Anticonvulsant Classes and Possible Mechanism of Actions.

Epilepsy is considered one of the most common neurological disorders worldwide; it needs long-term or life-long treatment. Despite the presence of several novel antiepileptic drugs, approximately 30% patients still suffer from drug-resistant epilepsy. Subsequently, searching for new anticonvulsants with lower toxicity and better efficacy is still in paramount demand. Using target-based studies in the discovery of novel antiepileptics is uncommon owing to the insufficient information on the molecular pathway of epilepsy and complex mode of action for most of known antiepileptic drugs. In this review, we investigated the properties of anticonvulsants, types of epileptic seizures, and mechanism of action for anticonvulsants.

Microwave-assisted synthesis of novel steroidal heterocyclic analogs as potent inhibitors of RANKL-induced osteoclastogenesis.

Osteoporosis is a significant public health issue in our aging population. It is an excessive bone resorption condition brought on by osteoclastogenesis, which makes bones more brittle. In the present work, a series of novel heterosteroidal derivatives have been synthesized using the microwave technique and were evaluated as antiosteoclastogenic agents. The structures of the newly synthesized compounds have been confirmed using analytical and spectral data. The antiosteoclastogenic activity of the newly synthesized compounds was estimated in vitro against osteoclast-differentiated cells from the RAW 264.7 cell line. The pregnenolone dimer 10, the pyridinotestosterone derivative 2, and the phenylnicotinonitrile pregnenolone derivative 8a attained the most promising antiosteoclastogenic activity displaying IC50 (the half maximal inhibitory concentration) values of 5.45 ± 5.30, 11.88 ± 2.09, and 13.40 ± 3.00 µM, respectively, in comparison with dimethyl itaconate (IC50 = 17.76 ± 3.20 µM) and alendronate (IC50 = 4.48 ± 1.89 µM) as reference compounds. Finally, an in silico ADME (Absorption, Distribution, Metabolism, and Excretion) study was conducted to evaluate the synthesized compounds' pharmacokinetic and drug-likeness properties. The results manifested that almost all the investigated compounds' properties were compatible with the specified optimal range, which indicates their reassuring pharmacokinetic properties.

Exploring new cyclohexane carboxamides based GABA agonist: Design, synthesis, biological evaluation, in silico ADME and docking studies.

The new series of 5a-e, 6a-e and 7a-e derivatives were designed, synthesized and tested for their anticonvulsant activity using "gold standard methods" ScPTZ and MES model, neurotoxicity, liver enzymes and neurochemical assay. Screening of the synthesized analogues exhibited variable anticonvulsant potential especially in chemically induced seizures. Quantification study showed that compounds 6d and 6e were the most potent analogues with ED50 44.77 and 11.31 mg/kg, respectively in ScPTZ test. Compound 6e (0.031 mmol/kg) was about 2 fold more potent than phenobarbital (0.056 mmol/kg) and was 30 folds more potent than Ethosuximide (0.92 mmol/kg) as reference standard drug. Moreover, all the synthesized compounds were screened for acute neurotoxicity using the rotarod method to recognize motor impairment, whereas all compounds devoid from neurotoxicity except compound 5a, 5b, 7a and 7e. The most active compounds were examined for acute toxicity and the estimates for LD50 were stated. Further neurochemical study was performed to investigate the effect of the most active compounds in ScPTZ test on GABA level in brain of the mice; a significant elevation in GABA level was obvious for compound 6d compared to control group confirming GABAergic modulating activity. Docking study was accomplished to examine the binding interaction of the newly synthesized analogues with GABA-AT enzyme. Additionally, physicochemical and pharmacokinetic parameters were predicted. The attained results indicate that the newly target compounds are considered a promising scaffolds for further development of newly anticonvulsants.

Design and synthesis of some barbituric and 1,3-dimethylbarbituric acid derivatives: A non-classical scaffold for potential PARP1 inhibitors.

Six series based on barbituric acid 5a-e, 10a-d; thiobarbituric acid 6a-e, 11a-d and 1,3-dimethylbarbituric acid 7a-e, 12a-d were prepared and screened for their in vitro PARP1 inhibition. They revealed promising inhibition at nanomolar level especially compounds 5c, 7b, 7d and 7e (IC50 = 30.51, 41.60, 41.53 and 36.33 nM) with higher potency than olaparib (IC50 = 43.59 nM). Moreover, compounds 5b, 5d, 7a, 12a and 12c exhibited good comparable activity (IC50 = 65.93, 58.90, 66.57, 45.40 and 50.62 nM, respectively). Furthermore, the most active compounds 5c, 7b, 7d, 7e, 12a and 12c against PARP1 in vitro were evaluated in the BRCA1 mutated triple negative breast cancer cell line MDA-MB-436 where 5c and 12c showed higher potency compared to olaparib and result in cell cycle arrest at G2/M phase. 5c and 12c showed apoptotic effects in MDA-MB-436 and potentiated the cytotoxicity of temozolomide in A549 human lung epithelial cancer cell line. Compounds 5c and 12c represent interesting starting points towards PARP1 inhibitors.

Discovery of novel urea-diarylpyrazole hybrids as dual COX-2/sEH inhibitors with improved anti-inflammatory activity and highly reduced cardiovascular risks.

Herein we describe our efforts to develop novel anti-inflammatory/analgesic agents devoid of known cardiovascular drawbacks. In doing so, two 1,5-diarylpyrazole series of urea linked (9a-f) and amide linked (11a-f) compounds were synthesized and evaluated in vitro as dual COX-2/sEH inhibitors using recombinant enzyme assays. The in vivo anti-inflammatory and analgesic activities were then examined using reported animal models. Compounds 9b and 9c showed the highest inhibitory activities against both COX-2 and sEH (IC50 of COX-2 = 1.85 and 1.24 µM; sEH = 0.55 and 0.40 nM, respectively), besides showing the best activity as anti-inflammatory agents. Interestingly, the cardiovascular profile of the two compounds 9b and 9c was evaluated through measuring some biochemical parameters such as prostacyclin (PGI2), lactate dehydrogenase (LDH), troponin-1 (Tn-1), tumor necrosis factor- α (TNF-α), creatine kinase-M (CK-M) and reduced glutathione (GSH) in addition to a histo-pathological study to investigate the changes in the heart muscle. The results confirmed that compounds 9b and 9c have a more favorable cardio-profile than celecoxib with much less cardiovascular risks associated with the common selective COX-2 inhibitors. Finally, the current work provided a promising approach that can be optimized to serve as a lead project to overcome the cardiovascular toxicity related to the traditional selective COX-2 inhibitors.

Design, synthesis and docking studies of novel benzopyrone derivatives as anticonvulsants.

A series of coumarin derivatives 6-8, 9a-h, 11 and 13a, b -16a, b was synthesized and screened for their anticonvulsant profile. Screening of these analogues using the 'gold standard methods' revealed variable anticonvulsant potential with remarkable effects observed particularly in chemically-induced seizure test. Compounds 6, 7, 13b disclosed the highest potency among the series with 100% protection against scPTZ. Quantification study confirmed that compound 6 (ED50 0.238 mmol/kg) was the most active congener in the scPTZ model and was approximately 1.5 folds more potent than ethosuximide as reference drug Meanwhile, in the MES test, candidate drugs exhibited mild to moderate anticonvulsant efficacy, the highest of which was compound 14a, imparting 50% protection at 2.1 mmol/kg, followed by other compounds with activity ranging from 14 to 33%, as compared to diphenylhydantoin. Additionally, all candidate compounds were screened for acute neurotoxicity using the rotarod method to identify motor impairment, where almost all compounds passed the test. Further neurochemical investigation was performed to unravel the effect of the most active compound (6) on GABA level in mouse brain, where a significant elevation was evident by 4 and 1.4 folds with respect to that of the control and reference groups at p < 0.05. Molecular modeling study using Discovery Studio program was performed, where compound 6 exhibited good binding interaction with γ-aminobutyric acid aminotransferase (GABA-AT) enzyme and this was consistent with the attained experimental results.

Design and synthesis of novel PARP-1 inhibitors based on pyridopyridazinone scaffold.

Various pyridopyridazinone derivatives were designed as Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. The pyridopyridazinone scaffold was used as an isostere of the phthalazine nucleus of the lead compound Olaparib in addition to some modifications in the tail part of the molecule. Preliminary biological evaluation indicated that most compounds possessed inhibitory potencies comparable to Olaparib in nanomolar level. The best PARP-1 inhibitory activity was observed for compound 8a with (IC50 = 36 nM) compared to Olaparib as a reference drug (IC50 = 34 nM). Molecular modeling simulation revealed that, the designed compounds docked well into PARP-1 active site and their complexes are stabilized by three key hydrogen bond interactions with both Gly863 and Ser904 as well as other favorable π-π and hydrogen-π stacking interactions with Tyr907 and Tyr896, respectively. Computational ADME study predicted that the target compounds 8a and 8e have proper pharmacokinetic and drug-likeness properties. These outcomes afford a new structural framework for the design of novel inhibitors for PARP-1.

Screening and optimization of samarium-assisted complexation for the determination of norfloxacin, levofloxacin and lomefloxacin in their corresponding dosage forms employing spectrofluorimetry.

Multivariate strategy was applied for setting a fluorescent technique for the determination of three fluoroquinolones: norfloxacin (NOR), levofloxacin (LEV) and lomefloxacin (LOM) in their pure powder and dosage forms. Based on their known interaction with lanthanides, and augmented fluorescence intensity obtained by antenna effect at λex/λem = 314/553, 312/553 and 310/556 for NOR, LEV and LOM, respectively, the current research was scrutinized. Four continuous factors were selected for study in the screening step by means of Plackett-Burman Design, where temperature factor was excluded for being non-significant and the other factors as volume of metal ion solution, pH and reaction time were evaluated through Central Composite Design. 3-D surfaces demonstrations and 2-D contour plots designated the factors interactions followed by optimization plots, which defined the best blend for factors conjunction. pH factor was the chief motor force affecting the response as the number of coordinated ligands formed depends on the pH, whereas 1:2 complex is the main species at higher pH values followed by the volume of metal ion solution and ended by little effect of the reaction time. Model verification was monitored, which showed the model superiority for the three fluoroquinolones, where all target points tested were in good agreement with the predicted ones. The linear range for the tested drugs were found to be 0.090-1.280 µg/mL for NOR, 0.068-1.448 µg/mL for LEV and 0.077-1.552 µg/mL in case of LOM, thus approving the suitability of this method for Quality Control testing. Furthermore, applying these conditions to test the fluoroquinolones in their pharmaceuticals was done as well as intra and inter-day effects as to confirm the validity of this technique for routine analysis. Recovery % and RSD were found to be 99.958 ±â€¯0.797, 99.887 ±â€¯0.935 and 100.427 ±â€¯0.698 for NOR, LEV and LOM respectively in their pure powder. While it was calculated to be 100.200 ±â€¯0.785, 100.530 ±â€¯0.396 and 100.620 ±â€¯0.896 for NOR, LEV and LOM in their corresponding dosage forms. This excellent precision and accuracy obtained in results impulse it to be one of the most appropriate methods for further analysis.

Design and synthesis of novel 5-(4-chlorophenyl)furan derivatives with inhibitory activity on tubulin polymerization.

AIM: Discovery of novel series of colchicine binding site inhibitors (CBSIs). MATERIALS & METHODS: Isoxazoline 3a-d, pyrazoline 4a-b, 7a-f and 8a-f, cyclohexenone 9a-b and 10a-b or pyridine derivatives 11a-b were synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity. Most of the compounds displayed potent to moderate antitumor activity against leukemia SR cell line.7c, 7e and 11a were more potent than colchicine with IC50 of 0.09, 0.05 and 0.06 µM, and percentage inhibition in tubulin polymerization of 95.2, 96.0 and 96.3%, respectively. Compounds 7c and 11a showed cell-cycle arrest at G2/M phase and induced apoptosis and were able to bind the colchicine binding site of tubulin with comparable affinity to colchicine. Docking study showed that these compounds may interact with tubulin exploiting a binding cavity not commonly reported in the binding of CBSI. CONCLUSION: Compounds 7c and 11a may be considered as promising CBSI based on their excellent activity and favorable drug likeness profile.

Design, synthesis and biological evaluation of some novel quinazolinone derivatives as potent apoptotic inducers.

AIM: Novel quinazolinone and triazinoquinazolinone derivatives were designed and synthesized as apoptotic inducers. METHODOLOGY/RESULTS: Most of the synthesized compounds showed excellent antiproliferative activity against MCF-7 and HCT-116 cell lines, respectively. Compounds 7a, 8a, 8d, 14a and 14d were superior to doxorubicin as activators of caspases 3, 8 and 9 in HCT-116 cell line. The most potent caspase inducers, 8d and 14a showed cell cycle arrest mainly in G1 and S phase, respectively and increased the levels of p53, Bax and the Bax/Bcl-2 ratio compared with doxorubicin in HCT-116 cells with excellent selectivity against CCD-18Co human colon normal cell line. CONCLUSION: The synthesized compounds can be considered as potent apoptotic inducers interfering with extrinsic and intrinsic apoptotic pathways.

Novel diphenylthiazole derivatives with multi-target mechanism: Synthesis, docking study, anticancer and anti-inflammatory activities.

Over the last few decades, a growing body of studies addressed the anticancer activity of NSAIDs, particularly selective COX-2 inhibitors. However, their exact molecular mechanism is still unclear and is not fully investigated. In this regard, a novel series of compounds bearing a COXs privilege scaffold, diphenyl thiazole, was synthesized and evaluated for their anticancer activity against a panel of cancer cell lines. The most active compounds 10b, 14a,b, 16a, 17a,b and 18b were evaluated in vitro for COX-1/COX-2 inhibitory activity. These compounds were suggested to exert their anticancer activity through a multi-target mechanism based on their structural features. Thus, compounds 10b and 17b with the least IC50 values in MTT assay were tested against three known anticancer targets; EGFR, BRAF and tubulin. Compounds 10b and 17b showed remarkable activity against EGFR with IC50 values of 0.4 and 0.2µM, respectively and good activity against BRAF with IC50 values of 1.3 and 1.7µM, respectively. In contrast, they showed weak activity in tubulin polymerization assay. The in vivo anti-inflammatory potential was assessed and interestingly, compound 17b was the most potent compound. Together, this study offers some important insights into the correlation between COXs inhibition and cancer treatment. Additionally, the results demonstrated the promising activity of these compounds with a multi-target mechanism as good candidates for further development into potential anticancer agents.

Design, synthesis and analgesic/anti-inflammatory evaluation of novel diarylthiazole and diarylimidazole derivatives towards selective COX-1 inhibitors with better gastric profile.

The inhibition of gastric cyclooxygenase 1 (COX-1) enzyme was believed to be the major cause of non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcer. Recent studies disproved this belief and showed that the gastric tissues vulnerability is not solely connected to COX-1 inhibition. This work aimed at exploring and rationalizing the differential analgesic and anti-inflammatory activities of novel selective COX-1 inhibitors with improved gastric profile. Two novel series of 4,5-diarylthiazole and diarylimidazole were designed, synthesized in analogy to selective COX-1 inhibitors (mofezolac and FR122047) which lack gastric damaging effects. The new compounds were evaluated in vitro for their COXs inhibitory activity and in vivo for their anti-inflammatory and analgesic potentials. Four compounds; diphenylthiazole glycine derivatives (15a, 15b) and diphenylimidazolo acetic acid derivatives (19a, 19b), which possess carboxylic acid group exhibited significant activity and selectivity against COX-1 over COX-2. Of these compounds, (4,5-bis(4-methoxyphenyl)thiazol-2-yl)glycine 15b was the most potent compound against COX-1 with an inhibitory half maximal concentration (IC50) of 0.32µM and a selectivity index (COX-2 IC50/COX-1 IC50) of 28.84. Furthermore, an ulcerogenicity study was performed where the tested compounds demonstrated a significant gastric tolerance. Interestingly, the most selective COX-1 inhibitor showed higher analgesic activity in vivo as expected compared to their moderate anti-inflammatory activity. This study underscores the need for further design and development of novel analgesic agents with low tendency to cause gastric damage based on improving their COX-1 affinity and selectivity profile.

Design, synthesis and molecular docking of novel diarylcyclohexenone and diarylindazole derivatives as tubulin polymerization inhibitors.

New target compounds were designed as inhibitors of tubulin polymerization relying on using two types of ring B models (cyclohexenone and indazole) to replace the central ring in colchicine. Different functional groups (R1) were attached to manipulate their physicochemical properties and/or their biological activity. The designed compounds were assessed for their antitumor activity on HCT-116 and MCF-7 cancer cell lines. Compounds 4b, 5e and 5f exhibited comparable or higher potency than colchicine against colon HCT-116 and MCF-7 tumor cells. The mechanism of the antitumor activity was investigated through evaluating the tubulin inhibition potential of the active compounds. Compounds 4b, 5e and 5f showed percentage inhibition of tubulin in both cell line homogenates ranging from 79.72% to 89.31%. Cell cycle analysis of compounds 4b, 5e and 5f revealed cell cycle arrest at G2/M phase. Molecular docking revealed the binding mode of these new compounds into the colchicine binding site of tubulin.[Formula: see text].

Novel pyrazolo[3,4-d]pyrimidines as dual Src-Abl inhibitors active against mutant form of Abl and the leukemia K-562 cell line.

Some novel 6-substituted pyrazolo[3,4-d]pyrimidines 4, 5, 6a-d, 7a-c, 8 and pyrazolo[4,3-e][1,2,4]triazolo[4,3-a]pyrimidines 9a-c, 10a-c, 11, 12a,b, 13a-c and 14 were synthesized and characterized by spectral and elemental analyses. They were screened for their biological activity in vitro against Abl and Src kinases. Compounds 7a and 7b revealed the highest activity against both wild and mutant Abl kinases as well as the Src kinase and the leukemia K-562 cell line. They can be considered as new hits for further structural optimization to obtain better activity.

Novel pyrazolopyrimidine derivatives targeting COXs and iNOS enzymes; design, synthesis and biological evaluation as potential anti-inflammatory agents.

A novel set of 4-substituted-1-phenyl-pyrazolo[3,4-d]pyrimidine and 5-substituted-1-phenyl-pyrazolo[3,4-d]pyrimidin-4-one derivatives were synthesized and evaluated as potential anti-inflammatory agents. The newly prepared compounds were assessed through the examination of their in vitro inhibition of four targets; cyclooxygenases subtypes (COX-1 and COX-2), inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF-κB). Compounds 8a, 10c and 13c were the most potent and selective ligands against COX-2 with inhibition percentages of 79.6%, 78.7% and 78.9% at a concentration of 2 µM respectively, while compound 13c significantly inhibited both COX subtypes. On the other hand, fourteen compounds showed high iNOS inhibitory activities with IC50 values in the range of 0.22-8.5µM where the urea derivative 11 was the most active compound with IC50 value of 0.22 µM. Most of the tested compounds were found to be devoid of inhibitory activity against NF-kB. Moreover, almost all compounds were not cytotoxic, (up to 25 µg/ml), against a panel of normal and cancer cell lines. The in silico docking results were in agreement with the in vitro inhibitory activities against COXs and iNOS enzymes. The results of in vivo anti-inflammatory and antinociceptive studies were consistent with that of in vitro studies which confirmed that compounds 8a, 10c and 13c have significant anti-inflammatory and analgesic activities comparable to that of the control, ketorolac. Taken together, dual inhibition of COXs and iNOS with novel pyrazolopyrimidine derivatives is a valid strategy for the development of anti-inflammatory/analgesic agents with the probability of fewer side effects.

Simultaneous determination of chlordiazepoxide and selected antidepressants using CZE.

A simple CE method was developed and validated for the simultaneous determination of chlordiazepoxide (CHL), amitriptyline, and nortriptyline (mixture I) or the determination of CHL and imipramine (mixture II) using the same BGE. Sertraline and amitriptyline were used as internal standards for the first and second mixtures, respectively. The method allows amitriptyline to be completely separated from its impurity and main metabolite nortriptyline, which can be quantified from 0.2 µg/mL. The separation was achieved using 20 mM potassium phosphate buffer pH 5 containing 12 mM ß-cyclodextrin and 1 mM carboxymethyl-ß-cyclodextrin. UV detection was performed at 200 nm and a voltage of 15 kV was applied on an uncoated fused-silica capillary at 25°C. These experimental conditions allowed separation of the compounds to be obtained in 7 min. Calibration graphs proved the linearity up to 40 µg/mL for CHL, up to 100 µg/mL for amitriptyline and imipramine, and up to 5 µg/mL for nortriptyline. The accuracy and precision of the method have been determined by analyzing synthetic mixtures and pharmaceutical formulations. The analytical results were quite good in all cases indicating that the method was linear, sensitive, precise, accurate, and selective for both mixtures.

3-{[5-(4-Chloro-phen-yl)-3-methyl-1H-pyrazol-1-yl]meth-yl}-4-m-tolyl-1H-1,2,4-triazole-5(4H)-thione.

In the title compound, C20H18ClN5S, the toluene and triazole rings are oriented almost perpendicular to each other, making a dihedral angle of 89.97 (9)°, whereas the dihedral angle between cholorophenyl and pyrazole rings is 54.57 (11)°. In the crystal, pairs of N-H⋯N hydrogen bonds link the mol-ecules into inversion dimers. Weaker C-H⋯S and C-H⋯Cl inter-actions are also present.

4-[5-(4-Chloro-phen-yl)-3-methyl-1H-pyrazol-1-yl]benzene-sulfonamide.

In the title compound, C(16)H(14)ClN(3)O(2)S, the dihedral angle between the benzene and pyrazole rings is 52.75 (2)°, while that between the pyrazole and 4-chloro-phenyl rings is 54.0 (3)°. The terminal sulfonamide group adopts an approximately tetra-hedral geometry about the S atom with a C-S-N angle of 108.33 (10)°. In the crystal, pairs of N-H⋯N hydrogen bonds lead to the formation of inversion dimers. These dimers are linked via a second pair of N-H⋯N hydrogen bonds and C-H⋯O interactions, forming a two-dimensional network lying parallel to the bc plane. The two-dimensional networks are linked via C-H⋯Cl interactions, forming a three-dimensional structure.

Design, Synthesis and Biological Evaluation of Novel Pyrimido[4,5-d]pyrimidine CDK2 Inhibitors as Anti-Tumor Agents.

A series of 2,5,7-trisubstituted pyrimido[4,5-d]pyrimidine cyclin-dependent kinase (CDK2) inhibitors is designed and synthesized. 6-Amino-2-thiouracil is reacted with an aldehyde and thiourea to prepare the pyrimido[4,5-d]-pyrimidines. Alkylation and amination of the latter ones give different amino derivatives. These compounds show potent and selective CDK inhibitory activities and inhibit in vitro cellular proliferation in cultured human tumor cells.