Abdul Roouf Bhat

Synthesis of new 2-(5-substituted-3-phenyl-2-pyrazolinyl)-1,3-thiazolino[5,4-b]quinoxaline derivatives and evaluation of their antiamoebic activity

In an effort to develop potent antiamoebic agents, we have synthesized chalcones (1-8), amino-5-substituted-(3-phenyl(2-pyrazolinyl))methane-1-thione derivatives (1a-8a) and 2-(5-substituted-3-phenyl-2-pyrazolinyl)-1,3-thiazolino[5,4-b]quinoxaline derivatives (1b-8b) and evaluated for their in vitro antiamoebic activity against HM1:IMSS strain of E. histolytica. All the compounds were characterized by electronic, IR, (1)H NMR and mass spectroscopic data. It was observed that the antiamoebic activity enhances on modifying the structure of chalcones to the pyrazolines and further to quinoxalines. The MTT assay was performed on human kidney epithelial cell line to check the cytotoxicity of the compounds and the results were compared with metronidazole. Compound 6b showed better antiamoebic activity and less toxicity than metronidazole.

Antiamoebic coumarins from the root bark of Adina cordifolia and their new thiosemicarbazone derivatives

In continuation of our search for potential antiamoebic agents from folklore Indian medicinal plants, we found that the benzene and ethyl acetate extracts from the root bark of Adina cordifolia exhibited strong antiamoebic activity with IC(50) values of 2.92 and 2.50 microg/ml, respectively. Bioassay-guided fractionation of benzene and ethyl acetate extracts led to the isolation of 7-hydroxycoumarin (umbelliferone 1) and 7-beta-D-glucosylcoumarin (skimmin 2), respectively. Umbelliferone 1 was converted into 7-acetoxycoumarin 1a, which on treatment with aluminium chloride afforded 7-hydroxy-8-acetylcoumarin 2a. A new series of thiosemicarbazones 3a-e of 7-hydroxy-8-acetylcoumarin with different thiosemicarbazides were synthesized. Umbelliferone was also converted into its methoxy derivative (7-methoxycoumarin 4). Subsequently, all the compounds were assessed for antiamoebic activity against HM1:IMMS strain of Entamoeba histolytica. Umbelliferone and skimmin were found to possess a very good activity with IC(50) values of 6.38 and 4.35 microM/ml, respectively. The activity drastically increased on converting compound 2a into its thiosemicarbazone derivatives 3a-e with IC(50) values ranging between 1.06 and 4.46 microM/ml. Compounds 3b,c and e with IC(50) values of 1.49, 1.56 and 1.06 microM/ml, respectively, exhibited even higher antiamoebic activity than the standard drug metronidazole (IC(50)=2.62 microg/ml). The activity of 7-methoxycoumarin (IC(50)=8.92 microM/ml) was less than umbelliferone. Compounds 3b, c and e were tested for toxicity using H9c2 cardiac myoblasts cell line. The compounds exhibit >80% viability at 3.125-200 microg/ml. It is apparent from these results that umbelliferone and skimmin may be a useful lead for the development of new antiamoebic drugs.

Bis-pyrazolines: Synthesis, characterization and antiamoebic activity as inhibitors of growth of Entamoeba histolytica

The cyclization of chalcone with N-4 substituted thiosemicarbazides under basic condition led to the formation of new compounds, thiocarbamoyl bis-pyrazoline derivatives. The structure of the compounds were elucidated by UV, IR, (1)H NMR, (13)C NMR and ESI-MS spectral data and thermogravimetric analysis, and their purities were confirmed by elemental analyses. The antiamoebic activity of these complexes was evaluated by microdilution method against HM1:IMSS strain of Entamoeba histolytica and the results were compared with the standard drug, metronidazole. Structure-activity relationship shows that the compound with aromatic substituents at the thiocarbamoyl group was more active than those with the cyclic groups. However, it was clear from the IC(50) values that the compounds 15 and 20 are more active and both showed a structural resemblance having an electron withdrawing groups attached to the phenyl ring. MTT assay showed that all the compounds are non-toxic to human kidney epithelial cell line.

Synthesis, characterization, antiamoebic activity and toxicity of novel bisdioxazole derivatives.

Cyclization of benzene-1,4-dicarbaldehyde dioxime 1 with different aromatic aldehydes in inert atmosphere yielded the corresponding new bisdioxazoles 2-11. The structure of 2-11 was elucidated by spectral data. In vitro antiamoebic activity was performed against HM1:IMSS strain of Entamoeba histolytica. The results showed that the compounds 3 (IC(50)=1.22 microM), 4 (IC(50)=1.41 microM), 7 (IC(50)=1.05 microM) and 10 (IC(50)=1.01 microM) exhibited better antiamoebic activity than the standard drug metronidazole (IC(50)=1.80 microM). The compounds 3, 4, 7 and 10 were tested for toxicity by MTT assay on H9c2 cardiac myoblasts and the results showed that the compounds 3, 4, 7 and 10 offered remarkable viability of 96.2%, 83.5%, 82% and 89%, respectively at a concentration of 12.5 microg/ml.

New Pd(II) complexes of the synthesized 1-N-substituted thiosemicarbazones of 3-indole carboxaldehyde: characterization and antiamoebic assessment against E. histolytica.

Reaction of 3-indole carboxaldehyde with aminothiocarbonyl hydrazines resulted in the formation of 3-indole carboxaldehyde thiosemicarbazones (TSCs) 1-13. The synthesized thiosemicarbazones were used as ligands in the formation of [Pd(TSC)Cl2] complexes with palladium(II) metal ion precursor, [Pd(DMSO)2Cl2]. The chemical structures of all the compounds were established by electronic, IR, 1H NMR and 13C NMR spectral data. The structure of the complexes was further established by FABMS and DTA. It is concluded that the thione sulphur and the azomethine nitrogen atom of the ligands are bonded to the metal ion. The testing of the antiamoebic activity of these compounds against the protozoan parasite Entamoeba histolytica suggests that compounds 5, 3a, 5a and 8a-13a might be endowed with important antiamoebic properties since they showed less IC50 values than metronidazole. Moreover, compound 12a displays remarkable antiamoebic activity than metronidazole (IC50 values of 0.29 vs 1.81 microM, respectively). MTT assay showed that the compounds are non-toxic to human kidney epithelial cell line.

Synthesis and biological evaluation of novel 4-substituted 1-{[4-(10,15,20-triphenylporphyrin-5-yl)phenyl]methylidene}thiosemicarbazides as new class of potential antiprotozoal agents.

A novel series of 4‐substituted 1‐{[4‐(10,15,20‐triphenylporphyrin‐5‐yl)phenyl]methylidene}thiosemicarbazide, 4a–4n, was synthesized in 9–21% yield by the condensation of 4‐(10,15,20‐triphenylporphyrin‐5‐yl)benzaldehyde (3) with various substituted thiosemicarbazides in presence of catalytic amount of AcOH. These compounds were assayed for in vitro antiamoebic activity, and the results showed that out of 14 compounds 9 were found with IC50 values lower than metronidazole corresponding to 1.05‐ to 4.7‐fold increase in activity. MTT Assay showed that all the compounds are nontoxic to human kidney epithelial cell line. 4‐(m‐Toluidinyl)‐1‐{[4‐(10,15,20‐triphenylporphyrin‐5‐yl)phenyl]methylidene}thiosemicarbazide (4h) showed the highest antiamoebic activity with least cytotoxicity. Some of the compounds were screened for their antimalarial activities and ability to inhibit β‐haematin formation, but none of them showed an activity better than chloroquine and quinine. Only one compound out of six showed an activity comparable to standard drug.

Nitroimidazolyl hydrazones are better amoebicides than their cyclized 1,3,4-oxadiazoline analogues: In vitro studies and Lipophilic efficiency analysis.

Two series of compounds with hydrazone derivatives (HZ1-HZl2, series 1) and oxadiazoline derivatives (OZ1-OZ12, series 2) of the 2-methyl-5-nitro-1H-imidazole scaffold were designed and synthesized. Physicochemical properties and Lipophilic efficiency (LipE) analysis predicted higher intrinsic quality of the acylhydrazone derivatives (series 1) than their corresponding oxadiazoline analogues (series 2). In vitro antiamoebic results supported the above findings and validated that the acylhydrazone derivatives (HZ1-HZl2) show better activity than the oxadiazoline derivatives (OZ1-OZ12). MTT assay, using HepG2 cell line, revealed noncytotoxic nature of the compounds. The most promising results were observed for compounds HZ5 (IC50 = 0.96 μM) and HZ9 (IC50 = 0.81 μM) both in silico and in vitro. Analysis of the Lipophilic efficiency (LipE) of the compounds provided new insight for the design of potent and selective amoebicides.

New dioxazole derivatives: synthesis and effects on the growth of Entamoeba histolytica and Giardia intestinalis.

Cyclization of oxime with different aldehydes and ketones under basic condition led to the formation of new dioxazole derivatives and the structure was elucidated by spectral data. The effects of diaoxazoles on the inhibition of growth of Entamoeba histolytica and Giardia intestinalis in vitro have been determined, and selected compounds further investigated for their toxicity. SAR showed that the compounds with 5-nitrothiophene group at the 3-postion of the diaoxazole ring were more active than those with the p-toluene group at the same position. It is interesting to note that the compounds found active against E. histolytica were not found active against G. intestinalis. Toxicity studies showed that the compound 8 and 9 were non-toxic against Vero cell line ATCC CCL-81.

New transition metal complexes containing imidazole rings endowed with potential antiamoebic activity

A useful concept for the rational design of anti-protozoal drug candidates is the complexation of bioactive ligands with transition metals. We previously reported that nitroimidazole acylhydrazones possess excellent antiamoebic activity; in this study, we synthesized some CuII, CoII and NiII metal complexes and chose 2-(5-methyl-2-nitro-1H-imidazol-1-yl)-N′-[(E)-pyridin-2-ylmethylidene]acetohydrazide as a ligand. Physical and spectroscopic characterization revealed a distorted octahedral geometry for the complexes. The pharmacological characterization, including assays against Entamoeba histolytica and cytotoxicity to mammalian cells, revealed that chelation improves the antiamoebic activity of the ligand. Docking of the ligand with thioredoxin reductase (EhTrR), a promising target for the treatment of amoebiasis, showed that the inhibitor snugly fits the active site of the target enzyme, which may well explain the excellent inhibitory activity.