Amir Azam

Anti-inflammatory, analgesic and antiamoebic activity evaluation of pyrimido[1,6-a]benzimidazole derivatives synthesized by the reaction of ketoisothiocyanates with mono and diamines.

(UN) substituted o-phenylenediamines 1a-g reacted with 3-isothiocyanatobutanal to give pyrimidobenzimidazole derivatives, 2a-g, respectively. Products 4, 6 and 8, 10 were obtained by condensation of 3-isothiocyanatobutanal with 2,3-diaminopyridine, 1,4-diaminobutane and 3-isothiocyanatopropanal with 4,5-dimethyl-1,2-phenylenediamine, o-nitroaniline, respectively. S-Methylation of 2f and 11b gave products 12a and 12b, respectively. Anti-inflammatory and analgesic activity evaluations of 2a-g and 12b were carried out at 50 mg kg(-1) p.o. Compound 2c exhibited good anti-inflammatory (46%) and mild analgesic activity (50%). Antiamoebic activity evaluations (using microdilution method) of 2a-g against Entamoeba-histolytica (strain HM1: IMSS) were carried out and compounds 2a, 2b, 2d and 2g exhibited good antiamoebic activity in vitro.

Synthesis, characterisation, reactivity and in vitro antiamoebic activity of hydrazone based oxovanadium(IV), oxovanadium(V) and µ-bis(oxo)bis{oxovanadium(V)} complexes

Binuclear, mu-bis(oxo)bis{oxovanadium(V)} complexes [(VOL)2(mu-O)2](2 and 7)(where HL are the hydrazones Hacpy-nah I or Hacpy-fah II; acpy = 2-acetylpyridine, nah = nicotinic acid hydrazide and fah = 2-furoic acid hydrazide) were prepared by the reaction of [VO(acac)2] and the ligands in methanol followed by aerial oxidation. The paramagnetic intermediate complexes [VO(acac)(acpy-nah)](1) and [VO(acac)(acpy-fah)](6) have also been isolated. Treatment of [VO(acac)(acpy-nah)] and [VO(acac)(acpy-fah)] with aqueous H2O2 yields the oxoperoxovanadium(V) complexes [VO(O2)(acpy-nah)](3) and [VO(O2)(acpy-fah)](8). In the presence of catechol (H2cat) or benzohydroxamic acid (H2bha), 1 and 6 give the mixed chelate complexes [VO(cat)L](HL =I: 4, HL =II: 9) or [VO(bha)L](HL =I: 5, HL =II: 10). Complexes 4, 5, 9 and 10 slowly convert to the corresponding oxo-mu-oxo species 2 and 7 in DMF solution. Ascorbic acid enhances this conversion under aerobic conditions, possibly through reduction of these complexes with concomitant removal of coordinated catecholate or benzohydroxamate. Acidification of 7 with HCl dissolved in methanol afforded a hydroxo(oxo) complex. The crystal and molecular structure of 2.1.5H2O has been determined, and the structure of 7 re-determined, by single crystal X-ray diffraction. Both of these binuclear complexes contain the uncommon asymmetrical {VO(mu-O)}2 diamond core. The in vitro tests of the antiamoebic activity of ligands I and II and their binuclear complexes 2 and 7 against the protozoan parasite Entamoeba histolytica show that the ligands have no amoebicidal activity while their vanadium complexes 2 and 7 display more effective amoebicidal activity than the most commonly used drug metronidazole (IC50 values are 1.68 and 0.45 microM, respectively vs 1.81 microM for metronidazole). Complexes 2 and 7 catalyse the oxidation of styrene and ethyl benzene effectively. Oxidation of styrene, using H2O2 as an oxidant, gives styrene epoxide, 2-phenylacetaldehyde, benzaldehyde, benzoic acid and 1-phenyl-ethane-1,2-diol, while ethyl benzene yields benzyl alcohol, benzaldehyde and 1-phenyl-ethane-1,2-diol.

Synthesis, characterization and biological evaluation of novel 6-ferrocenyl-4-aryl-2-substituted pyrimidine derivatives.

A new series of 6-ferrocenyl-4-aryl-2-substituted pyrimidines were synthesized and evaluated for in vitro antiamoebic activity against HM1:IMSS strain of Entamoeba histolytica. Out of 16 compounds 10 compounds have shown IC(50) values in the range of 0.41-1.73 microM and 1.80 microM. Pyrimidine derivatives having thiomethyl group, chloro group and mono-, di-, and trimethoxy substitution, exhibited higher antiamoebic activity than the reference drug metronidazole (IC(50)=1.80 microM). The toxicological studies of these compounds on human kidney epithelial cell line showed that all compounds were non-toxic. 4-(4-Chlorophenyl)-6-ferrocenyl-2-piperidin-1-yl-pyrimidine (4f) was found most active (IC(50)=0.41 microM) and least toxic among all the compounds.

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.

Synthesis and in vitro antiprotozoal activity of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazone derivatives

Several thiosemicarbazone derivatives of 5-nitrothiophene-2-carboxaldehyde were prepared by the simple process in which N(4)-thiosemicarbazone moiety was replaced by aliphatic, arylic and cyclic amine. Among these thiosemicarbazones compound 11 showed significant antiamoebic activity whereas compound 3 was more active antitrichomonal than the reference drug.

Synthesis, characterization, antiamoebic activity and cytotoxicity of novel series of pyrazoline derivatives bearing quinoline tail

The cyclization of chalcones (1a-1j) with 2-(quinolin-8-yloxy) acetohydrazide (2) under basic condition led to the formation of new compounds, pyrazoline derivatives (3a-3j). In vitro antiamoebic activity was performed against HM1: IMSS strain of Entamoeba histolytica. The results showed that the compounds 3d, 3g, 3h, and 3j exhibited promising antiamoebic activity (IC(50) = 0.05 microM, 0.31 microM, 0.06 microM, 0.29 microM) respectively than the standard drug metronidazole (IC(50) = 1.84 microM). The toxicological studies of these compounds on human breast cancer MCF-7 cell line showed that all the compounds 3d, 3g, 3h, 3j and metronidazole were nontoxic at the concentration range of 1.56-50 microM.

New palladium(II) complexes of 5-nitrothiophene-2-carboxaldehyde thiosemicarbazones: synthesis, spectral studies and In vitro anti-Amoebic activity

Thiosemicarbazones (1-7) and their palladium(II) complexes (1a-7a) of the type [Pd(TSCN)Cl(2)] (where TSCN=thiosemicarbazone) were prepared from 5-nitro thiophene-2-carboxaldehyde and [Pd(DMSO)(2)Cl(2)], respectively. Coordination via the thionic sulphur and the azomethine nitrogen atom of the thiosemicarbazones to the metal ion were confirmed by spectral data. These compounds were screened in vitro against (HK-9) strain of Entamoeba histolytica possess amoebicidal properties. Enhancement of antiamoebic activity resulted due to the introduction of palladium metal in the thiosemicarbazone moiety. The most promising of the group tested are [Pd(5-N-2-TCA-COTSCN)Cl(2)] and [Pd(5-N-2-TCA-AdmTSCN)Cl(2)] comparable to that of metronidazole.

Antiprotozoal activity of chloroquinoline based chalcones.

A new series of chloroquinoline based chalcones were synthesized and evaluated for in vitro antiamoebic and antimalarial activities. The results showed that out of fifteen compounds, four were found to be more active against the Entamoeba histolytica; while one compound was moderatively active compared to the standard drug metronidazole (IC50=1.46 μM). In contrast, in vitro antimalarial activity against the chloroquine-sensitive (3D7) strain of P. falciparum indicated relatively low activity when compared to controls such as chloroquine and quinine (IC50=0.0065 μM and 0.14 μM, respectively). The toxicological studies of these compounds on human breast cancer MCF-7 cell line showed that all the compounds were non-toxic at the concentration range of 1.56-50 μM.

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.