Synthesis,biological evaluations and molecular modelling studies of novel indolin-2-ones designing as FGFR inhibitors

A series of novel 3,5-disubstituted indolin-2-ones were designed and synthesized as selective FGFR inhibitors. In the design process of 3,5-disubstituted indolin-2-ones for FGFRs, molecular docking studies were performed to generate and optimize novel compounds which have FGFR inhibitory potency, theoretically. In vitro enzyme inhibitory and selectivity profiles of the synthesized compounds, and their cytotoxicity against NIH-3T3 cells were evaluated. According to enzyme inhibition assay, compound A1 (FGFR1-4; IC₅₀ = 19.82; 5.95; 1419; 37150 nM), compound A5 (FGFR1-4; IC₅₀ = 1890; Nd; 6.50; 18590 nM) and compound A13 (FGFR1-4; IC₅₀ = 6.99; 1022; 17090; 8993 nM) have displayed best inhibitory potency against FGFR2, FGFR3 and FGFR1, respectively. The studied compounds have displayed low affinity to FGFR4 in comparison with other isoforms. Molecular docking study data were used to determine the binding orientations of the synthesized compounds inside FGFRs in accordance with enzyme inhibition assay data. Molecular dynamics simulations and free energy calculations were performed to determine stability, binding modes and dynamics behaviors of compound A1, A5 and A13 inside FGFR-2, FGFR-3 and FGFR-1, respectively. The compounds bearing aromatic groups at the C5 position of indolin-2-one could be lead compounds for the development of more effective and selective FGFR1-3 inhibitors.     

Synthesis of 2-(aryl)-5-(arylidene)-4-thiazolidinone derivatives with potential analgesic and anti-inflammatory activity

A series of novel N-[5-(arylidene)-2-(aryl)-4-oxo-thiazolidin-3-yl]-4-biphenylcarboxamide derivatives was synthesized and evaluated for analgesic and anti-inflammatory activity. In this study, biphenyl-4-carboxylic acid hydrazide was converted to the corresponding aryl hydrazones using aryl aldehydes in the presence of catalytic amount of glacial acetic acid. The aryl hydrazones on reaction with thioglycolic acid in the presence of anhydrous zinc chloride yielded N-[2-(aryl)-4-oxo-thiazolidin-3-yl]-4-biphenylcarboxamide which further on reaction with aromatic aldehydes in the presence of anhydrous sodium acetate and glacial acetic acid furnished the title compounds. All compound exhibited anti-inflammatory activity at the dose 10?mg/kg. The structures of all these newly synthesized compounds were confirmed by their elemental analyses (C, H, N) and spectral data (IR and ¹H NMR).     

Synthesis of 3-{4-[4-dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-phenyl-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-thiazolidin-4-one and their biological evaluation

A novel series of thiazolidinone derivatives namely 3-{4-[4-dimethylamino-6-(4-methyl-2-oxo-2H-chromen-7-yloxy)-[1,3,5]triazin-2-ylamino]-phenyl}-2-phenyl-5-(4-pyridin-2-yl-piperazin-1-ylmethyl)-thiazolidin-4-one have been synthesized from the intermediate 7-[4-(4-amino-phenylamino)-6-dimethylamino-[1,3,5]triazin-2-yloxy]-4-methyl-chromen-2-one (7). Condensation reaction of compound 7 with different aldehyde derivatives were performed to give Schiff base derivatives, which after cyclization gave thiazolidinones and they were incorporated with 1-pyridin-2-yl-piperazine to get target compounds. The newly synthesized compounds were evaluated for their antimicrobial activity against eight bacteria (S. aureus, B. cereus, E. coli, P. aeruginosa, K. pneumoniae, S. typhi, P. vulgaris, and S. flexneria) and four fungi (A. niger, C. albicans, A. fumigatus, and A. clavatus).     

New thiazolidinyl analogs containing pyridine ring: synthesis, biological evaluation and QSAR studies

A series of pyridine derivatives of thiazolidin-4-ones (4a–4o) has been synthesized. Structures of these compounds were established on the basis of elemental analysis, IR, ¹H NMR, ¹³C NMR, and Mass spectral data. All the synthesized compounds have been evaluated for their anti-inflammatory and analgesic effects. The results showed that compound 2-[4-methylphenylimino]-5-(1H-pyridin-2-ylmethylidene)-1,3-thiazolidin-4-one (4d), 2-(2,4-dinitro-phenylhydrazinylidine)-5-(1H-pyridin-2-yl-methylidene)-1,3-thiazolidin-4-one (4h), and 2-[3-nitro-phenylimino]-5-(1H-pyridin-2-yl-methylidene)-1,3-thiazolidin-4-one (4j) exhibited good anti-inflammatory and analgesic activity. Compound 4h was found to be the most active compound of the series with an interesting dual anti-inflammatory and analgesic activity. Docking simulation was performed to position synthesized compounds into the active site of COX-2. The relationships of energy-based docking score with analgesic and anti-inflammatory activities were also investigated by linear regression method. The QSAR models with R ² of 0.621 and 0.740 were developed for analgesic and anti-inflammatory activities, respectively.     

Synthesis,characterization, and screening for analgesic and anti-inflammatory activities of new 1,3,4-oxadiazole derivatives linked to quinazolin-4-one ring

In the present study, several new 1,3,4-oxadiazole derivatives linked with quinazolin-4-one moiety were synthesized by following steps. 2-methyl -4H-3, 1-benzoxazin-4-one, and 2-phenyl -4H-3, 1-benzoxazin-4-one were synthesized in the first and second step by stirring anthranilic acid in pyridine with benzoyl chloride and with an acetic anhydride for 30?min at room temperature. On treatment with semicarbazide with the above synthesized intermediates, that is, 2-methyl-4H-3,1-benzoxazin-4-one, and 2-phenyl-4H-3,1-benzoxazin-4-one in the third step afforded 2-methyl-4-oxoquinazoline-3(4H)-carbohydrazide and 2-phenyl-4-oxoquinazoline-3(4H)-carbohydrazide. These were introduced in cyclization reaction with different aromatic acids, aromatic aldehydes, and carbon disulfide in the next step, producing the corresponding 3-(4-acetyl-5-aryl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-phenyl-quinazolin-4(3H)-one derivatives, 3-(4-acetyl-5-aryl-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-methyl-quinazolin-4(3H)-one derivatives, 3-(5-aryl-1,3,4-oxadiazol-2-yl)-2-phenylquinazolin-4(3H)-one derivatives and 3-(5-aryl-1,3,4-oxadiazol-2-yl)-2-methylquinazolin-4(3H)-one derivatives. Purity of these synthesized derivatives was confirmed by thin layer chromatography, melting point. Structure of the derivatives was set up by determining infrared spectroscopy, nuclear magnetic resonance, and mass spectroscopy. All the synthesized derivatives were evaluated for their analgesic and anti-inflammatory activities in mice and rats. In animal studies, the derivatives 3-[4-acetyl-5-(2-hydroxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one and 3-[4-acetyl-5-(4-hydroxy-3-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one shown more potent analgesic activity and the derivatives 3-[4-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-phenylquinazolin-4(3H)-one and 3-[4-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2-methylquinazolin-4(3H)-one shown more potent anti-inflammatory activity as compared to other derivatives. The results of current study indicate that cyclization of carbohydrazide group of intermediate 2-methyl-4-oxoquinazoline-3(4H)-carbohydrazide and 2-phenyl-4-oxoquinazoline-3(4H)-carbohydrazide with different aromatic acids, aromatic aldehydes, and carbon disulfide produces novel quinazolin-4-one linked oxadiazole derivatives with potent analgesic and anti-inflammatory activities.     

Synthesis,Anti-Inflammatory,and Ulcerogenicity Studies of Novel Substituted and Fused Pyrazolo[3,4-d]pyrimidin-4-ones

In the present investigation, some new pyrazolo[3,4-d]pyrimidin-4(5H)-one derivatives (7–12) as well as fused pyrazolo[3′,4′:4,5]pyrimido[1,2-b]pyridazin-4(1H)-one (14–16) and 7,8,9,10-tetrahydropyrazolo[3′,4′:4,5]pyrimido[1,2-b]-cinnolin-4(1H)-one (17) ring systems were synthesized using the starting compound 5-amino-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (5). The structures of the newly synthesized compounds were elucidated by IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis. The theoretical calculation of their lipophilicity as C log P was performed. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw edema test in rats using indomethacin as the reference drug. Ulcer indices for the most active compounds were calculated. Seven compounds (10b, 11a–f) showed consistently good anti-inflammatory activity. In particular, 5-{[4-(4-bromophenyl)-3-(4-chlorophenyl)-1,3-thiazol-2(3H)-ylidene]amino}-6-methyl-1-phenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (11e) and its 3,4-bis(4-chlorophenyl) analog (11f) were found to be the most effective among the other derivatives, showing activity comparable to that of indomethacin with minimal ulcerogenic effects. Correlation of the biological data of the active compounds with their theoretically calculated C log P values revealed that lipophilicity influences the biological response.     

Design,Synthesis, Toxicity Estimation and Molecular Docking Studies of N-(furan-2-yl)-1-(5-substituted) phenyl-1,3,4-oxadiazol-2-yl) methanimine as Antitubercular Agents

A series of novel N-(furan-2-yl)-1-(5-substituted) phenyl-1,3,4-oxadiazol-2-yl) methanimines (Fa-e) were synthesized and evaluated for antitubercular activity against Mycobacterium tuberculosis (H₃₇Rv) strain by using alamar blue assay. The synthesized compounds were characterized based on IR, ¹HMR and mass spectral analysis. The toxicity profile was predicted by organic chemistry portal, a web based application for predicting in silico absorption, distribution, metabolism, excretion and toxicity, and the novel derivatives under study did not show any toxicity issues. The mechanism of action of the titled derivatives was predicted by docking on the Mycobacterium tuberculosis Enoyl-ACP reductase enzyme. The docking study concluded that Fb and Fa possessed good binding energy indicating more prominent interaction towards the active sites NAD and TYR 158. The antitubercular studies showed that the both Fa and Fb possessed significant activity with the MIC as low as 3.125 μg/ml.     

Design,Synthesis, and Biological Evaluation of New 2-Phenyl-4H-chromen-4-one Derivatives as Selective Cyclooxygenase-2 Inhibitors

In order to develop new selective COX-2 inhibitors, a new series of 2-phenyl-4H-chromen-4-one derivatives possessing a methylsulfonyl pharmacophore group at the para position of the C-4 phenyl ring were designed, synthesized, and evaluated for cyclooxygenase-2 inhibitory activity. In vitro COX-1/COX-2 isozyme inhibition structure-activity studies identified 3-(benzyloxy)-2-[4-(methylsulfonyl)phenyl]-4H-chromen-4-one (5d) as a potent COX-2 inhibitor (IC₅₀ = 0.07 μM) with a high COX-2 selectivity index (SI = 287.1) comparable to the reference drug celecoxib (COX-2 IC₅₀ = 0.06 μM; COX-2 SI = 405). A molecular modeling study where 3-(benzyloxy)-2-[4-(methylsulfonyl)phenyl]-4H-chromen-4-one (5d) was docked into the active site of COX-2 showed that the p-MeSO₂ substituent on the C-4 phenyl ring was well-oriented in the vicinity of the COX-2 secondary pocket (Arg⁵¹³, Val⁵²³, and His⁹⁰) and the carbonyl group of the chromene ring could interact with Ser⁵³⁰. The structure-activity data acquired indicated that the nature and size of the substituent on the C-3 chromene scaffold are important for COX-2 inhibitory activity. Our results also indicated that the chromene moiety constitutes a suitable template to design new COX-2 inhibitors.     

Ulcerogenicity devoid novel non-steroidal anti-inflammatory agents (NSAIDS): syntheses,computational studies,and activity of 5-aryliden-2-imino-4-thiazolidinones

A series of new 5-aryliden-2-imino-4-thiazolidinones (5a–e and 6a–e) were synthesized via a three-step reaction and characterized by physicochemical and spectral data. The uniqueness of the derivatives lies in the fact that none of them had an acidic group, like conventional NSAIDS, but exhibited significant in vivo activity in acute inflammation models. In particular, 5-(3-chlorobenzyliden)-2-(pyridin-2-yl-imino)-4-thiazolidinone(5a) and 5-(3-chlorobenzyliden)-2-(5-methylisoxazol-3-yl-imino)-4-thiazolidinone (6a) showed remarkable paw oedema inhibition (67.76 and 74.47 % oedema inhibition, respectively, after 3 h) comparable to that of Ibuprofen (74.56 % oedema inhibition, after 3 h) at half of the dose of the standard drug. Also, compounds 5a (72.86 %) and 6a (80.20 %) were found to possess significant inhibition of albumin denaturation when screened for in vitro anti-inflammatory activity. In addition, these compounds were docked into the known active site of COX-2 protein using Glide XP and QPLD algorithms, and the binding-free energy was calculated using Prime MM/GBSA simulation methods. The combined use of molecular docking and MM/GBSA methods gave a good correlation between the predicted binding-free energy and experimentally determined biological activities. It was also evident from the docking results that 2-methylisoxazolylimino or 2-(pyridin-2-yl-imino substitution and 3-chloro moiety on 5-benzylidin nucleus of these 4-thiazolidinone derivatives can easily occupy the COX-2 binding pocket, considered as the critical interaction for COX-2 inhibition. Moreover, pharmacokinetic properties of all the synthesized compounds were predicted, with good results. Further, the synthesized derivatives showed neither acute toxicity nor symptoms of gastric ulceration, at extended doses, owing to the absence of an acidic group.     

Synthesis,HIV-1 RT inhibitory,antibacterial, antifungal and binding mode studies of some novel N-substituted 5-benzylidine-2,4-thiazolidinediones

Background

Structural modifications of thiazolidinediones at 3^rd and 5^th position have exhibited significant biological activities. In view of the facts, and based on in silico studies carried out on thiazolidine-2,4-diones as HIV-1- RT inhibitors, a novel series of 2,4-thiazolidinedione analogs have been designed and synthesized.

Methods

Title compounds were prepared by the reported method. Conformations of the structures were assigned on the basis of results of different spectral data. The assay of HIV-1 RT was done as reported by Silprasit et al. Antimicrobial activity was determined by two fold serial dilution method. Docking study was performed for the highest active compounds by using Glide 5.0.

Results

The newly synthesized compounds were evaluated for their HIV-1 RT inhibitory activity. Among the synthesized compounds, compound 24 showed significant HIV-1 RT inhibitory activity with 73% of inhibition with an IC₅₀ value of 1.31 μM. Compound 10 showed highest activity against all the bacterial strains.A molecular modeling study was carried out in order to investigate the possible interactions of the highest active compounds 24, 10 and 4 with the non nucleoside inhibitory binding pocket(NNIBP) of RT, active site of GlcN-6-P synthase and cytochrome P450 14-α-sterol demethylase from Candida albicans (Candida P450DM) as the target receptors respectively using the Extra Precision (XP) mode of Glide software.

Conclusion

A series of novel substituted 2-(5-benzylidene-2,4-dioxothiazolidin-3-yl)-N-(phenyl)propanamides (4–31) have been synthesized and evaluated for their HIV-1 RT inhibitory activity, antibacterial and antifungal activities. Some of the compounds have shown significant activity. Molecular docking studies showed very good interaction.     

Synthesis, antimicrobial activity, and molecular modeling of novel 4-(3-(4-benzylpiperazin-1-yl)propoxy)-7-methoxy-3-substituted phenyl-2H-chromen-2-one

A series of novel 4-(3-(4-benzylpiperazin-1-yl)propoxy)-7-methoxy-3-substituted phenyl-2H-chromen-2-one (7a–7j) were synthesized by the reductive amination of 7-methoxy-3-phenyl-4-(3-piperizin-1-yl-propaxy)chromen-2-one (6) with different substituted aromatic aldehydes by using sodium cyanoborohydride in methanol. The newly synthesized compounds were purified and their structures were characterized by IR, ¹H NMR, ¹³C NMR, and mass spectroscopy. The representative analogs were screened for in vitro antimicrobial activity. The compounds exhibited significant antibacterial and antifungal activity as that of standards. The data was further compared with structure-based investigations using docking studies with the crystal structure of oxidoreductase (1XDQ and 3QLS) protein organisms. The estimated score by genetic algorithm was found to have a good correlation with the experimental inhibitory potency of the derivatives.     

Synthesis, analgesic, anti-inflammatory, and in vitro antimicrobial activities of some novel quinazolin-4(3H)-one derivatives

With the aim of developing potent analgesic, anti-inflammatory, and antimicrobial agents a series of novel quinazolin-4(3H)-one derivatives were synthesized and characterized by FT-IR, ¹H-NMR, mass spectroscopy and bases of elemental analysis. Tail-flick technique, carrageenan-induced foot paw edema test, and agar streak dilution test were performed for screening analgesic, anti-inflammatory, and in vitro antimicrobial activity, respectively. Moreover, all compounds were examined for its ulcerogenicity. Results revealed that entire series of compounds exhibited mild to good analgesic, anti-inflammatory, and antimicrobial activity with low to moderate ulcer index. The relationship between the functional group variation and the biological activity of the evaluated compounds were discussed. Compound 2-(2-(4-(trifluoromethyl)benzylidene)hydrazinyl)-N-(4-(2-methyl-4-oxoquinazolin-3(4H)-yl) phenyl) acetamide 5e was determined to be the most active compound.     

Synthesis and antimycobacterial activities of some new N-acylhydrazone and thiosemicarbazide derivatives of 6-methyl-4,5-dihydropyridazin-3(2H)-one

In this study, twenty-five new 6-methyl-4,5-dihydropyridazin-3(2H)-one derivatives having N-acylhydrazone and thiosemicarbazide moieties were synthesized. The target compounds were tested for their antimycobacterial activity in vitro against Mycobacterium tuberculosis H₃₇R_v using the agar dilution method. Among the synthesized compounds, N′-(2,4-dichlorobenzylidene)-2-(3-methyl-6-oxo-5,6-dihydropyridazin-1(4H)-yl)acetohydrazide 4g was found to be the most active compound with minimum inhibitory concentration of 0.78?μM and was more potent than ethambutol and ciprofloxacin.     

Novel N-(pyrimidin-4-yl)thiazol-2-amine derivatives as dual-action hypoglycemic agents that activate GK and PPARγ

A series of novel N-(pyrimidin-4-yl)thiazol-2-amine derivatives have been synthesized and evaluated as glucokinase (GK) activators. Ethyl 2-(6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methylpyrimidin-4-yl-amino)thiazole-5-carboxylate was found to be a potent dual-acting hypoglycemic agent activating both GK and PPARγ. When given orally to normal mice, the compound demonstrated significant efficacy in decreasing the glucose level after oral glucose loading.     

Discovery of novel 4-phenylquinazoline-based BRD4 inhibitors for cardiac fibrosis

Bromodomain containing protein 4 (BRD4), as an epigenetic reader, can specifically bind to the acetyl lysine residues of histones and has emerged as an attractive therapeutic target for various diseases, including cancer, cardiac remodeling and heart failure. Herein, we described the discovery of hit 5 bearing 4-phenylquinazoline skeleton through a high-throughput virtual screen using 2,003,400 compound library (enamine). Then, structure–activity relationship (SAR) study was performed and 47 new 4-phenylquinazoline derivatives toward BRD4 were further designed, synthesized and evaluated, using HTRF assay set up in our lab. Eventually, we identified compound C-34, which possessed better pharmacokinetic and physicochemical properties as well as lower cytotoxicity against NRCF and NRCM cells, compared to the positive control JQ1. Using computer-based molecular docking and cellular thermal shift assay, we further verified that C-34 could target BRD4 at molecular and cellular levels. Furthermore, treatment with C-34 effectively alleviated fibroblast activation in vitro and cardiac fibrosis in vivo, which was correlated with the decreased expression of BRD4 downstream target c-MYC as well as the depressed TGF-β1/Smad2/3 signaling pathway. Taken together, our findings indicate that novel BRD4 inhibitor C-34 tethering a 4-phenylquinazoline scaffold can serve as a lead compound for further development to treat fibrotic cardiovascular disease.     

Synthesis and biological evaluation of 1-(3-chloro-2-oxo-4-phenylazetidin-1-yl)-3-(2-oxo-2-(10H-phenothiazin-10-yl)ethyl)urea derivatives

A new series of eleven novel 1-(3-chloro-2-oxo-4-phenylazetidin-1yl)-3-(2-oxo-2-(10H-phenothiazin-10-yl)ethyl)urea derivatives were synthesized by cyclocondensation of various Schiff bases of phenothiazine with chloroacetyl chloride in the presence of triethylamine. Various Schiff bases of phenothiazine were synthesized by condensation of 4-(2-oxo-2-(10H-phenothiazin-10-yl)ethyl semicarbazide with various aryl aldehydes. The synthesized compounds were characterized by IR, MASS and ¹H NMR spectral data and evaluated for in vitro antimicrobial, antitubercular, antioxidant and anticancer activities by disc diffusion method, MIC method, REMA, DPPH, FRAP and MTT assay method, respectively. All synthesized compounds showed moderate-to-significant anti-bacterial and anti-fungal activity and compound 4d, 4g, 4h and 4k showed good antioxidant activity with EC₅₀ value of 55, 57, 56 and 47 μg/ml tested by DPPH method. The compounds 4j at a concentration of 10 μg/ml showed inhibition against the growth of Mycobacterium tuberculosis and 4f showed significant activity against human cervical cancer cell line with IC₅₀ values of 18.26 μM.     

Design,synthesis, docking study and cytotoxic activity evaluation of some novel letrozole analogs

Background

Breast cancer is the most common type of female cancer. One class of hormonal therapy for breast cancer drugs -non steroidal aromatase inhibitors- are triazole analogues. In this work, some derivatives of these drugs was designed and synthesized. All synthesized compounds were evaluated for their cytotoxic activities on breast cancer cell lines (MDA-MB-231, T47D and MCF-7).

Methods

Our synthetic route for designed compounds started from 4-bromotolunitrile which was reacted with 1H-1,2,4-triazole to afford 4-(4-cyanobenzyl)-1,2,4-triazole. The reaction of later compound with aromatic aldehydes led to formation of the designed compounds. Eleven novel derivatives 1a-k were tested for their cytotoxic activities on three human breast cancer cell lines.

Results

Among the synthesized compound, 4-[2-(3-chlorophenyl)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1c) showed the highest activity against MCF-7 and MDA-MB-231 cell lines and 4-[2-(4-methoxyphenyl)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1 h) exhibited highest activity against T47D cell line. According to cytotoxic activities results, compound 4-[2-(4-dimethylamino)-1-(1H-1,2,4-triazol-1-yl)ethenyl]benzonitrile (1 k) showed comparative activity against T47D and MDA-MB-231 cell lines with compound (1 h) and our reference drug Etoposide.

Conclusion

In the process of anti-cancer drug discovery, to find new potential anti-breast cancer agents, we designed and synthesized a novel series of letrozole analogs. Cytotoxicity evaluation revealed that compounds (1c) and (1 k) were the most potent compounds with comparative activity with Etoposide. The results revealed that π-π interactions are responsible for the enzyme inhibitions of compounds (1 c) and (1 k).Keyword: Breast cancer, Non-steroidal aromatase inhibitor, Cytotoxic activity     

Efficient synthesis, anticonvulsant and muscle relaxant activities of new 2-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-6-phenyl-4,5-dihydropyridazin-3(2H)-one derivatives

A series of 2-(2-(3-(4-chlorophenyl)-6-oxo-5,6-dihydropyridazin-1(4H)yl)acetyl)hydrazine carbothioamide and 2-((5-amino-1,3,4-thiadiazol-2-yl)methyl)-6-(4-chlorophenyl)-4,5-dihydropyridazin-3(2H)-one derivatives were synthesized, characterized, and evaluated for anticonvulsant activity and muscle relaxant activity. The synthesized compounds 5d (82.75 %) and 5e (85.44 %) showed promising anticonvulsant activity by protection against tonic hind limb extensor phase in maximal electroshock model (MES) at (50 mg/kg) compared to standard drug phenytoin and also compounds 5d (82.75 %), and 5e (85.44 %) showed significant anticonvulsant activity by protection against pentylenetetrazole-induced generalized convulsions in pentylenetetrazole model (PTZ) at (100 mg/kg) compared to standard drug diazepam. On the other hand, compound 5e showed significant muscle relaxant activity (84.57 %) by rotarod and traction test model comparing with diazepam as a standard drug.     

Synthesis of pyranochromene and pyranopyrimidine derivatives from substituted natural coumarin isolated from Ammi majus L. and their biological evaluation

A series of novel coumarin derivatives were synthesized from 6-hydroxy-7-methoxy-4-methyl coumarin which was isolated from the aerial parts of the Egyptian medicinal plant Ammi majus L. (Apiaceae). The key intermediate 3-amino-5-methoxy-1-(4-methoxyphenyl)-10-methyl-8-oxo-1,8-dihydropyrano[3,2-f]chromene-2-carbonitrile (3c) was obtained in one-pot synthesis by treating α-cyanocinnamonitrile (1-c) with the natural compound: 6-hydroxy-7-methoxy-4-methyl coumarin (2). Chemical, elemental and spectroscopic evidences confirmed the structures of the synthesized compounds. Some of the newly synthesized compounds exhibited better anti-inflammatory activities at low concentrations compared with indomethacin as positive control.