Design, synthesis and anti-inflammatory assessment of certain substituted 1,2,4-triazoles bearing tetrahydroisoquinoline scaffold as COX 1/2-inhibitors.

Aiming to discover effective and safe non-steroidal anti-inflammatory agents, a new set of 1,2,4-triazole tetrahydroisoquinoline hybrids 9a-g, 11a-g and 12a-g was synthesized and evaluated as inhibitors of COX-1 and COX-2. In order to overcome the adverse effects of highly selective COX-2 and non-selective COX-2 inhibitors, the compounds of this study were designed with the goal of obtaining moderately selective COX-2 inhibitors. In this study compounds 9e, 9g and 11f are the most effective derivatives against COX-2 with IC50 values 0.87, 1.27 and 0.58 µM, respectively which are better than or comparable to the standard drug celecoxib (IC50 = 0.82 µM) but with lower selectivity indices as required by our goal design. The results of the in vivo anti-inflammatory inhibition test revealed that compounds 9e, 9g and 11f displayed a higher significant anti-inflammatory activity than celecoxib at all-time intervals. In addition, these compounds significantly decreased the production of inflammatory mediators PGE-2, TNF-ɑ and IL-6. Compounds 9e, 9g and 11f had a safe gastric profile compared to indomethacin, also compound 11f (ulcerogenic index = 1.33) was less ulcerous than the safe celecoxib (ulcerogenic index = 3). Moreover, histopathological investigations revealed a normal architecture of both paw skin and gastric mucosa after oral treatment of rats with compound 11f. Furthermore, molecular docking studies were performed on COX-1 and COX-2 to study the binding pattern of compounds 9e, 9g and 11f on both isoenzymes.

Synthesis, molecular modeling studies, and anticonvulsant evaluation of novel 1-((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides and their acetate esters.

A series of 1-((2-hydroxyethyl)(aryl)amino)-N-substituted cycloalkanecarboxamides IXa-l and their acetate esters Xa-l were designed and synthesized as new anticovulsant agents. The evaluation of the anticonvulsant effect was performed in vivo by subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) tests in mice. Further, neurotoxicity, hepatotoxicity, and acute toxicity were determined. All the new candidates displayed 100% anticonvulsant activity in the scPTZ screen in the dose range of 0.0057-0.283 mmol/kg. The most potent compounds in the scPTZ screen were Xh (ED50 = 0.0012 mmol/kg), Xd (ED50 = 0.002 mmol/kg), Xf (ED50 = 0.004 mmol/kg), IXj (ED50 = 0.0047 mmol/kg), Xl (ED50 = 0.0076 mmol/kg), and Xi (ED50 = 0.008 mmol/kg). They exhibited higher fold activity in the anticonvulsant potential than the gold standards, phenobarbital and ethosuximide. Compound Xf was active in both scPTZ and MES screens. It showed ED50 of 0.016 mmol/kg in MES screen. In the neurotoxicity screens, none of the test compounds displayed any minimal motor impairment at the maximum administered dose. The 3D pharmacophore model using Biova 1 Discovery Studio 2016 programs exhibited high fit value. The anticonvulsant evaluation results were compatible with the molecular modeling study.

Enantioseparation of Substituted 1, 3-Diazaspiro [4.5]Decan-4-Ones: HPLC Comparative Study on Different Polysaccharide Type Chiral Stationary Phases.

Enantioseparation of substituted 1,3-diazaspiro[4.5]decan-4-ones (1-14) was achieved using different polysaccharide type chiral stationary phases (CSPs), namely, Chiralcel OJ, Chiralcel OD and Lux-Amylose-2 using different mobile phases which were either n-hexane/2-propanol or n-hexane/ethanol mixtures of various ratios (v/v) at flow rate 1 mL min-1. UV detection was carried out at 254 nm and temperature of 20°C. The retention behavior and selectivity of these CSPs were examined in isocratic normal phase high-performance liquid chromatography mode. The results revealed that the amylose CSP (Lux-Amylose-2) could separate almost all the compounds under investigation in contrast to cellulose CSPs (Chiracel OJ and Chiracel OD) which resolved fewer compounds.

Design, synthesis and antibacterial potential of 5-(benzo[d][1,3]dioxol-5-yl)-3-tert-butyl-1-substituted-4,5-dihydropyrazoles.

A series of 5-(benzo[d][1,3]dioxol-5-yl)-3-tert-butyl-1-substituted-4,5-dihydropyrazole derivatives 4a-e and 6a-g have been synthesized and spectrally characterized. The antibacterial activity of the novel candidates has been screened using the agar diffusion test. These compounds were endowed with high antibacterial activity against different Gram +ve and Gram -ve bacteria when compared with standard antibacterial drugs. In the light of zone of inhibition and MIC results, Sarcina and Staphylococcus aureus are the most sensitive bacteria where pyrrolidinomethanone derivative 4e showed MICs at 80 and 110 nM, respectively. While hydroxypiperidinoethanone derivative 6c showed MIC at 90 nM for Sarcina.

Anticonvulsant profiles of certain new 6-aryl-9-substituted-6,9-diazaspiro-[4.5]decane-8,10-diones and 1-aryl-4-substituted-1,4-diazaspiro[5.5]undecane-3,5-diones.

Synthesis and anticonvulsant potential of certain new 6-aryl-9-substituted-6,9-diazaspiro[4.5]decane-8,10-diones (6a-l) and 1-aryl-4-substituted-1,4-diazaspiro[5.5] undecane-3,5-diones (6m-x) are reported. The intermediates 1-[(aryl)(cyanomethyl)amino] cycloalkanecarboxamides (3a-f) were prepared via adopting Strecker synthesis on the proper cycloalkanone followed by partial hydrolysis of the obtained nitrile functionality and subsequent N-cyanomethylation. Compounds 3a-f were subjected to complete nitrile hydrolysis to give the respective carboxylic acid derivatives 4a-f which were cyclized under mild conditions to give the spiro compounds 5a-f. Ultimately, compounds 5a-f were alkylated or aralkylated to give the target compounds 6a-i and 6m-u. On the other hand, compounds 6j-l and 6v-x were synthesized from the intermediates 5a-f through alkylation, dehydration and finally tetrazole ring formation. Anticonvulsant screening of the target compounds 6a-x revealed that compound 6g showed an ED50 of 0.0043 mmol/kg in the scPTZ screen, being about 14 and 214 fold more potent than the reference drugs, Phenobarbital (ED50 = 0.06 mmol/kg) and Ethosuximide (ED50 = 0.92 mmol/kg), respectively. Compound 6e exhibited an ED50 of 0.019 mmol/kg, being about 1.8 fold more potent than that of the reference drug, Diphenylhydantoin (ED50 = 0.034 mmol/kg) in the MES screen. Interestingly, all the test compounds 6a-x did not show any minimal motor impairment at the maximum administered dose in the neurotoxicity screen.

Anticonvulsant potential of certain new (2E)-2-[1-Aryl-3-(1H-imidazol-1-yl)propylidene]-N-(aryl/H)hydrazinecarboxamides.

Anticonvulsant potential and neurotoxicity of certain new imidazole-containing arylsemicarbazones 6a-p are reported. The test compounds 6a-p exhibited anticonvulsant activity mainly in the scPTZ screen. Compound 6p emerged as the most active surrogate displaying 100% protection at a dose level of 636 µ mol/kg in the scPTZ screen without any neurotoxicity. The assigned (E)-configuration of the title compounds 6a-p was confirmed via single crystal X-ray structure of compound 6g.

1-{(E)-[3-(1H-Imidazol-1-yl)-1-(4-meth-oxy-phen-yl)propyl-idene]amino}-3-(2-methyl-phen-yl)urea.

In the title compound, C(21)H(23)N(5)O(2), the conformation about the imine bond [1.287 (3) Å] is E. Overall, the mol-ecule has a disk shape, the dihedral angles between the imidazole ring and the meth-oxy-phenyl and methyl-phenyl rings being 49.42 (13) and 42.62 (13)°, respectively; the dihedral angle between the benzene rings is 20.11 (11)°. In the urea moiety, the N-H atoms are anti to each other and one of these forms an intra-molecular N-H⋯N hydrogen bond. In the crystal, centrosymmetric dimers are formed via N-H⋯N(imidazole) hydrogen bonds, which are connected into a three-dimensional architecture by C-H⋯O(carbon-yl) and (methyl-ene)C-H⋯π inter-actions. The crystal studied was a non-merohedral twin with a minor component of 48.3 (1)%.

1-{(E)-[3-(1H-Imidazol-1-yl)-1-phenyl-propyl-idene]amino}-3-(2-methyl-phen-yl)urea.

In the title compound, C(20)H(21)N(5)O, the conformation about the imine bond [1.289 (3) Å] is E. Overall, the mol-ecule is disk-shaped with the imidazole ring located above the remainder of the mol-ecule and with the dihedral angles of 10.97 (15) and 12.11 (15)°, respectively, between the imidazole ring and the phenyl and methyl-benzene rings; the dihedral angle between the aromatic rings is 8.17 (14)°. Within the urea unit, the N-H atoms are anti to each other and one of the N-H atoms forms an intra-molecular N-H⋯N hydrogen bond. Helical supra-molecular chains along [001] are formed via N-H⋯N(imidazole) hydrogen bonds in the crystal structure. These are connected into a three-dimensional architecture by C-H⋯O(carbon-yl) and C-H⋯π inter-actions.

Design and synthesis of novel stiripentol analogues as potential anticonvulsants.

A series of stiripentol (STP) analogues namely, 2-[(1E)-1-(1,3-benzodioxol-5-yl)-4,4-dimethylpent-1-en-3-ylidene]-N-(aryl/H)hydrazinecarboxamides 7a-h, (±)-(5RS)-N-(aryl/H)-(1,3-benzodioxol-5-yl)-3-tert-butyl-4,5-dihydro-1H-pyrazole-1-carboxamides (±)-8a-h, and (±)-[(5RS)-(1,3-benzodioxol-5-yl)-3-tert-butyl-4,5-dihydro-1H-pyrazol-1-yl](aryl)methanones (±)-13a-f was synthesized by adopting appropriate synthetic routes and was pharmacologically evaluated in the preliminary anticonvulsant screens. The selected bioactive new chemical entities were subjected to ED(50) determination and neurotoxicity evaluation. The most active congeners are 7h in MES screen and (±)-13b in scPTZ screen which displayed ED(50) values of 87 and 110 mg/kg, respectively, as compared to that of STP (ED(50) = 277.7 and 115 mg/kg in MES and scPTZ, respectively).

A cyclohexanecarboxamide derivative with inhibitory effects on Schistosoma mansoni cercarial serine protease and penetration of mice skin by the parasite.

A cyclohexanecarboxamide derivative, N-phenyl-N-[1-(piperidine-1-carbonyl)cyclohexyl] benzamide (MNRC-5), was evaluated for its inhibitory effects on Schistosoma mansoni cercarial serine protease activity and cercarial penetration. MNRC-5 exerted an inhibitory effect on S. mansoni cercarial serine protease at serial concentrations of the specific chromogenic substrate Boc-Val-Leu-Gly-Arg-PNA for such enzyme family and the inhibitory coefficient (Ki) value was deduced. Moreover, topical treatment of mice tails with the most potent inhibitory concentration of MNRC-5 formulated in jojoba oil successfully blocked cercarial penetration as demonstrated by a significant reduction (75%; p < 0.05) in the recovered S. mansoni worms from treated mice in comparison to control ones whose tails were painted with jojoba oil base containing no MNRC-5. In addition, the IgM and IgG reactivities to crude S. mansoni cercarial, worm and egg antigens were generally lower in sera from treated infected mice than untreated infected mice. In conclusion, we report on a new serine protease inhibitor capable for blocking penetration of host skin by S. mansoni cercariae as measured by lowering worm burden and decrease in the levels of both IgM and IgG towards different bilharzial antigens upon topical treatment.

Ligand design and synthesis of new imidazo[5,1-b]quinazoline derivatives as alpha1-adrenoceptor agonists and antagonists.

A series of new imidazo[5,1-b]quinazoline derivatives (VII-IX) was designed, synthesized, and biologically evaluated for their in vivo hypotensive or hypertensive activities. The design of these compounds was based upon the molecular modeling simulation of the fitting values and conformational energy values of the best-fitted conformers to both the alpha(1)-adrenoceptor (alpha(1)-AR) agonist and alpha(1)-adrenoceptor (alpha(1)-AR) antagonist hypotheses. These hypotheses were generated from their corresponding lead compounds using CATALYST software. The simulation studies predicted that compounds IXa and IXe would have probable affinity for the alpha(1)-AR antagonist hypothesis, while compounds IXb, IXc, and IXg predicted a higher affinity for the alpha(1)-AR agonist hypothesis. In vivo biological evaluation of these compounds for their effects on the blood pressure of normotensive cats was consistent with the results of molecular modeling studies, where compounds IXa and IXe exhibited hypotensive activity, while compounds IXb, IXc, and IXg resulted in increasing the blood pressure of the experimental animals at different doses.