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Synthesis Of Novel 2,4 Diaminoalkyl Substituted Oxopyrimidinyl Formimidic Acids As Potent Cytotoxic Agents In Human Cancer Cell Lines

1728 words - 7 pages

The starting compound 1 was prepared from 4-bromoethylbezoate in two steps by reaction with hydrazine hydrate in ethanol to give the hydrazide which on reaction with bromocyane in Ethanol [Kaupp et al., 1998], compound 1 was treated with Bis (1,3,5,trichloro phenyl) malonate in Chlorobenzene under reflux conditions to get 2-(4-bromophenyl)-7-hydroxy-5H-[1,3,4]oxadiazolo[3,2-a]pyrimidin-5-one (2) [Soliman et al., 1982, Badawey et al., 1990], Bis(1,3,5,trichlorophenyl)malonate was prepared from malonic acid and 2,4,6-trichlorophenol in phosphorous oxychloride [Marton et al., 2003]. Then the compound 2 was reacted with phosphorous oxychloride under reflux condition to get ...view middle of the document...

47%) (Table 1). Excess equivalents of Morpholine in DMSO gave the product 6j in good yield at higher temperature without using any base.
The optimized K2CO3 in DMF reaction conditions was applied to all the amines 4a-k to get the ring opened products 5a-k in good yields (Table 2). The 1H NMR spectra of 5 in DMSO showed, in each case, the presence of –CO=NH- protons and LC-MS spectra showed the corresponding molecular mass to the respective products. FT-IR spectra showed the presence of stretch due to –NH- in the region 3500-3250cm-1. This finding clearly assigned the structure of 3-substituted-6-(pyridine-3-yl)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles (5a-k). Further the 13C NMR and gHSQC, 15N-HSQC, gHMBC spectra of 5j are supporting its structure. Compounds 6a-k showed IR absorption bands around 3470–3300, attributed to -NH, groups. 1H NMR spectra revealed that the presence of -NH peak and -CH- at 10–9 and 6.2–5.8 δ ppm corresponds to -NH and –CH- protons (pyrimidone ring), confirm the formation of title compounds. This was further confirmed by 13C NMR spectra.
Biological Activity

Antibacterial activity
The antibacterial activity of compounds 5a-i and 6a-i were assessed against Streptomycin using agar well diffusion method [Gerald et al., 1962]. The activity expressed as the minimum inhibitory concentration (MIC) in μg/mL. The MIC was defined as the lowest drug concentration required to complete inhibition of bacterial growth. The MICs of the compounds were reported in Table 3. Most of the tested compounds 5a-i & 6a-i showed good in vitro activity (MIC 25-50 μg/mL) compared to Streptomycin (MIC of 100 μg/mL) which is a first line antibiotic drug.
Cytotoxicity Assay
The compounds were tested for cytotoxicity by measuring their effect on the percentage viability of two different cell lines, adenocarcinomic human alveolar basal epithelial cells (A549) and human lung cancer cells (H460) by applying the XTT reagent [Manthey and Guthrie, 2002]. Compounds were tested over a range of concentrations from 1mM to 0.051 μM, and the calculated IC50 values i.e. the concentration (μM) of compounds able to cause 50% of cell death with respect to the control culture, are reported in Table 4. Result shows that few compounds inhibited the growth of human cancer cell lines with IC50 values in the micromolar range. Compound 5g with longer and bulky side chain (Aminoethyl cyclohexane) showed significant activity (IC50 0.4µM), lipophilic group containing 5i (piperidine) and 5k (amino pyrrolidine) showed moderate inhibition against A549 cell line, while 5k (IC50 15µM), 5g & 5i showed moderate activity in H460 cell line compared to puromycin. Compounds with apolar, lipophobic and shorter side chain were less active (IC50 about 10 fold higher).


In conclusion, we have synthesized the 2-alkylamino-6-oxopyrimidin-1(6H)-yl)formimidic acids (5) and 2,6-Dialkylamino-6-oxopyrimidin-1(6H)-yl)formimidic acids (6) derivatives from ring opening of...

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