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ArticleCoumarin amino acid derivatives:Exploring molecular, Docking, ADMET in silico, and anticancer propertiesElhenawy1*, M.A El-Gazzar1, Manal M Khowdiary3,4, A. Moustfa11 Chemistry Department, Faculty of Science, Al-Azhar University (Boys Branch), Nasr City, Cairo, Egypt.University, P.O. Box 80203, Jeddah 21589, Saudi Arabia3Egyptian Petroleum Research Institute, Applied Surfactant Laboratory, Nasr City 11727, Cairo, Egypt.4 Chemistry Department, Faculty of Applied Sciences, Um El Qura University, Makkah, Saudi Arabia*Corresponding Author(Ahmed. A. Elhenawy ); email: elhenawy_sci@hotmail.com.; Tel.: +966508678586Abstract: Novel coumarin amino acid was synthesized. The structure of synthesized compounds have established on basis of different spectral data. The optimization geometry, frontier molecular orbitals (FMOs), thermodynamic parameters and chemical reactivity, were discussed using DFT\B3LYP by 6- 311G* basis set, to identify a clear view for inter and intramolecular interaction of tested compounds. The molecular electrostatic potentials (MEP) has plotted to investigate a recognition manner of synthesized compounds upon COX-2 receptor. All tested compounds showed a promising (NLOs) nonlinear optical properties. Bond dissociation energy (BDE) has studied to investigate a potency of these molecule against autoxidation mechanism Polynomial molecular docking logarithms have performed into the COX-2 active site for tested compounds. The docking protocol that have low RMSD has selected for discussion the binding affinity The compounds with a high docking score 3,4,6-8,10 and 11 were selected for additional study against ADMET insilico ADMET profile showed that these compounds are a good oral bioavailability without observed carcinogenesis affect The passed compounds (3,4,6-8,10 and11) through docking and ADMET profile has examined the potency against (MCF-7) breast cancer cell line in vitro. The compound7 showed a highest potency against MCF-7 with IC50 value 0.39 µM. The QSAR model has created to discover the structural necessity inhibition of MCF-7. The derived QSAR model has a statistically significant with a good predictive power. This work could be useful in designed a new potent anticancer agent.Keywords: Anticancer; DOCKIN, ADMET and QSAR.1. Introduction(MDR) is a challenge problem for cancer treatment [1, 2]. Coumarin class are widely sound in several medicinal field. The observed results for naturally and synthetic coumarin class against (MDR) treatment [3, chemists to enhancement therapeutic anticancer features for this class[5, role of cyclooxygenase-2 inhibitors (COX2 I.) in treatment cancer cell [7].COX2.I prevent generation of prostaglandinE2 (PGE2), which induce proliferation through production a new blood vessel, and support tumor cell by oxygen and nutrients. That led to increase mass of tumor and metastasis[8]. In addition, PGE2 capable of fight cell, escape from immune system and resistance against chemotherapeutic drugs [9]. Thus, targeting inhibiting or reducing PGE2 by evaluation of bioactive COX-2 inhibitor is effective strategy for development chemotherapeutic cancer drug[10]. Non-steroidal anti-inflammatory drugs (NSAIDs) class are able to inhibit the PGE2 production [9, derivatives especially containing hydrophobic residue possess diverse biological activities, as anti-inflammatory, anti-tumor and antimicrobial activities[12, derivatives are naturally metabolite, with a promising inhibition action against tumor cell generation[14] Hence, we aimed to synthesis a novel class series of coumarine derivatives containing hydrophobic amino acid moiety acting as new anticancer agent2. Results& Discussion:2.1. Chemistry:2 was carried out according to earlier reported[5]. The compound 2was fussed with L-alanine (L-Ala.) and o- aminobezoic acid (o ABA), respectively, to afford free acid derivatives 3and 4, respectively, (Scheme 1). The appearance of characteristic NH bands at IR spectra (υcm-1 = 3212 and 3396), and 1HNMR spectrum (δ= 6.00 and 5.93 ppm) for compounds 3 and 4 , respectively, which supported the proposed structures.Synthesis of compounds ( 1-4)methylated to corresponding methyl ester derivative 6 via acid chloride synthesis 5 (Scheme2). The structure of 6 was supported by HNMR data, through appearance of characteristic OCH3 peak (δH=3.6 ppm), and disappearance of characteristic COOH proton for compound 4 . The presence of the characteristic peak for NH2 group (δH=6.2 ppm) was proved by formation hydrazide derivative (7 ) via ester hydrazinolysis of 6 .Synthesis of compounds (5-7)with glycine to give free dipeptide derivative (8 ). That esterified via acid chloride formation (9 ) using SOCl2/MeOH to give dipeptide methyl ester (10 ), which also prepared through fused glycine methyl ester with compound (4 ). Compound (10 ) was reacted with alcoholic hydrazine to form dipeptide hydrazide (11 ) in good yield. (Scheme 3).Scheme(3): Synthesis of compounds (8-11)Single crystal for compounds 4,6-8,10 and 11 didn’t available till now. Thus, the optimization geometries and was pre performed using the PM3 semi-empirical in MOPAC16 package [15], followed by exported to DFT for final optimization , using Gaussian 09 package as implemented in MOE.2015[16], all calculated energies were summarized in (table 1). The compounds 3 ,4,6-8,10 and 11 have stabilized by arrangement of benzocoumarin rings in planner and coplanar mode with Ala fragments for all ligands, except 10and 11 have stabilized by arrangement of Ala. residues in parallel way with benzocumarine rings (S Figure 1-7supplementary materials.). The CO group of alninyl fragments ( (CH3)CHCــــ O) has shown a bond length for (4,6 -8,10 and 11 ); respectively: C20ــــ O22(1.34°A), C19ــــ O21(1.29°A), C18ــــ O20 (1.24°A), C23ــــ O24 (1.21°A), C23ــــ O25 (1.109°A) and C23ــــ O25 (1.1°A), respectively. The bond angle (C13-O5-N2) of compounds (4,6 and 7 ) showed; (120.31, 122.96° and 119.91°), respectively. The decreasing length of COAla group for (4,6 and 7 ) than (8,10 and 11 ) may explain by withdrawing effect of attached carbonyl group in glycyl fragment, which support ring formation, through H-bond interaction between NHALa and Cــــ OGly for (8,10 and 11 ).HOMO (donating electrons) and LUMO (accepting electrons). are a vital orbital for the molecule These orbitals define as “FMOs” frontier molecular orbital’s, which can decide the interaction rout with receptor. The “simple Hückel Molecular Orbital theory (SHMO)” [17] used for determine FMOs gap, which lead to characterize the chemical reactivity and kinetic stability of the molecule.Table 1 : Calculated energetic of reactivity parameters for compounds (3,4,6-8,10 and 11) at DFT with a B3LYP\6-31G* Basics sets.