Synthesis and antihepatotoxic activity of 5-(2,3-dihydro-1,4-benzodioxane-6-yl)-3-substituted-phenyl-4,5-dihydro-1H-pyrazole derivatives

In continuance of our search for newer antihepatotoxic agents some novel pyrazoline derivatives containing 1,4-dioxane ring system were synthesized starting from 3-(2,3-dihydro-1,4-benzodioxane-6-yl)-1-substituted-phenylprop-2-en-1-one. Some of the synthesized compounds were evaluated for antihepatotoxic activity against CCl(4)-induced hepatotoxicity in rats. Among them some compounds have shown significant antihepatotoxic activity comparable to standard drug silymarin.     

Synthesis and antiparasitic activity of 2-(trifluoromethyl)-benzimidazole derivatives

2-(Trifluoromethyl)benzimidazole derivatives substituted at the 1-, 5-, and 6-positions have been synthesized and in vitro tested against the protozoa Giardia lamblia, Entamnoeha histolytica. and the helminth Trichinella spiralis. Results indicate that all the compounds tested are more active as antiprotozoal agents than Albendazole and Metronidazole. One compound (20) was as active as Albendazole against T. spiralis. These compounds were also tested for their effect on tubulin polymerization and none inhibited tubulin polymerization.     

Design,Synthesis, Molecular Docking Studies,and Biological Evaluation of Pyrazoline Incorporated Isoxazole Derivatives

Russian Journal of Bioorganic Chemistry - A novel series of pyrazoline incorporated isoxazole derivatives were designed and synthesized. The synthesized compounds were characterized by 1H NMR, IR...     

Synthesis and antiamoebic activities of 1-N-substituted cyclised pyrazoline analogues of thiosemicarbazones

A series of 21 new 1-N-substituted cyclised pyrazoline analogues of thiosemicarbazones were synthesised by cyclisation of Mannich bases with thiosemicarbazides of variegated nature. The chemical structures of the compounds were proved by UV, IR, (1)H NMR, (13)C NMR spectroscopic data and elemental analyses. The antiamoebic activities of these compounds were evaluated by microdilution method against HM1:1MSS strain of Entamoeba histolytica. It was found that 3-chloro and 3-bromo substituents on the phenyl ring at position 3 of the pyrazoline ring enhanced the antiamoebic activity as compared to unsubstituted phenyl ring. Compounds 15, 17, 18, 20 and 21 showed less IC(50) value than metronidazole. Moreover, compound 21 have shown the most promising antiamoebic activity (IC(50)=0.6 microM vs IC(50)=1.8 microM of metronidazole).     

Synthesis and enzymatic transformations of 5-halo-6-methoxy-5,6-dihydro derivatives of 5-[1-methoxy-2-halo (or 2,2-dihalo)ethyl]-2'-deoxyuridines as potential herpes simplex virus inhibitors

The 5-halo-6-methoxy-5,6-dihydro derivatives of 5-[1-methoxy-2-halo(or 2,2-dihalo)ethyl]-2'-deoxyuridines (3-12) were synthesized and investigated as potential anti-herpes agents. These 5,6-dihydro derivatives were designed to act as potential prodrugs to 5-[1-methoxy-2-halo(or 2,2-dihalo)ethyl]-2'-deoxyuridines (2a-e), with enhanced metabolic stability, and ready conversion to the parent molecules. These 5,6-disubstituted-5,6-dihydro analogs are stable to E. coli thymidine phosphorylase, and undergo regeneration of the 5,6-olefinic bond to provide parent moieties (2a-e), upon incubation with glutathione at 37 degrees C. The compounds (3-12) themselves were found to be non-inhibitory against herpes simplex virus type-1 (HSV-1), likely due in part to their inability to undergo conversion to parent compounds in cell culture medium.     

Thiosemicarbazone fragment embedded within 1,2,4-triazole ring as inhibitors of Entamoeba histolytica

A series of 1,2,4-triazole derivatives containing thiosemicarbazone linkage was synthesized and evaluated for their in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica. All the compounds were capable of inhibiting the growth of E. histolytica out of which four compounds (IC(50)=0.28-1.38 μM) were found to have better efficacy than the standard drug Metronidazole (IC(50)=1.8 μM). Cytotoxicity of the active compounds was assessed by MTT assay using human breast cancer MCF-7 cell line, which revealed that all the compounds were low cytotoxic in the concentration range of 2.5-250 μM.     

Discovery of novel methanone derivatives acting as antimycobacterial agents

A series of pyrazoline derivatives were synthesized and in vitro activity against Mycobacterium tuberculosis H37Rv was carried out. Among the synthesized compounds, compounds (4d) and (4f) 4-aminophenyl-3-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-ylmethanone and 4-aminophenyl-6,7-dimethoxy-3-phenyl-2,3,3a,4-tetrahydroindeno[1,2-c]pyrazol-2-ylmethanone were found to be the most active agent against M. tuberculosis H37Rv with a minimum inhibitory concentration of 10 μg/mL.     

Design and synthesis of novel inhibitors of human kynurenine aminotransferase-I

Herein we report 6-ethoxy-6-oxo-5-(2-phenylhydrazono) hexanoic acid and 3-(2-carboxyethyl)-1H-indole-2-carboxylic acid derivatives as synthetically accessible leads for human kynurenine aminotransferase-I (KAT-I) inhibitors. In total, 12 compounds were synthesized and their biological activities were determined using the HPLC-UV based KAT-I inhibition assay. Of the 12 compounds synthesized, 10 were found to inhibit human KAT-I and the most active compound was found to be 5-(2-(4-chlorophenyl) hydrazono)-6-ethoxy-6-oxohexanoic acid (9a) with an IC(50) of 19.8 μM.     

Design, synthesis, and biological evaluation of 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines as cyclooxygenase-2 (COX-2) and lipoxygenase (LOX) inhibitors

A series of 20 novel 1-(4-sulfamylphenyl)-3-trifluoromethyl-5-indolyl pyrazolines were designed, synthesized, and screened in vitro for anti-inflammatory activity. These compounds were designed for evaluation as dual inhibitors of cyclooxygenases (COX-1 and COX-2) and lipoxygenases (LOX-5, LOX-12, and LOX-15) that are responsible for inflammation and pain. All pyrazoline molecules prepared are optically active and compounds that are more potent in COX-2 inhibitory activity (5a and 5f) were resolved by chiral column and each enantiomer was tested for cyclooxygenase inhibitory activity. Molecular modeling and comparison of molecular models of 5a enantiomers with that of celecoxib model shows that 5a (enantiomer-1) and 5a (enantiomer-2) have more hydrogen bonding interactions in the catalytic domain of COX-2 enzyme than celecoxib. Compounds 5a, 5e, and 5f showed moderate to good LOX-5 and LOX-15 inhibitory activity and this is comparable to that of celecoxib and more potent than rofecoxib.     

Benzotriazoles and indazoles are scaffolds with biological activity against Entamoeba histolytica

Parasitic infections caused by Entamoeba histolytica are still major threats against public health, especially in developing countries. Although current therapies exist, the problems associated with parasite resistance and negative side effects make it imperative to search for new therapeutic agents. A systematic scaffold analysis reported herein of a public database containing 474 antiamoebic compounds reveals that benzimidazole is the most active scaffold reported thus far. To gain insights into the antiamoebic activity of novel compounds, the authors report herein the biological activity of 12 compounds, including benzotriazole and indazole derivatives, scaffolds not previously tested against E. histolytica. Compounds with the benzotriazole and indazole scaffolds showed low micromolar activity (IC(50) = 0.304 and 0.339 μM) and are more active than metronidazole, which is the drug of choice used for the treatment of amebiosis. The novel compounds have similar properties to approved drugs. Compounds with novel scaffolds represent promising starting points of an optimization program against E. histolytica.     

Synthesis of novel 3-(alkylcarbamoyl)-2-aryl-1,2-dihydro-6,7-(methylenedioxy)-3H-quinazolin-4-ones as anticonvulsant agents

A series of 3-(alkylcarbamoyl)-2-aryl-1,2-dihydro-6,7-(methylenedioxy)-3H-quinazolin-4-ones, compounds 3-6, were synthesized, and screened as anticonvulsant agents in DBA/2 mice against sound-induced seizure (Table). The new compounds were found to display anticonvulsant properties inferior to those of the known dehydro congeners 1 and 2. The binding affinities of 1-6 at the AMPA and NMDA receptors were also evaluated.     

Design, microwave-assisted synthesis, and spasmolytic activity of 2-(alkyloxyaryl)-1H-benzimidazole derivatives as constrained stilbene bioisosteres

A simple, fast, and efficient method for the preparation of several 2-(alkyloxyaryl)-1H-benzimidazole derivatives is reported. Compounds were synthesized through a rapid one-pot three component reaction via microwave irradiation, starting from commercially available aldehydes and o-phenylenediamine, in the presence of Na(2)S(2)O(5) and solvent-free conditions. The design of these compounds explore the hypothesis that the stilbene framework could be mimicked with an appropriate 2-(Alkyloxyphenyl)benzimidazole scaffold. This framework has a similar structural motif as the 6-phenylnaphthalene and behaves like stilbene bioisosteres. The spasmolytic activity of these compounds was recorded using isolated rat ileum test. Compound 12 was the most active of the series, showing an IC(50) of 1.19 microM.     

Modification,Biological Evaluation and 3D QSAR Studies of Novel 2-(1,3-Diaryl- 4,5-Dihydro-1H-Pyrazol-5-yl)Phenol Derivatives as Inhibitors of B-Raf Kinase

A series of novel 2-(1,3-diaryl- 4,5-dihydro-1H-pyrazol-5-yl)phenol derivatives (C1–C24) have been synthesized. The B-Raf inhibitory activity and anti-proliferation activity of these compounds have been tested. Compound C6 displayed the most potent biological activity against B-Raf^V600E (IC₅₀ = 0.15 µM) and WM266.4 human melanoma cell line (GI₅₀ = 1.75 µM), being comparable with the positive control (Vemurafenib and Erlotinib) and more potent than our previous best compounds. The docking simulation was performed to analyze the probable binding models and poses while the QSAR model was built to check the previous work as well as to introduce new directions. This work aimed at seeking more potent inhibitors as well as discussing some previous findings. As a result, the introduction of ortho-hydroxyl group on 4,5-dihydro-1H-pyrazole skeleton did reinforce the anti-tumor activity while enlarging the group on N-1 of pyrazoline was also helpful.     

Antihistamine, anticholinergic and cardiovascular effects of 2-substituted-4-phenylquinoline derivatives

Eleven new derivatives of 4-phenylquinoline, having various substituents at the 2-position of the quinoline ring, were previously synthesized. The antidepressant activities of these derivatives were demonstrated by their antagonism to reserpine-induced hypothermia in mice. The ED50 values were found to be in the range of 12-42 mg/kg (imipramine is 21.0 mg/kg). In the present work, comparative studies of the effects of these new drugs on the cholinergic and histaminergic (H1) systems, as well as their effects on the cardiovascular system, are presented. Both imipramine and trazodone were utilized as standards representing typical and atypical antidepressant drugs, respectively. All these new compounds have very low antihistaminic (H1) activities, as compared to imipramine. In addition, a clear cut separation of the antidepressant activity from the antihistaminic (H1) activity was observed. These compounds have weak anticholinergic (atropine-like properties) activity as compared to imipramine, using the isolated guinea-pig ileum. Animal studies of the cardiac toxicity of these compounds showed reduced lethality for some of them as compared to imipramine. Arrhythmias commonly associated with imipramine were absent for most of these compounds. The effects of these compounds on the heart conduction were determined by electrocardiographic studies. Although some of these compounds do not interfere with heart conduction, as compared to imipramine most were inferior to trazodone. Correlation between the pharmacological activities and structural modifications of these derivatives has also been observed.     

Synthesis and bioactivity studies on new 4-(3-(4-Substitutedphenyl)-3a,4-dihydro-3H-indeno[1,2-c]pyrazol-2-yl) benzenesulfonamides

A series of new 4-(3-(4-substitutedphenyl)-3a,4-dihydro-3H-indeno[1,2-c]pyrazol-2-yl) benzenesulfonamides (7–12) was synthesized starting from 2-(4-substitutedbenzylidene)-2,3-dihydro-1H-inden-1-one (1–6) and 4-hydrazinobenzenesulfonamide. The substituted benzaldehydes from which the key intermediate was prepared by introducing 2- or 4-substituents such as fluorine, hydroxy, methoxy, or the 3,4,5-trimethoxy moieties. The compounds were tested for their cytotoxicity, tumor-specificity and potential as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. The 3,4,5-trimethoxy and the 4-hydroxy derivatives showed interesting cytotoxic activities, which may be crucial for further anti-tumor activity studies, whereas some of these sulfonamides strongly inhibited both human (h) cytosolic isoforms hCA I and II.     

Novel 2-(2-(4-aryloxybenzylidene) hydrazinyl)benzothiazole derivatives as anti-tubercular agents

A series of structurally novel, substituted 2-(2-(4-aryloxybenzylidene) hydrazinyl)benzothiazole derivatives incorporating 2-hydrazinyl benzothiazole and 4-(aryloxy)benzaldehyde were designed and synthesized using molecular hybridization approach. All the synthesized compounds exhibited promising activity (MIC 1.5-29.00μg/ml) against Mycobacteriumtuberculosis H37Rv strains of using REMA. Five of the evaluated compounds exhibit MIC <3.0μg/ml. Compound (E)-6-chloro-2-(2-(4-(2,4-dichlorophenoxy)benzylidene)hydrazinyl) benzothiazole showed MIC of 1.5μg/ml. Thus, this compound could act as a potential lead for further development of new anti-tubercular drugs.     

Synthesis and preliminary pharmacological evaluation of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides as novel atypical antipsychotic agents

A series of N-2-(4-(4-(2-substitutedthiazol-4-yl) piperazin-1-yl)-2-oxoethyl)acetamides were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized by either microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, (1)H NMR, and MS) and the purity was ascertained by microanalysis. All the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. D(2) antagonism studies were performed using climbing mouse assay model and 5-HT(2A) antagonism studies were performed using quipazine induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy. AG 3 was found to be the most active compound.     

Synthesis and initial biological evaluation of substituted 1-phenylamino-2-thio-4,5-dimethyl-1H-imidazole derivatives

In this work, some new 2-[(4,5-dimethyl-1-(arylamino)-1H-imidazol-2-yl)thio]-1-(aryl)ethanone derivatives were synthesized and investigated for their antibacterial, antifungal and anticancer activities. Toxicity of the most effective compounds was established by performing Brine-Shrimp lethality assay. Antifungal activity of the compounds was found to be higher than antibacterial and anticancer activities of the compounds.     

Synthesis and antiprotozoal activity of novel 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives

A series of 19 new 2-{[2-(1H-imidazol-1-yl)ethyl]sulfanyl}-1H-benzimidazole derivatives was synthesized starting from the properly substituted 1,2-phenylendiamine. These compounds have hydrogen or methyl at position 1; while hydrogen, chlorine, ethoxy or methoxycarbonyl group is at position 5 and/or 6. The novel compounds were tested against protozoa Trichomonas vaginalis, Giardia intestinalis and Entamoeba histolytica. Experimental evaluations revealed strong activity for all tested compounds, having IC₅₀ values in the nanomolar range, which were even better than metronidazole, the drug of choice for these parasites.     

Synthesis and antiparasitic activity of 1H-benzimidazole derivatives

Compounds 1-18 have been synthesized and tested in vitro against the protozoa Giardia lamblia, Entamoeba histolytica and the helminth Trichinella spiralis. Inhibition of rat brain tubulin polymerization was also measured and compared for each compound. Results indicate that most of the compounds tested were more active as antiprotozoal agents than Metronidazole and Albendazole. None of the compounds was as active as Albendazole against T. spiralis. Although only compounds 3, 9 and 15 (2-methoxycarbonylamino derivatives) inhibited tubulin polymerization, these were not the most potent antiparasitic compounds.