3h was subjected to further biological studies such as caspase-3 activity and Annexin-V assay to evaluate their inhibitory potentials. The activity results displayed that compound 3h increased caspase-3 activation and the number of cells to early apoptosis. The additional studies like pharmacokinetics, bioavailability scores and drug-likeness properties were also evaluated. The in silico pharmacokinetics predictions displayed that the bioavailability of these compounds may be high.

Design, Synthesis, In Silico ADMET Studies and Anticancer Activity of Some New Pyrazoline and Benzodioxole Derivatives.

A new series of 2-pyrazoline derivatives starting from substituted benzodioxole chalcones were designed and synthesized. IR and 1H NMR spectral data and elemental analysis were used to characterize the structures of the synthesized compounds. The cytotoxic activities on HeLa, MCF-7 cancer cell lines and NIH-3T3 for these compounds were tested by using MTT assay. Among the synthesized compounds 2d, 2j, 3j and 3n against MCF-7 cells, and 3c against HeLa exhibited significant cytotoxic activity with IC50 between 10.08 and 27.63 µM. Compound 3f showed the most potent anticancer activity against both cancer cells with good selectivity (IC50 = 11.53 µM on HeLa with SI = 81.75 and IC50 = 11.37 µM on MCF-7 with SI = 82.90). Furthermore, in silico ADMET analyses were performed and the drug-likeness properties of the compounds were investigated.

N-Substituted Arylidene-3-(Methylsulfonyl)-2-Oxoimidazolidine-1-Carbohydrazide as Cholinesterase Inhibitors: Design, Synthesis, and Molecular Docking Study.

The development of new enzyme inhibitors in degenerative brain diseases has gained more attention. Enzyme inhibitors play an effective role in controlling central nervous system diseases. For this purpose, a novel series of hydrazone derivatives containing imidazolidine ring aimed against Alzheimer's disease (AD), have been designed and synthesized. The acetylcholinesterase (AChE) enzyme inhibitory activity of these compounds was investigated. The structures of the compounds were determined by IR, 1 H and 13 C-NMR and mass spectroscopic methods. Inhibition studies on the cholinesterase (ChE) enzymes and ß-amyloid plaque inhibition test of the compounds were performed. Based on the experimental results, compound 3j bearing dimethoxy substituent on the aromatic ring like donepezil exhibited the most AChE inhibitory activity with the IC50 values of 0.023±0.001 µM. Owing to obtained biological activity and molecular docking study results, it is thought that the most active compound 3j may play a role in both symptomatic and palliative treatment of AD.

Synthesis, Biological Evaluation and in Silico Studies of New Pyrazoline Derivatives Bearing Benzo[d]thiazol-2(3H)-one Moiety as Potential Urease Inhibitors.

Novel pyrazoline derivatives containing benzo[d]thiazol-2(3H)-one moiety were synthesized and screened for their inhibitory properties against urease, a clinically important metabolic enzyme. In vitro enzyme inhibition studies revealed that all pyrazolines (7.21-87.77 µM) were more potent than the standard inhibitor acetohydroxamic acid (251.74 µM) against the urease enzyme. Most notably, compound 2m, which is more active than the other compounds in vitro and molecular docking studies, showed a significant inhibition potential and efficient IC50 values (7.21±0.09 µM) and in silico inhibition constant (0.11 µM). Furthermore, molecular dynamics (MD) simulation analysis suggests that the binding stability of urease enzyme and compound 2m were stably maintained during the 100 ns simulation time. Compound 2m also exhibited good physicochemical and pharmacokinetic parameters. The overall results of urease inhibition have indicated that these pyrazoline derivative compounds can be further optimized and developed for the discovery of novel urease inhibitors.

Induction of Divergent Cell Death Pathways by Urea and Carbohydrazide Derivatives.

BACKGROUND: The complexity of cancer biology and the development of chemotherapy resistance are two main obstacles to cancer treatment and necessitate novel anticancer molecules that target different cell death pathways. Modulation of Endoplasmic Reticulum (ER) stress and subsequent activation of the Unfolded Protein Response (UPR) has been proposed as a potential chemotherapeutic target, as prolonged ER stress can lead to cell death via apoptosis or necrosis. OBJECTIVE: The present study aims to evaluate the molecular mechanism underlying the cytotoxic activity of selected urea and carbohydrazide derivatives. METHODS: Cell proliferation assays were performed on HeLa, Capan-1, MCF-7, HCC-1937, and MRC-5 cell lines by WST-1 assay. The expression levels of selected ER stress, autophagy, and apoptosis marker proteins were compared by immunoblotting to characterize the underlying mechanism of cytotoxicity. Flow cytometry was used to detect apoptosis. RESULTS: Of the tested cytotoxic compounds, 3a, 4a, 5a, 6a, and 1b dramatically and 5b moderately increased ER stress-related CHOP protein levels. Interestingly, 5b but not 3a, 4a, 5a, 6a, or 1b increased the expression of proapoptotic proteins such as cleaved PARP-1 and cleaved caspase-3 and -7. The flow-cytometry analysis further confirmed that the cytotoxic activity of 5b but not the other compounds is mediated by apoptosis, demonstrated by a significant increase in the percentage of late apoptotic cells (7-AAD/annexin V double-positive cells). CONCLUSION: Our results suggest that changing a substituent from trifluoromethyl to nitro in urea and carbohydrazide core structure alters the cell death mechanism from apoptosis to an apoptosis-independent cell death pathway. This study shows an example of how such simple modifications of a core chemical structure could cause the induction of divergent cell death pathways.

Synthesis of new hydrazone derivatives and evaluation of their monoamine oxidase inhibitory activity.

A novel series of hydrazone derivatives were designed and synthesized. Their structures were characterized by IR, 1H NMR, 13C NMR and HR-MS spectroscopic methods. The newly synthesized compounds were evaluated for their inhibitory activity against monoamine oxidase enzymes (MAO-A and MAO-B). Compounds 2a, 2k, 4a and 4i showed significant inhibitory activity against MAO-A, with IC50 value in the range of 0.084-0.207 µM compared to reference drug moclobemide (IC50 value = 6.061 µM). These compounds (2a, 2k, 4a and 4i) were exposed to cytotoxicity tests to establish their preliminary toxicological profiles and were found to be non-cytotoxic. Moreover, the most effective compound 4i was evaluated using enzyme kinetics and docking studies to elucidate the plausible mechanisms of inhibition of MAO-A. According to enzyme kinetic studies, compound 4i was a reversible and competitive inhibitor with similar inhibition features as the substrates. Also, it was seen that this compound was settled down very properly at the active site of MAO-A enzyme by doing important interactions owing to the docking studies. Finally, ADME predictions were applied to estimate pharmacokinetic profiles of synthesized compounds. According to calculated ADME predictions, all parameters of the compounds were within the standard ranges in terms of "Rule of Five" and "Rule of Three" and it was detected that the synthesized compounds (2a-4i) have good and promising pharmacokinetic profiles.

Novel 2,5-disubstituted-1,3,4-oxadiazole derivatives as MAO-B inhibitors: Synthesis, biological evaluation and molecular modeling studies.

Thirty novel 2,5-disubstituted-1,3,4-oxadiazole derivatives bearing urea moiety were designed and synthesized. IR, 1H-NMR, 13C-NMR and mass spectroscopic methods and elemental analysis were used to confirm the structures of the compounds. Their monoamine oxidase inhibitory activity was determined against the MAO-A and MAO-B isoforms. None of the compounds showed the potent MAO-A inhibitory activity, while the MAO-B inhibition was significantly found in the range of 62 to 98%. Among them, the compounds H8, H9 and H12 bearing chloro substituent at the fourth position of phenylurea were found to show potent monoamine oxidase B inhibitory activity with IC50 values 0.039-0.066 µM. To define and evaluate the interaction mechanism between compound H8 and monoamine oxidase B, molecular docking studies have been made.

Design, synthesis and biological evaluation of some new 2-Pyrazoline derivatives as potential anticancer agents.

A new series of N-(4-(1-Phenyl-5-aryl-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-4-substitutedbenzamide derivatives were designed and synthesized from new chalcone derivatives. All newly synthesized compounds were determined by using IR, 1H-NMR, 13C-NMR spectroscopic methods, elemental analysis and evaluated for their in vitro antiproliferative activities on HeLa, MCF-7, MKN-45 cancer cell lines and NIH-3T3 cell line using MTT assay. Expression of Bax and Bcl-2 proteins was detected by Western-blot analysis and caspase-3 enzyme activity was measured. Notably, compounds 1f and 2f showed a significant cytotoxic effect in all three cancer cells and did not display cytotoxicity on NIH-3T3 normal cells. (IC50 = 26.66 ± 2.73 µM on HeLa, IC50 = 9.41 ± 2.19 µM on MCF-7, IC50 = 5.17 ± 3.54 µM on MKN-45 for 1f. IC50 = 17.96 ± 3.34 µM on HeLa, IC50 = 0.69 ± 0.13 µM on MCF-7, IC50 = 0.88 ± 0.16 µM on MKN-45 for 2f.) Moreover, 1f and 2f upregulated protein expression level of Bax and downregulated protein expression level of Bcl-2 in cells. Similarly, caspase-3 activity was increased in cells via 1f and 2f. It can be concluded that 1f and 2f activated apoptosis by inducing mitochondrial apoptotic proteins in HeLa, MCF-7, MKN-45. This could be potentially new anti-cancer derivatives and used to contribute to new therapeutic development.

Design, Synthesis and Biological Screening of Novel 1,5-Diphenyl-3-(4-(trifluoromethyl)phenyl)-2-pyrazoline Derivatives.

1-Phenyl-5-substituted-3-(4-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole derivatives were synthesized from chalcone derivatives. The structures of compounds were characterized by IR, 1H NMR spectroscopic methods and elemental analysis. All compounds were evaluated for their in vitro antioxidant activity using DPPH and ABTS methods, anti-inflammatory activity using lipoxygenase inhibitory method and antidiabetic activity using the ?-glucosidase inhibitory method. Especially, pyrazoline derivatives exhibited stronger anti-inflammatory activity than the reference drug indomethacin (IC50: 50.45 µM) and their IC50 values were in the range of 0.68 and 4.45 µM. In addition, the ADME properties of all chalcone and pyrazoline derivatives were calculated by Lipinski's and Veber's rules.

Comparison of the effectiveness of partial body weight-supported treadmill exercises, robotic-assisted treadmill exercises, and anti-gravity treadmill exercises in spastic cerebral palsy.

OBJECTIVES: This study aims to compare the effectiveness of the partial body weight-supported treadmill exercise (PBWSTE), robotic-assisted treadmill exercise (RATE), and anti-gravity treadmill exercise (ATE) in children with spastic cerebral palsy (CP). PATIENTS AND METHODS: Between December 01, 2015 and May 01, 2016, a total of 29 children (18 males, 11 females; mean age 9.3±2.3 years; range, 6 to 14 years) with spastic CP were included in the study. The patients were randomly divided into three groups as the PBWSTE group (n=10), RATE group (n=10), and ATE group (n=9). Each group underwent a total of 20 treadmill exercise sessions for 45 min for five days a week for a total of four weeks. The patients were assessed using three-dimensional gait analysis, open-circle indirect calorimeter, six-minute walking test, and Gross Motor Functional Measurement (GMFM) scale before and after treatment and at two months of follow-up. RESULTS: No significant change compared to baseline was found in the walking speed on gait analysis among the groups after the treatment. There was no statistically significant difference among the groups in terms of the GFMF-D, GMFM-E and six-minute walking test (p>0.05). There was a significant improvement in the oxygen consumption in the ATE group (p>0.05) and RATE group (p>0.05), but not in the PBWSTE group (p<0.05). CONCLUSION: Our study findings indicate that all three treadmill exercises have a positive impact on walking, and RATE and ATE can be used more actively in patients with spastic CP.

Synthesis and biological evaluation of new pyrazolone Schiff bases as monoamine oxidase and cholinesterase inhibitors.

In the current work, Schiff base derivatives of antipyrine were synthesized. The chemical characterization of the compounds was confirmed using IR, 1H NMR, 13C NMR and mass spectroscopies. The inhibitory potency of synthesized compounds was investigated towards acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and monoamine oxidases A and B (MAO-A and MAO-B) enzymes. Some of the compounds displayed significant inhibitory activity against AChE and MAO-B enzymes, respectively. According to AChE enzyme inhibition assay, compounds 3e and 3g were found as the most potent derivatives with IC50 values of 0.285 µM and 0.057 µM, respectively. Also, compounds 3a (IC50 = 0.114 µM), 3h (IC50 = 0.049 µM), and 3i (IC50 = 0.054 µM) were the most active derivatives against MAO-B enzyme activity. So as to understand inhibition type, enzyme kinetics studies were carried out. Furthermore, molecular docking studies were performed to define and evaluate the interaction mechanism between compounds 3g and 3h and related enzymes. ADME (Absorption, Distribution, Metabolism, and Excretion) and BBB (Blood, Brain, Barier) permeability predictions were applied to estimate pharmacokinetic profiles of synthesized compounds.

Synthesis and structure-activity relationships of carbohydrazides and 1,3,4-oxadiazole derivatives bearing an imidazolidine moiety against the yellow fever and dengue vector, Aedes aegypti.

BACKGROUND: 1,3,4-Oxadiazole and imidazolidine rings are important heterocyclic compounds exhibiting a variety of biological activities. In this study, novel compounds with oxadiazole and imidazolidine rings were synthesized from 3-(methylsulfonyl)-2-oxoimidazolidine-1-carbonyl chloride and screened for insecticidal activities. The proposed structures of the 17 synthesized compounds were confirmed using elemental analysis, infrared (IR), proton nuclear magnetic resonance (1 H-NMR), and mass spectroscopy. RESULTS: None of the compounds showed larvicidal activity at the tested concentrations against first-instar Aedes aegypti larvae. However, nine compounds exhibited promising adulticidal activity, with mortality rates of ≥80% at 5 µg per mosquito. Further dose-response bioassays were undertaken to determine median lethal dose (LD50 ) values. Compounds 1, 2b, 2c, 2d, 2 g, 3b, 3c, 3 g, and 3 h were effective, with typical LD50 values of about 5 - 10 µg per mosquito against female Ae. aegypti. Compounds 2c (bearing a nitro group on the aromatic ring; LD50 = 2.80 ± 0.54 µg per mosquito) and 3 h (double halogen groups at 2,4 position on the phenyl ring; LD50 = 2.80 ± 0.54 µg per mosquito) were the most promising compounds. CONCLUSION: Preliminary mode of action studies failed to show consistent evidence of either neurotoxic or mitochondria-directed effects. Further chemical synthesis within this series may lead to the development of new effective insecticides. © 2017 Society of Chemical Industry.

Design, Synthesis and Evaluation of the Biological Activities of Some New Carbohydrazide and Urea Derivatives.

OBJECTIVES: Urea and carbohydrazide derivatives are important compounds exhibiting cytotoxic activities. In this study, a series of new urea and carbohydrazide derivatives containing an pyridine ring were synthesized and evaluated for cytotoxic activity. MATERIALS AND METHODS: The proposed structures of the synthesized compounds were confirmed using elemental analysis, IR, and 1H-NMR spectroscopic techniques. The cytotoxic potencies of synthesized compounds were determined using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) on BRCA mutant-carrying HCC1937 and Capan-1 cell lines, as well as on MCF7, HeLa, and MRC5 cells. RESULTS: 3a, 3b, 3c and 3d showed cytotoxic activity against all cancer cell lines. CONCLUSION: Our data indicate that compounds 3a-d are more selective to cancer cells compared with nontumoral fibroblasts; however, these compounds are not more potent on HR defective cells with BRCA mutants.

Sonographic guide for botulinum toxin injections of the upper limb: EUROMUSCULUS/USPRM spasticity approach.

The pertinent literature lacks overt technical data for optimal upper limb muscle botulinum toxin injections using ultrasound (US) imaging. Therefore, this guide is prepared for the commonly injected muscles of the upper limb and the shoulder girdle mainly in spasticity. It includes clinical information, anatomical description and explanation regarding the US imaging of several muscles. The figures have been organized to orient the readers on the innervation, injection sites, probe positioning and the US images simultaneously.

Sonographic guide for botulinum toxin injections of the lower limb: EUROMUSCULUS/USPRM spasticity approach.

The pertinent literature lacks overt technical data for optimal lower limb muscle botulinum toxin injections using ultrasound (US) imaging. Therefore, this guide is prepared for the commonly injected muscles of the lower limb and the pelvic girdle mainly in spasticity. It includes clinical information, anatomical description and explanation regarding the US imaging of several muscles. The figures have been organized to orient the readers on the innervation zones, injection sites, probe positionings and the US images simultaneously.