Waquar Ahsan

Triazole incorporated thiazoles as a new class of anticonvulsants: design, synthesis and in vivo screening.

Various 3-[4-(substituted phenyl)-1,3-thiazol-2-ylamino]-4-(substituted phenyl)-4,5-dihydro-1H-1,2,4-triazole-5-thiones (7a-t) were designed keeping in view the structural requirements suggested in the pharmacophore model for anticonvulsant activity. Thiazole and triazole moieties being anticonvulsants were clubbed together to get the titled compounds and their in vivo anticonvulsant screening were performed by two most adopted seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Two compounds 7d and 7f showed significant anticonvulsant activity in both the screens with ED(50) values 23.9 mg/kg and 13.4 mg/kg respectively in MES screen and 178.6 mg/kg and 81.6 mg/kg respectively in scPTZ test. They displayed a wide margin of safety with Protective index (PI), median hypnotic dose (HD(50)) and median lethal dose (LD(50)) much higher than the standard drugs.

Synthesis, anticonvulsant and toxicity screening of newer pyrimidine semicarbazone derivatives

A number of N-(4,6-substituted diphenylpyrimidin-2-yl) semicarbazones (4a-t) were synthesized and tested for their anticonvulsant activity against the two seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). All the synthesized compounds possessed the four essential pharmacophoric elements for good anticonvulsant activity. Most of the compounds displayed good anticonvulsant activity with lesser neurotoxicity. To assess the unwanted effects of the compounds on liver, estimation of enzymes and proteins was carried out.

Synthesis, anticonvulsant and toxicity evaluation of 2-(1H-indol-3-yl)acetyl-N-(substituted phenyl)hydrazine carbothioamides and their related heterocyclic derivatives

Synthesis, anticonvulsant and toxicity evaluation of 2-(1H-indol-3-yl)acetyl-N-(substituted phenyl)hydrazine carbothioamides and their related heterocyclic derivatives A series of new 5-(1H-indol-3-yl)methyl-4-(substituted aryl)-2,4-dihydro-3H-1,2,4-triazole-3-thiones (4a-g), 5-(1H-indol-3-yl)methyl-N-(substituted aryl)-1,3,4-oxadiazol-2-amines (5a-g) and 5-(1H-indol-3-yl)methyl-N-(substituted aryl)-1,3,4-thiadiazol-2-amines (6a-g) were prepared by treating 2-(1H-indol-3-yl)acetyl-N-(substituted phenyl) hydrazine carbothioamides (3a-g) with suitable reagents. All the newly synthesized compounds were screened for their anticonvulsant activity in the MES model and were compared with the standard drugs phenytoin sodium and carbamazepine. Out of the twenty-one compounds studied, 4b, 4e, 4f, 5b, 5d, 5g, 6b, 6d and 6e showed comparable MES activity to phenytoin and carbamazepine after 0.5 h. Compound 5b showed to be more potent than carbamazepine after 4 h. Compounds 4a, 4c, 4d, 5a, 5c, 5e, 5f, 6f and 6g showed lower neurotoxicity than phenytoin. Sinteza 2-(1H-indol-3-il)acetil-N-(supstituiranih fenil)hidrazinkarbotioamida i srodnih heterocikličkih spojeva te procjena njihovog antikonvulzivnog djelovanja i toksičnosti Reakcijom 2-(1H-indol-3-il)acetil-N-(supstituiranih fenil)hidrazinkarbotioamida (3a-g) s odgovarajućim reaktantom sintetizirana je serija novih 5-(1H-indol-3-il)metil-4-(supstituiranih aril)-2,4-dihidro-3H-1,2,4-triazol-3-tiona (4a-g), 5-(1H-indol-3-yl)metil-N-(supstituiranih aril)-1,3,4-oksadiazol-2-amina (5a-g) i 5-(1H-indol-3-il)metil-N-(supstituiranih aril)-1,3,4-tiadiazol-2-amina (6a-g). Ispitano je antikonvulzivno djelovanje sintetizi- ranih spojeva na MES modelu i uspoređeno s djelovanjem fenitoin natrija i karbamazepina. Spojevi 4b, 4e, 4f, 5b, 5d, 5g, 6b, 6d i 6e pokazali su MES djelovanje usporedivo s djelovanjem fenitoina i karbamazepina nakon 0,5 h, dok je spoj 5b nakon 4 sata imao snažnije djelovanje od karbamazepina. Osim toga, spojevi 4a, 4c, 4d, 5a, 5c, 5e, 5f, 6f i 6g su manje neurotoksični od fenitoina.

Synthesis and pharmacological evaluation of newer thiazolo [3,2-a] pyrimidines for anti-inflammatory and antinociceptive activity

A new series of thiazolo [3,2-a] pyrimidine derivatives was designed and synthesized using 4-fluoroaniline and ethylacetoacetate as starting material. Anti-inflammatory activity was assessed by the rat paw edema method and antinociceptive activity was evaluated by thermal stimulus technique. The compounds 5-(4-chlorophenyl)-2-(4-fluorobenzylidene)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid (4-fluorophenyl)amide (3l) and 2-(4-chlorobenzylidene)-5-(4-fluorophenyl)-7-methyl-3-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylic acid (4-fluorophenyl)amide (3q) were found to possess significant anti-inflammatory and antinociceptive activities. These compounds also showed lower ulcerogenic activity and higher ALD50 values. Compounds with an aryl ring substituted with a smaller electron withdrawing group at the fourth position displayed better activity than the other derivatives.

Antihypertensive activity of newer 1,4-dihydro-5-pyrimidine carboxamides: Synthesis and pharmacological evaluation

A number of 5-(4-substituted phenyl)-2-(substituted benzylsulfanyl)-4-(substituted phenyl)-6-methyl-1,4-dihydro-5-pyrimidine carboxamides (1-30) were designed and synthesized keeping in view the structural requirements as suggested in the pharmacophore model for antihypertensive activity. All the synthesized compounds were tested for antihypertensive activity by non-invasive blood pressure (NIBP) measurements (tail-cuff method) in rats. Almost all the tested compounds displayed considerable decrease in the blood pressure as compared to control. Thirteen compounds showed significant antihypertensive activity comparable to the standard drug nifedipine.

Design, Synthesis, and In-vivo Pharmacological Screening of N,3-(Substituted Diphenyl)-5-phenyl-1H-pyrazoline-1-carbothioamide Derivatives

Various 3,5‐(substituted diphenyl)‐4,5‐dihydro‐pyrazole‐1‐carbothioic acid phenylamides were synthesized starting from substituted acetophenones. Structures of the compounds were confirmed on the basis of spectral data. The compounds were evaluated for their anticonvulsant and antidepressant activity. Interestingly, out of 26 compounds, four (3f, 3g, 3t, and 3u) were found to protect 100% of the animals in the MES screen at a dose of 25 mg/kg. They were also found to have appreciable anticonvulsant activity in scPTZ screen. Two compounds, 3j and 3o, significantly reduced the duration of the immobility time at 25 mg/kg dose, when compared to control.

Sulfonamide derivatives of thiazolidin-4-ones with anticonvulsant activity against two seizure models: synthesis and pharmacological evaluation

A series of 4-thiazolidinones bearing a sulfonamide group (4a–w) were prepared by cyclizing various 5-bromo-2-methoxy-N’-[(1E)-arylmethylene/arylethylidene]benzenesulfonohydrazides. All the compounds were characterized by IR, 1H NMR, and elemental analysis. The compounds were tested for their anticonvulsant activity utilizing MES and scPTZ animal models. The majority of the compounds exhibited significant activity against both animal models; however, compounds 4c, 4m, and 4o displayed promising activity and could be considered as leads for further investigations.

Design, Synthesis and Evaluation of Anticonvulsant Activity of Pyridinyl-Pyrrolidones: A Pharmacophore Hybrid Approach

Various 1‐[6‐(4‐substituted phenyl)‐3‐cyano‐4‐(substituted phenyl)‐pyridin‐2‐yl]‐5‐oxopyrrolidine‐3‐carboxylic acids (3a–t) were designed and synthesized by clubbing pyrrolidinones and pyridines, the two active anticonvulsant pharmacophores. All the synthesized compounds fulfilled the requirements of suggested pharmacophoric model for anticonvulsant activity. Their in vivo anticonvulsant evaluation was performed by maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. The minimal motor impairment was assessed by rotorod test and the estimation of various liver enzymes was performed to check the magnitude of liver toxicity posed by the synthesized compounds. Compounds 3d and 3k displayed comparable anticonvulsant activity to the standard drugs with ED50 values of 13.4 and 18.6 mg/kg in electroshock screen, repectively. The compounds 3d and 3k were also found to have encouraging anticonvulsant activity (ED50 = 86.1 and 271.6 mg/kg, respectively) in scPTZ screen. Interestingly, they did not show any sign of motor impairment at the maximum dose administered and were not toxic to the liver.

Synthesis, anticonvulsant and toxicity screening of thiazolyl–thiadiazole derivatives

Various thiazole-substituted thiadiazole derivatives (7a–t) were designed and synthesized using substituted acetophenones and substituted anilines as starting materials. Thiazole and thiadiazole moieties being anticonvulsants were clubbed together to get the titled compounds and their in vivo anticonvulsant screening were performed by two most adopted seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Three compounds 7i, 7l and 7n were found to be potent in both the screens with comparable ED50 and better TD50 values than some standard drugs. These compounds were also found to exert lesser toxic effects on liver.

Benzothiazole Incorporated Barbituric Acid Derivatives: Synthesis and Anticonvulsant Screening

A series of 1‐(6‐substituted‐1,3‐benzothiazol‐2‐yl)‐3‐(substituted phenyl)hexahydro‐2,4,6‐pyrimidinetriones 4a–t were synthesized starting from substituted anilines. These compounds contained two active anticonvulsant pharmacophores, benzothiazole and barbituric acid. Structures of the compounds were confirmed on the basis of different spectroscopic techniques. All the compounds were evaluated for their anticonvulsant activity. Three compounds 4c, 4d, and 4s showed promising anticonvulsant activities in Maximal Electroshock Seizure test (MES) and subcutaneous pentylenetetrazole test (scPTZ). They also displayed a wide safety profile when tested for the minimal motor impairment test.