Six most potent compound. Compound 8 with the less

Six lipophilic and one hydrophilic derivatives ofhydroxyurea (table 1) were synthesized in 24-72% yield based on method thatshown in scheme 1. All of compounds characterized by TLC followed by IR andproton NMR.The cytostatic activity of compounds 2-9 were determinedusing an in-vitro assay against Hella and Panc-1 cell lines and the results at24 and 48 hours are summarized in tables 2-4 and figure 2.

Due to greatdifference of molecular weight of Hydroxyurea and compounds 2-9, the IC50values were reported in micrograms and micromole scales. Based on the IC50value (table 4) all the designed and prepared compounds are more potent than hydroxyureaat 24 and 48 hours on both cell lines, that cytostatic activity at 48 hour ismore than of 24 hour. Lipophilicity (log P) strongly affect the cytostaticactivity of prepared ligands and compounds 7 and 5 with high amount of logp,4.88 and 2.79 respectively, showed the high cytostatic activity that compound 7with the highest logp was the most potent compound.

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Compound 8 with the lessamount of logp was the less cytostatic agent in this series. Comparison ofcompounds 4, 5 and 6 with close amounts of lipophilicity which having 2 phenylring with different structure, orientation and volumes reveals in addition tothe logp, size and volume of substituent play very important role in activity. Socompound 4 with logp around 3.05 due to its more blocker structure is lessactive than compounds 5 and 6 with logp 2.79 and 2.

54 respectively.  Also compound 9 with high lipophilicity, dueto it geometrical shape, imine moiety, showed weak cytostatic activity. Comparisonof compound 8 with hydroxyurea that have close amounts of logp (-0.83 and -.082respectively) and different amounts of molecular weight, reveals heaviercompound 8 is more active than hydroxyurea. Based on our docking studies andin-vitro evaluation results, it is suggested that size, shape and hydrophobiccharacter of substituents strongly affect the pharmacodynamics andpharmacokinetic of these ligands. Finally, overall cytostatic activity (table 4) show that  all the synthetized compounds are very activespecially compounds 7, 5 and 3  can beacted as a new lead compounds to design and finding novel and too potentcytostatic agents.

     The dockedconformations of compound 7 as the most potent ligand were ranked intoclusters based on the binding energy and the top ranked conformations werevisually analyzed. Drug-receptor interaction profile was analyzed usingAutoDock Tools (version 1.50) and Ligplot 16.   As it was reported already the inhibitormust be ready to destroy the Tyrosyl radical and thus the inhibitors such as compound7 should be bonded at the active site with Tyrosine 176 that is aradical harboring, to reduce the radical activity and inhibit cell division12.The docking energies of compound 7 and hydroxyurea asreference drug, are noted as -5.49 and -4.11 kcal/mol, respectively that basedon the lowest docking energy compound 7 shows higher affinity thanhydroxyurea to human RNR protein.

The LIGPLOT diagrams of compound 7 andhuman RNR docking interactions are shown in figure 1.Compound 7 is easily occupied at the active site ofreceptor via two strong hydrogen bonds using the residue of Ser173. Inaddition, some hydrophobic interactions by the residues Tyr176, Ala135, Ser177,Arg190, Ala132, Leu193 and Ile180 also help the drug for its conformationalstability in the active site. Dichlorophenyl moiety of ligand was incorporatedinto the hydrophobic pocket that created by Arg190, Ala132, Leu193 and Ile180.

Hydroxylmoiety of ligand has good interactions with surrounding residues, Ser173, Tyr176and Ala135.  Conclusions   All studiedcompounds have more cytotoxic effect against Hella and Punc cell line thanhydroxyurea at 24 and 48 hours.  Compound7 is the most active against both cell lines. It was concluded that lipophilicity,size and shape of substituents strongly affect the cytostatic activity andligands with high lipophilicity and small size and the compact shape has goodpharmacokinetic (cell permeability and stability) and pharmacodynamics.