Design and synthesis of some new quinazolin-4-(3H)-ones as anticonvulsant and antidepressant agents

A series of 3-[(4-substituted-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-ones (5a–k) were synthesized by reacting 3-amino-2-phenyl-1H-quinazolin-4-one with p-hydroxybenzaldehyde, and then further with various alkyl/benzyl halides or substituted phenacyl bromides. The structures of the compounds were confirmed on the basis of IR, NMR, MS and elemental analysis. Anticonvulsant activities were evaluated using the MES and scPTZ tests. Some of the selected compounds were evaluated for antidepressant activity by forced swim pool test. Compound 3-[(4-butoxy-benzylidene)-amino]-2-phenyl-3H-quinazolin-4-one was emerged as the most promising anticonvulsant agent without any motor impairment effect. The whole brain GABA estimation of brain homogenate indicated that the anticonvulsant activity of above mentioned quinazolinone derivatives might be due to an increased GABA concentration.     

Design, synthesis, and potential CNS activity of some new bioactive 1-(4-substituted-phenyl)-3-(4-oxo-2-methyl-4H-quinazolin-3-yl)-urea

Twelve new 1-(4-substituted-phenyl)-3-(4-oxo-2-methyl-4H-quinazolin-3-yl)-urea were synthesized and screened for anticonvulsant, CNS depressant, and sedative-hypnotic activity. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight 2,3-Disubstituted-quinazolin-4(3H)-one were examined in the maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. Spectroscopic data and elemental analysis were consistent with the newly synthesized compounds. The neurotoxicity was assessed using the rotorod method. M3, M4, and M10 were found to be active in both MES screen and scPTZ screen at 0.5 h. All except M11 showed more than 44% decrease in locomotor activity after 1 h of compound administration via actophotometer screen. CNS-depressant activity screened with the help of the forced swim method resulted into some potent compounds. Except for M6 and M11 other tested compounds were found to exhibit potent CNS depressants activity as indicated by increased immobility time. It can be concluded that newly synthesized compounds possessed sedative-hypnotic and CNS depressant activities.     

Novel 1-phenylcycloalkanecarboxylic acid derivatives as potential anticonvulsant agents

A series of analogues based on the anticonvulsant carbetapentane (1, 2-[2-(diethylamino)ethoxy]ethyl 1-phenyl-1-cyclopentylcarboxylate) was prepared as potential novel anticonvulsant drugs. Structure-activity relationships of analogues in which the ester function and cyclopentane moieties were modified have been investigated by evaluating their ability to prevent seizures in the rat maximal electroshock test. These compounds (11, ED50 = 16 mumol/kg; 12, ED50 = 86 mumol/kg, and 23, ED50 = 173 mumol/kg) were effective anticonvulsants. Compound 11, an alkyl ether derivative of 1, was more potent than the parent compound (ED50 = 48 mumol/kg) and also showed a 2-fold increase in potency compared to that of the prototypic anticonvulsant drug diphenylhydantoin.     

Synthesis of 6-(3-substituted-4H-1,2,4-triazol-4-yl)-2-phenylbenzo[d]oxazoles as potential anticonvulsant agents

A series of 6-(3-substituted-4H-1,2,4-triazol-4-yl)-2-phenylbenzo[d]oxazoles was synthesized. The anticonvulsant effect and neurotoxicity of the compounds were calculated with maximal electroshock (MES) test, subcutaneous pentylenetetrazole (Sc-PTZ), and rotarod tests in intraperitoneally injected mice. Among the synthesized compounds, compound 2-phenyl-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazole (3a) could be considered the potentially most useful and safe therapeutic compound, with ED₅₀ = 29.6 mg/kg, TD₅₀ = 285 mg/kg, and PI = 9.7. Its neurotoxicity was the lowest of all the synthesized compounds and was also markedly lower than that of the reference drug carbamazepine with PI value of 6.4.     

Design and synthesis of some new 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-ureas as potent anticonvulsant and antidepressant agents

A series of 1-phenyl-3/4-[4-(aryl/heteroaryl/alkyl-piperazine1-yl)-phenyl-urea derivatives (29–42) were designed, synthesized and evaluated for their anticonvulsant activity by using maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) seizure tests. The acute neurotoxicity was checked by rotarod assay. Most of the test compounds were found effective in both seizure tests. Compound 30 (1-{4-[4-(4-chloro-phenyl)-piperazin-1-yl]-phenyl}-3-phenyl-urea) exhibited marked anticonvulsant activity in MES as well as scPTZ tests. The phase II anticonvulsant quantification study of compound 30 indicates the ED₅₀ value of 28.5 mg/kg against MES induced seizures. In addition, this compound also showed considerable protection against pilocarpine induced status epilepticus in rats. Seizures induced by 3-mercaptopropionic acid model and thiosemicarbazide were significantly attenuated by compound 30, which suggested its broad spectrum of anticonvulsant activity. Interestingly, compound 30 displayed better antidepressant activity than standard drug fluoxetine. Moreover, compound 30 appeared as a non-toxic chemical entity in sub-acute toxicity studies.     

1-苄基-2-(4''''-甲磺酰基-1-羟基-苯乙基)-1,2,3,4-四氢异喹啉类化合物的合成及其抗心律失常活性

目的寻找具有Ⅲ／Ⅱ复合作用的新型抗心律失常药物。方法拼合1-苄基-1，2，3，4-四氢异喹啉与具有Ⅲ／Ⅱ复合作用的sotalol结构片段，设计合成1-苄基-2-（4’-甲磺酰基-1-羟基-苯乙基）-1，2，3，4-四氢异喹啉类化合物，通过离体豚鼠心肌标本不应期测定法对所合成的目标化合物进行筛选。结果合成了18个未见文献报道的新化合物（1a～1r）。体外结果表明化合物1d、1e、1i、1j具有较好的延长动作电位时程的作用。结论化合物1d、1e、1i、1j表现出Ⅲ类抗心律失常药物延长动作电位时程的特征，有关Ⅲ／Ⅱ复合作用的药理实验有待进行。     

Design, synthesis and pharmacological evaluation of some novel 2-(4-nitrophenyl)-3-methylthio-3-(substituted)arylamino acrylamides as potential anti-inflammatory agents

On the basis of structure based drug design we have designed a series of 2-(4-nitrophenyl)-3-methylthio-3-(substituted)arylamino acrylamides as potential antiinflammatory agents. Good 3D similarity was observed between the designed molecule and rofecoxib (r.m.s.d. 0.161). The effect of opening the central ring and introducing a spacer (-NH-) between one of the aryl rings and the central ring of the basic structure of the COX-2 inhibitors was also studied. The designed molecules were synthesised by thiocarbomylation of the 4-nitro-phenylacetamide with aryl isothiocyanates followed by subsequent methylation of the enethiolate salts. All compounds were screened for their antiinflammatory activity by the carrageenan induced rat paw edema method. Compounds 4 and 6 exhibited potent antiinflammatory activity, which was found to be comparable with the standard drug, rofecoxib. Both the potent molecules were also screened for their ulcerogenic potential in Albino rats. A very low ulcer index was observed with both compounds, although higher than rofecoxib.     

Synthesis of 1-phenyl-2-(phenylcarbamoyl)pyrazolidines as potential anticonvulsant agents.

Twelve 1-phenyl-2-(phenylcarbamoyl)pyrazolidines were synthesized from 1-arylpyrazolidines and aryl isocyanates. These adducts showed little anticonvulsant activity in the maximal electroshock seizure and pentylenetetrazol seizure assays.     

Synthesis of some derivatives of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(piperazin-1-yl)-3-quino linecarbo xylic acid (norfloxacin) as potential antibacterial agents

Twelve new fluoroquinolones, structurally related to norfloxacin, have been synthesized in order to investigate the effect of substituents at the secondary nitrogen of the piperazine ring on antimicrobial activity. The new substances (carbamates, isoureas, guanidines, ureas and cyanamides) tested on a variety of gram-positive and gram-negative organisms showed lower activity than the model compound.     

Design, synthesis, and pharmacological characterization of 4-[4, 4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]- 2-iodobenzonitrile as a high-affinity nonsteroidal androgen receptor ligand

4-[4, 4-Dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-+ ++trif luoromethylbenzonitrile (RU 59063) is a prototype of a new class of high-affinity nonsteroidal androgen receptor (AR) ligands. The search for a radioiodinated AR ligand prompted us to synthesize 4-[4, 4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-i odo benzonitrile (DTIB) wherein the trifluoromethyl group of RU 59063 was substituted with the similarly hydrophobic iodine atom. DTIB displayed subnanomolar binding affinity (K(i) = 0.71 +/- 0.22 nM) for the rat AR in competitive binding assays. Additionally, DTIB demonstrated potent agonist activity, comparable to that of the natural androgen 5alpha-dihydrotestosterone (DHT), in a cell-based functional assay (cotransfection assay). DTIB represents a new lead for the development of high-affinity radioiodinated AR radioligands.     

Design and synthesis of 3-[3-(substituted phenyl)-4-piperidin-1-ylmethyl/-4-morpholin-4-ylmethyl-4,5-dihydro-isoxazol-5-yl]-1H-indoles as potent anti-inflammatory agents

The synthesis of new indole derivatives bearing isoxazoline moiety (3a–d and 4a–d) has been described. IR, ¹H NMR, and mass spectral data supported the structures of synthesized compounds. The compounds were tested in vivo for their anti-inflammatory activity by carrageenin-induced rat paw edema method. The compounds that showed good anti-inflammatory activity were screened for their ulcerogenic and lipid peroxidation activities. The most active compound of this series is 3-[3-(4-methoxyphenyl)- 4-morpholin-4-ylmethyl)-4,5-dihydro-isoxazol-5yl]-1H-indole 4d.     

Design, synthesis, molecular docking, and biological evaluation of N-methyl-3-nitro-4-(nitromethyl)-4H-chromen-2-amine derivatives as potential anti-cancer agents

A series of N-methyl-3-nitro-4-(nitromethyl)-4H-chromen-2-amine derivatives 8 were synthesized from 2-((E)-2-nitrovinyl)phenol 7 and ((E)-N-methyl)-1-(methylthio)-2-nitroethenamine 5. The cytotoxic activity of these molecules was tested against two cancer cell lines namely HeLa (cervical cancer) and HEp-2 (epidermoid laryngeal carcinoma). Among them, two molecules (4H-chromenes 8h and 8i) displayed potent anti-proliferative activity with IC₅₀ values of 115.04 and 18.96 μM for HeLa and 86.94 and 25.08 μM for Hep-2 cell lines, respectively. Morphological evaluation of the cell lines revealed that both 8h and 8i induce the apoptotic process. Molecular docking studies of all the 4H-chromenes 8 with anti-apoptotic Bcl-2, Bcl-w, and Bcl-xL proteins revealed that the 4H-chromenes 8h and 8i have good docking score and thus corroborated in vitro studies. Furthermore, evaluation of Lipinski and ADMET properties revealed their drug-like pharmacokinetic profiles. Thus, 4H-chromenes 8h and 8i exhibit promising anti-cancer properties and can be used as lead compounds for further development.     

Design and synthesis of 2-hydroxyl-4-methoxyl-3-(3-methylbut-2-en-1-yl)-6-(4-phenylbenzoylamino)benzoic acid derivatives as antibacterial agents based on cajaninstilbene acid scaffold hopping

The prevalence of multidrug resistance among clinically significant bacterial pathogens underlines a critical need for the development of new classes of antibacterial agents with novel structural scaffolds. Cajaninstilbene acid (CSA), which is isolated from pigeonpea leaves, has shown potent antibacterial activity. In this study, a series of 2-hydroxyl-4-methoxyl-3-(3-methylbut-2-en-1-yl)-6-(4-phenylbenzoylamino)benzoic acid derivatives derived from CSA were designed and synthesized, and their antibacterial activities were evaluated. Several synthesized compounds exhibit better antibacterial activity than CSA against Staphylococcus aureus, Staphylococcus epidermidis, and two strains of methicillin-resistant S. aureus. Meanwhile, the results of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide assays illustrate the good selectivity between bacteria and normal cells of the most active compounds 6u and 6v . Furthermore, well combinations with bacterial RNA polymerase of 6u arising from docking study imply the possible mechanism of antibacterial activity of these synthetic compounds.     

Design and synthesis of some novel 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2-phenylquinazoline-4(3H)-ones as possible anticonvulsant agent

A novel series 7(a–f) 3-[5-(4-substituted) phenyl-1,3,4-oxadiazole-2yl]-2 phenylquinazoline-4(3H)-ones have been synthesized and screened for its anticonvulsant and neurotoxic activity. After i.p. injection to mice at doses of 30, 100, and 300 mg/kg body weight 2,3-disubstituted-quinazolin-4(3H)-ones were examined in the maximal electroshock induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. Spectroscopic data were consistent with the structure of newly synthesized compounds. The neurotoxicity was assessed using the rotorod method. In the prepared series, 7a was found to be active in the MES screen at 0.5 h, whereas 7f showed anticonvulsant activity at both 0.5 and 4 h.     

Design and synthesis of 3-(4-chlorophenyl)-2-(2-(4-substituted)-2-oxoethylthio)quinazolin-4(3H)-one as antihistamine agents

A series of novel 3-(4-chlorophenyl)-2-(2-(4-substituted)-2-oxoethylthio)quinazolin-4(3H)-one was synthesized by the reaction of 2-(3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetyl chloride with various amines. The starting material, (3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetyl chloride was synthesized from 4-chloroaniline by a multistep synthesis. All the title compounds were tested for their in vivo H₁-antihistaminic activity on conscious guinea pigs at the dose level of 10 mg/kg using chlorpheniramine maleate as the reference standard. The results of the biological activity indicate that the test compounds protected the animals from histamine-induced bronchospasm significantly. Compound 3-(4-chlorophenyl)-2-(2-(4-methylpiperazin-1-yl)-2-oxoethylthio)quinazolin-4(3H)-one (1) emerged as the most potent compound of the series (71.13 % protection) when compared to the reference standard chlorpheniramine maleate (70.09 % protection). Interestingly, compound A1 shows negligible sedation (12 %) compared to chlorpheniramine maleate (32 %). Therefore, compound A1 can serve as the lead molecule for further development.     

Design,synthesis, and biological evaluation of 4-methoxy-3-arylamido-N-(substitutedphenyl)benzamide derivatives as potential antiplatelet agents

A series of 4-methoxy-3-arylamido-N-(substitutedphenyl)benzamides 6a – u were designed according to the splicing principle of structural design in the medicinal chemistry theory and were synthesized in five steps: nitration, acylation, ammoniation, reduction, and secondary ammoniation. The structures of the target compounds were characterized and verified by infrared, ¹H nuclear magnetic resonance (NMR), ¹³C NMR, and electron spray ionization spectroscopy. Their in vitro antiplatelet aggregation activities induced by adenosine diphosphate (ADP) or arachidonic acid (AA) were assessed by Born's method. The biological evaluation revealed that all compounds exhibited certain levels of activities in both of the antiplatelet aggregation assays; compounds 6c (IC₅₀ = 3.84 μM) and 6f (IC₅₀ = 3.12 μM) displayed the strongest antiplatelet aggregation activities in the ADP-induced and AA-induced assay, separately. Moreover, compounds that had stronger activities were chosen for cell toxicity testing via the cell counting kit-8 assay. The results indicated that none of the compounds had obvious cell toxicity against L929 cells at the doses of 10 and 20 μM. It is worth pointing out that compound 6c showed the highest antiplatelet activity and the lowest cell toxicity. In general, 4-methoxy-3-arylamido-N-(substitutedphenyl)benzamides have the potential to become a kind of safer and more effective antiplatelet agents.     

Design and synthesis of novel N-substituted-3-chloro-2-azetidinone derivatives as potential anticonvulsant agents

Abstract  

A new series of N-[3-chloro-2-(substitutedphenyl)-4-oxo-azetidin-1-yl]isonicotinamide (2a–l) were synthesized through condensation reaction of isoniazide with substituted aldehyde. The newly synthesized compounds were characterized by spectral data (IR, ¹H NMR, mass spectra) and elemental analysis. Compound 2e exhibited excellent anticonvulsant activity and no neurotoxicity in comparison to reference drug phenytoin.     

beta-Lactam derivatives as enzyme inhibitors: derivatives of (E)-2-[(RS)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-ylidene]propionic acid

The 1,4-diaryl disubstituted azetidin-2-one (beta-lactam) 1 is transformed into the 3-methylidene derivative (E)-2-[(RS)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-ylidene]propionic acid (3), and then, using the DCC/NHS method reacted with amino acid esters and dipeptide esters forming 3-(peptidyl)-beta-lactams 5 and 7. Structures and properties are evaluated mainly by spectroscopic methods and discussed. As molecular modeling experiments might suggest a potential activity as inhibitors of PPE(HLE), a number of selected compounds has been tested in an enzyme assay. But none of them showed any remarkable inhibitory activity. Evaluation of the data was done with the new program EnKinPlot.