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1 BAO CAO NGHIEM THU DETAI 2 FULL pdf Trang 111 CHƯƠNG 4 KẾT LUẬN VÀ KIẾN NGHỊ 10 α amino phosphate mới có cấu trúc tương tự theo hướng tiếp cận xanh hơn dựa trên xúc tác xanh PEG 400 đã được tổng hợp, sàng lọc trong vitro kháng khuẩn, nấm, tế bào ung thư và trong silico molecular docking model Hợp chất (3c) và (3h) kháng rất mạnh trở lại nấm Candida albicans và nấm Saccharomyces cerevisiae tương ứng ở cùng nồng độ 200 μg mL 1 Các kết quả nghiên cứu trong silico molecular docking model của một s.
CHƯƠNG : KẾT LUẬN VÀ KIẾN NGHỊ 10 α-amino phosphate có cấu trúc tương tự theo hướng tiếp cận xanh dựa xúc tác xanh PEG- 400 tổng hợp, sàng lọc vitro kháng khuẩn, nấm, tế bào ung thư silico molecular docking model Hợp chất (3c) (3h) kháng mạnh trở lại nấm Candida albicans nấm Saccharomyces cerevisiae tương ứng nồng độ 200 μg.mL-1 Các kết nghiên cứu silico molecular docking model số hợp chất có hoạt tính cao vitro với vi khuẩn: (3c)> (3h)> Fluconazole Trong silico docking model với dòng vi khuẩn nấm cho thấy liên kết hydro hình thành từ tâm hoạt động receptor với nhóm dietyl phosphate nguyên tử hydro liên kết N-H nhóm amine bậc hai Các hợp chất (3c), (3f) (3i) hoạt tính ức chế mạnh trở lại dịng tế bào ung thư HeLa kết hoàn toàn vitro Giá trị IC50 (3f) kháng lại tế bào ung thư HeLa vitro số chất ức chế, Ki tương đương số hợp chất có hoạt tính cao Trong silico docking với dịng tế bào ung thư cho thấy liên kết hydro hình thành từ hầu hết residual amino acid receptor đến nguyên tử oxy liên kết đơi O=P, ngun tử oxy nhóm ethoxy ngun tử nitơ hydro nhóm N-H ligand (3a-j), chúng hình thành từ residual amino acid receptor đến nguyên tử Flo nhóm CF3 với (3i) Các hợp chất (3a), (3c) (3h) cho thấy khả ức chế mạnh trở lại dòng tế bào ung thư MCF-7 Hơp chất (3c), (3e) (3h) ức chế cao dòng tế bào ung thư A-549 vitro Cơng trình nghiên cứu nhóm thiết kế, tổng hợp, sàng lọc vitro silico docking model dymanic molecular docking dẫn xuất α-amino phosphate dựa Carbazole thông qua Kabachnik sử dụng thu hồi PEG-400 Trang 111 REFERENCES [1] Moonen K, Laureyn I, Stevens C V Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity Chem Rev 2004;104(12):6177–6216 [2] Hiratake J, Oda J Aminophosphonic and Aminoboronic Acids as Key Elements of a Transition State Analogue Inhibitor of Enzymes Biosci Biotechnol Biochem 2009;61(2):211–218 [3] Jin L, Song B, Zhang G, Xu R, Zhang S, Gao X Synthesis, X-ray crystallographic analysis, and antitumor activity of 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Design and one-pot synthesis of α-aminophosphonates and bis(α-aminophosphonates) by iron(III) chloride and cytotoxic activity Eur J Med Chem 2009;44(11):4266–4275 [19] Bhagat S, Chakraborti A.K Zirconium(IV) compounds as efficient catalysts for synthesis of α-aminophosphonates J Org Chem 2008;73(15):6029–6032 [20] Hosseini-Sarvari M TiO2 as a new and reusable catalyst for one-pot three-component syntheses of α-aminophosphonates in solvent-free conditions Tetrahedron 2008;64(23):5459–5466 [21] Mitragotri S.D, Pore D.M, Desai U V, Wadgaonkar P.P Sulfamic acid: An efficient and costeffective solid acid catalyst for the synthesis of α-aminophosphonates at ambient temperature Catal Commun 2008;9(9):1822–1826 [22] Lee S.G, Park J.H, Kang J, Lee J.K Lanthanide triflate-catalyzed three component synthesis of α-amino phosphonates in ionic liquids: A catalyst reactivity and reusability study Chem Commun 2001;1(17):1698–1699 [23] Akiyama T, Morita H, Bachu P, Mori K, Yamanaka M, Hirata T Chiral 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Pawar T.B, Chobe S.S Efficient Synthesis, Antibacterial, Antifungal, Antioxidant and Cytotoxicity Study of 2-(2-Hydrazineyl)thiazole Derivatives ChemistrySelect 2020;5(9):2778–2786 [29] Kumar K.S, Rajesham B, Kumar N.P, Ramulu S A Ligand / Additive / Base-Free C ( sp ) H Activation and Isocyanide Insertion in PEG-400 : Synthesis of Indolizine / ImidazolineFused Heterocycles 2018;4581–4585 [30] Kumar R, Chaudhary P, Nimesh S, Chandra R Polyethylene glycol as a non-ionic liquid solvent for Michael addition reaction of amines to conjugated alkenes Green Chem 2006;8(4):356–358 [31] Mao J, Guo J, Fang F, Ji S.J Highly efficient copper(0)-catalyzed Suzuki-Miyaura crosscoupling reactions in reusable PEG-400 Tetrahedron 2008;64(18):3905–3911 [32] Kumar M.A, Lee K.D A simple and catalyst-free one-pot synthesis of α-aminophosphonates in polyethylene glycol Phosphorus, Sulfur Silicon Relat Elem 2012;187(8):899–905 [33] Nguyen M.A.T, Kumar M.A, Kim J.A, Lee K.D, Park S Synthesis, anticancer and antioxidant activity of novel carbazole-based thiazole derivatives Phosphorus, Sulfur Silicon Relat Elem 2015;190(2):191–199 [34] Tran Nguyen Minh An, Nguyen Van Cuong, Nguyen Minh Quang, Truong Vu Thanh, Alam M New Carbazole Based on α -Aminophosphonate Chemselect 2020;5:6339–6349 [35] Karimi-Jaberi Z, Zare H, Amiri M, Sadeghi N Cobalt(II) chloride accelerated one-pot threecomponent synthesis of α-aminophosphonates at room temperature Chinese Chem Lett Trang 114 .2011;22(5):559–562 [36] Zhang F.F, Gan L.L, Zhou C.H Synthesis, antibacterial and antifungal activities of some carbazole derivatives Bioorganic Med Chem Lett 2010;20(6):1881–1884 [37] Meissner A, Boshoff H.I, Vasan M, Duckworth B.P, Barry C.E, Aldrich C.C Structure-activity relationships of 2-aminothiazoles effective against Mycobacterium tuberculosis Bioorganic Med Chem 2013;21(21):6385–6397 [38] Sudileti M, Nagaripati S, Gundluru M, Chintha V rGO-SO3H Catalysed Green Synthesis of Fluoro-Substituted Aminomethylene Bisphosphonates and their Anti-cancer, Molecular Docking studies 2019;13006–13011 [39] Hanwell M.D, Curtis D.E, Lonie D.C, Vandermeerschd T, Zurek E, Hutchison G.R Avogadro: An advanced semantic chemical editor, visualization, and analysis platform J Cheminform 2012;4(8) [40] Thiratmatrakul S, Yenjai C, Waiwut P, Vajragupta O, Reubroycharoen P, Tohda M Synthesis, biological evaluation and molecular modeling study of novel tacrine-carbazole hybrids as potential multifunctional agents for the treatment of Alzheimer’s disease Eur J Med Chem 2014;75:21–30 [41] Huey R, Morris GM, Forli S Using autodock and autodock vina with autodocktools : a tutorial 2012; Available from: http://autodock.scripps.edu/faqs-help/tutorial/using-autodock4-with-autodocktools/2012_ADTtut.pdf [42] Gomha S.M, Salaheldin T.A, Hassaneen H.M.E, Abdel-Aziz H.M, Khedr M.A Synthesis, characterization and molecular docking of novel bioactive thiazolyl-thiazole derivatives as promising cytotoxic antitumor drug Molecules 2016;21(1):1–17 [43] Warren G.L, Andrews C.W, Capelli A.M, Clarke B, LaLonde J, Lambert M.H A critical assessment of docking programs and scoring functions J Med Chem 2006;49(20):5912–5931 [44] Edition S Neuro-proteomics 2016;1598:391–403 Trang 115 PHỤ LỤC Hình Cấu dạng ổn định Fluconazole sau hoàn thành docking với nấm C.albincans, (6TZM: PDB), xây dựng mô hình DSC Client 2019 Hình Sự tương tác amino acid lại 6TZM với cấu dạng bền Fluconazole Trang 116 Hình Sự tương tác amino acid lại, Thr-426, Asn-444, Asp-445 Asn-476 6TZM với Fluconazole Hình Các tương tác nguyên tử hoạt tính receptor (6TZM) cấu dạng bền (Fluconazole) sơ đồ 2D Trang 117 Hình Bản đồ ligand tương tác bậc hai Fluconazole 6TZM Hình Cấu dạng Fluconazole sau hồn thành tính tốn docking với Saccharomyces cerevisiae Hình Sự tương tác amino acid 3ET5 với cấu trúc bền Fluconazole Trang 118 Hình Các tâm hoạt động liên kết ligand-receptor, 3ET5 sơ đồ 2D Hình Sự tương tác amino amin lại 3ET5: Ser-164, Val-165 Arg-147 với tâm hoạt động Fluconazole Trang 119 Hình 10 Bản đồ ligand tương tác thứ cấp Fluconazole 3ET5 sơ đồ 2D Hình 11 Cấu dạng ổn định 3b sau docking với Bacillus megatherium, 6NVW Trang 120 [IY[OU] ChemistrySelect Full Papers doi.org/10.1002/slct.202000855 z Organic & Supramolecular Chemistry Green Synthesis Using PEG-400 Catalyst, Antimicrobial Activities, Cytotoxicity and In Silico Molecular Docking of New Carbazole Based on -Aminophosphonate Tran Nguyen Minh An,*[a] Nguyen Van Cuong,[a] Nguyen Minh Quang,[a] Truong Vu Thanh,[b] and Mahboob Alam[c] New analog –amino phosphate series with high yield through an effective and environmentally friendly protocol using the PEG-400 catalyst via Kabachnik-Fields has been reported They were performed to screen antimicrobial activities by the dish diffusion method, anticancer against MCF-7, A-549, and HeLa human cancer cell lines by MTT assay, and carried out in silico molecular docking by Avogadro, AutoDockTools, Discovery Studio 2019 Client, and Molegro Molecular Viewer packages The 3c and 3h displayed excellent inhibition against Candida albicans and Saccharomyces cerevisiae fungi, respectively The molecular docking model indicated the reasonable explanations between the receptor and bioactive compounds in vitro of 3c, h, and 3b The 3c was shown as an excellent inhibitor Introduction The -amino phosphonate or diester of amino phosphonic acids were significant objects, valuable medical compounds because they had a structural analogy to amino acids, peptides, natural phosphates, and interesting biochemistry recently.[1] The strategy of synthesis and biological activities of some phosphorus organic derivatives have been reported in the literature.[2] The bioactivities that we performed as potential fungicides,[3] antibacteria, antitumor,[4] antioxidant,[5] inhibitors of enzymes involving in amino acid and peptide metabolism,[6] UDP-galactopyranose mutase,[7] human plasma renin.[8] Many amino phosphonate synthesis methods were performed, but the synthesis approach via Kabachnik-Fields (K.F) reaction conducted the most effective and the reaction processes three components, amine, aldehyde and phosphites derivatives by magnesium perchlorate catalyst, which in high yielded in [a] Dr T N M An, Prof N V Cuong, Dr N M Quang Faculty of Chemical Engineering, Industrial University of Ho Chi Minh City, Ho Chi Minh city, Vietnam, 12 Nguyen Van Bao Road, Ward 4, Go Vap District, Ho Chi Minh City,Vietnam E-mail: trannguyenminhan@iuh.edu.vn [b] Prof T V Thanh Faculty of Chemical Engineering, Ho Chi Minh City University of Technology, VNU-HCM, Vietnam, 268 Ly Thuong Kiet, Ward 14, District 10, Ho Chi Minh City, Vietnam [c] Dr M Alam Division of Chemistry and Biotechnology, Dongguk University, Gyeongju 780–714, Republic of Korea Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.202000855 ChemistrySelect 2020, 5, 6339 – 6349 against Candida albicans, which was a new result in vitro and in silico molecular docking model The 3c, f, and 3i pointed out excellent inhibitions against HeLa cell lines and new anticancer results of +–amino phosphate compounds The docking studies of structures against receptors of three human cancer cell lines were conducted and recommended that the hydrogen bonds only formed from active sites of receptors to oxygen atom of the ethoxy group, nitrogen and hydrogen atoms of NÀH group, oxygen atom of the P=O double bond group, and the fluorine atoms of the CF3 group in 3i for calculated docking of the receptors of bacteria, fungi, and cancer cell lines to all ligands amino phosphonate products.[9] The heterogeneous catalyst, solid catalyst series applied reactions to obtain in high yields, for instance, antimony trichloride adsorbed on alumina, cobalt chloride,[10] iron(III) chloride,[11] zirconium(IV),[12] commercial titan dioxide under solvent-free conditions,[13] and sulfamic acid.[14] Some of lanthanide triflates-catalyzed in ion liquid formed products and conducted easily to reuse solid catalyst.[15] The chiral Brønsted acid made a catalyst for products with high enantioselectivities.[16] The super magnetic nano iron oxide in solvent-free conditions performed magnetically recyclable catalysts.[17] The sodium dodecyl sulfate in water, Lewis acid and surfactant supported to yield amino phosphonic acid diesters via K.F.[18] The homogeneous catalysts were used for K.F reaction as KHSO4 under the solvent-free condition at ambient temperature for moderate yields.[19] Recently, as extensive attention, the polyethylene glycol-400 (PEG-400) has been identified as a green catalyst, inexpensive, green media, non-toxics, reuse, short-time reaction, high yield, an efficient and eco-friendly reaction, greener approach, alternative reaction medium, and medium for the broad synthesis of transformation organic functional groups and biodegradable material.[20] The PEG-400 carried out the catalyst for Michael’s addition reaction as a non-ionic liquid solvent,[21] Suzuki crosscoupling reaction, Suzukie Miyaura cross-coupling reactions,[22] the nucleophile additions of phosphonic acid diesters to C=N, the double bond in K.F reaction.[23] As interested PEG-400, green approach and continuous report of new -amino phosphonate derivatives based on carbazole via K.F reaction, we carried out synthesis, anticancer, antimicrobial activities, 6339 © 2020 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim ChemistrySelect Full Papers doi.org/10.1002/slct.202000855 and conducted in silico molecular docking, which discovered structure-activity relationship (SAR) and designed core structures having biological activities results Results and Discussion Reaction Mechanism Scheme The proposed reaction mechanism of Kabachnik–Fields: the reaction of components: 9–ethyl–9H–carbazole–3–carbaldehyde, analogue primary aromatic amine, and diethyl phosphite by a green catalyst, PEG-400 Scheme Synthesis of intermediate derivatives 1, 2, and products, a-j Reagents and conditions: a) Et–Br, KOH catalyst, dry DMSO, reflux 24 h, 91% 1; b) Vilsmeier–Haack reaction: DMF(dry) in CH2Cl2; POCl3 in ClCH2CH2Cl, N2, reflux, 48 h, NaOH, 95% 2; c) Kabachnik-Fields: 9–ethyl–9H–carbazole–3– carbaldehyde (1 mmol), diethyl phosphite (1.3 mmol), analog primary aromatic amine (1 mmol), PEG–400 catalyst (0.38% mol), 100 °C, 6–7 h, a-j: 84–91% Physical chemistry In 1H NMR as shown in the experimental section, the signals of the methine protons of HN–CH–P=O(OEt)2 groups showed the resonances as the doublet peaks in entries a–c, g–h, and j with chemical shifts () in region 4.88–4.95 ppm with coupling constants in the range of 23.5 –24.0 Hz, and doublet of doublet (dd) peaks in d–f and i with the chemical shifts from 4.89 – 5.25 ppm and coupling constants between 23.0 and 24.4 Hz, due to its near coupling with the hydrogen nucleus of the N–H group and phosphorus nucleus The proton signals of N–H bonds appeared as triplet peaks in d, f, and i with the chemical shifts in the range of 5.29 to 6.08 ppm and the coupling constants from 7.4–8.6 Hz They also showed quartet peaks in c and e with J and in the range of 5.4 –10.9 Hz and 4.88–6.19 ppm, respectively The proton signals of N–H ChemistrySelect 2020, 5, 6339 – 6349 bonds were resonance as triplets in d, f, and i, or quartet in c and e, because of coupling to occur with the nuclei of hydrogen and phosphorous nearby, HN–CH–P The proton signals of NÀH bonds in the others like a–b, g–h, and j disappeared because of the proton exchange in commercial CHCl3 solvent, which remained residual CHCl3 peak The signal for the exchangeable proton was merged into a single peak with an unpredictable chemical shift The methyl protons of N– ethyl groups were resonance as triplet signals from 1.04 to 1.23 ppm with coupling constants variety between 7.0 and 7.1 Hz in entries a–i except for j The methyl protons of diethyl phosphite groups coupled with methylene protons nearby, which formed two distinction triplet resonance signals in the range of 1.29–1.52 and 1.41–1.61 ppm with coupling constants from 6.8–9.0 and 7.1–7.2 Hz at all entries except for e, respectively The methylene protons of N–ethyl groups coupled with methyl protons nearby exposed the quartet peaks in the region of 4.34–4.38 ppm with the coupling constants of 6.8–7.2 Hz The methylene protons of diethyl phosphite groups indicated three differential resonance arranges, which corresponded multiplet peaks in ranges were listed 3.38–3.9, 3.78–4.11, and 4.09–4.29 ppm, which were one, one, and two of methylene protons, respectively, except that two signals of methylene groups at j and i that showed the quartet and triplet signals at 3.57 and 4.15 with coupling constants of 8.2 and 7.1 Hz, respectively The signals of protons of carbazole ring, H–4 protons exposed as singlet peaks in the region of 8.15–8.45 The remained resonance signals of aromatic protons appeared in the expected ranges 6340 © 2020 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim ChemistrySelect Full Papers doi.org/10.1002/slct.202000855 The 13C NMR showed the signals of methine carbons bound to nitrogen and phosphorus atoms, HN–CH–P coupled near range with them so that the methine carbons established those double peaks in the range of chemical shifts from 56.1 to 57.7 with coupling constants between 151.0 and 152.5 Hz The resonance signals of the phosphorus nucleuses indicated in the range of 23.13–24.70 ppm The infrared absorption bands were identified typically strong functional groups, stretching vibrations in the ranges of 3268–3396 (N–H), 2977–2981 (C–H, alkyl), 1596–1617, 1516–1599, 1480–1493, 1385–1387(C=C),1233– 1234 (P=O), 1300–1336 (C–O), 1024–1054 (C–N), and 748– 752 cmÀ1 (P–CH) In Silico Molecular docking model Antimicrobial activities The results of docking pose or ligand of the activity structures in vitro like c and h against fungi, Candida albicans, and Saccharomyces cerevisiae, respectively, the b against the bacterium, Bacillus megaterium and standard drugs were shown in Figures 5–12, Table 1–3, and Figures S.1.1–S.1.20 As shown Antimicrobial activities Antifungal activity The entry c and h exposed excellent activities against both S cerevisiae and C.albincans fungi at a concentration of 200 #g.mLÀ1 compared to the standard drug, Fluconazole at a concentration of 1000 #g.mLÀ1 The entry h also pointed out good inhibition again S cerevisiae at the concentrations of 50 and 100 #g.mLÀ1 Antibacterial activity The entry b designated good antibacterial activity against B.megaterium at a concentration of 200 #g mLÀ1, moderate activity at a concentration of 100 #g mLÀ1, and no inhibition at a concentration of 50 #g mLÀ1 The j showed moderate activity against B cereus at all concentrations Figure The entry c in the image exhibited excellent activity against C.albincans at a concentration of 200 #g.mLÀ1 (377.78 #M) and compared to the standard drug, Fluconazole at a concentration of mg.mLÀ1 (3265 #M) Anticancer activity The compounds a, c, and h showed excellent cytotoxicity activity against MCF–7 with the IC50 values of 9.78 Æ 0.93, 9.39 Æ 0.64, and 6.38 Æ 0.22 #M against breast cancer cell lines, MCF–7, respectively as shown in Table and Figure 13 The compounds c, e, and h showed the highest inhibitions with the IC50 values, 7.32 Ỉ 0.07, 3.82 Ỉ 0.01, and 2.29 Æ 0.02 #M against small lung cancer cell lines, A–549, respectively as shown in Table and Figure 14 For cervical cancer cell lines, HeLa, the compounds, c, f, and i exposed high inhibitions against HeLa cancer cell lines with the IC50 values, which performed 5.98 Ỉ 0.02, 5.16 Ỉ 0.04, and 7.19 Ỉ 0.02 #M, respectively as shown in Table and Figure 15 These results of cytotoxicity of c, f, and i against cervical cancer cell lines, which were reported the first time screening cytotoxicity activity for +-amino phosphate compounds The IC50 values and inhibition abilities of entries a-j against MCF–7, A–549, and HeLa cancer cell lines depicted in Figures 13 and 15 and Figures 16–18, respectively Figure The h image exposed excellent activity against S cerevisiae at a concentration of 200 #g.mLÀ1 (455.38 #M) compared to the standard drug, Fluconazole at a concentration of mg mLÀ1 (3265 #M) and the h also showed good activity at the concentrations of 50 and 100 #g.mLÀ1 ChemistrySelect 2020, 5, 6339 – 6349 6341 © 2020 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim ChemistrySelect Full Papers doi.org/10.1002/slct.202000855 Figure The entry b demonstrated good inhibition against B.megaterium at a concentration of 200 #g mLÀ1(388 #M), moderate activity at a concentration of 100 #g mLÀ1, and no inhibition at a concentration of 50 #g mLÀ1 It was compared to Ampicillin at a concentration of mg.mLÀ1 (5724 #M) Figure The compound j showed moderate activity against B cereus at all concentrations compared to standard drug–Ampicillin at a concentration of mg mLÀ1 in Table 1, the maximum negative value of the energy of binding at the active sites of a receptor and the docking pose c and an inhibitor constant of it with the receptor 6TZM (6TZM: PDB) were performed –7.03 kcal.molÀ1 and 6.98 #M, ChemistrySelect 2020, 5, 6339 – 6349 Figure The most stable conformation c after completion of docking calculation with C.albincans, 6TZM, the value of the lowest negative free energy of binding (ligand-receptor, c–6TZM) of –7.03 kcal.molÀ1 and an inhibitor constant, Ki of 6.98 #M were calculated by AutoDockTools-1.5.6rc3 and visualized by Discovery Studio 2019 Client package Figure The active site atoms in a 2D diagram between a receptor 6TZM and the most stable conformation c including the hydrogen bond, Van der Waals, halogen, unfavorable positive–positive, pi–carbon, alkyl, and pi–alkyl interactions respectively They were used to select and analyze the best conformation for docking with a receptor, which embedded in 6342 © 2020 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim ChemistrySelect Full Papers doi.org/10.1002/slct.202000855 Figure The binding sites of the most stable conformation c with active sites of C.albincans, 6TZM, four hydrogen bonds forming between residual amino acids of 6TZM and the best docking poses of conformation c by Discovery Studio 2019 Client package Figure The most stable conformation h after completion of the docking calculation with S cerevisiae, 3ET5, the value of the lowest negative free energy of binding (ligand-receptor, h–3ET5) of –9.59 kcal.molÀ1 and an inhibitor constant, Ki of 0.094 #M Figure The ligand map indicated the extra secondary interactions like the hydrogen bonds, steric and overlap interactions between a docking pose c and the active sites of a receptor, 6TZM by Molegro Molecular Viewer package a receptor 6TZM in Figure The values of inhibition constant and the free energy of binding of the best conformation c and receptor–6TZM in Table were calculated and compared to those of the standard drug indicated that the compound c at a concentration of 200 #g.mLÀ1 (377.78 #M) has stronger inhibition than that of the standard drug The value of the lowest negative of free energy of binding of the best docking pose, c to receptor 6TZM was smaller than that of a drug to the same receptor indicated these bonds of docking pose c to the receptor were more stable bonds than those bonds of docking pose of standard drug, Fluconazole to the receptor The value of free energy of binding (~G) calculated based on the difference between amounts of the total of the Val der ChemistrySelect 2020, 5, 6339 – 6349 Figure 10 The active site atoms between a receptor 3ET5 and the most stable conformation h on a 2D diagram including the secondary interactions as the hydrogen bonds, Van der Waals, carbon-hydrogen bond, pi–donor hydrogen bond, pi–sigma, alkyl, and pi–alkyl Waals forces, hydrogen bond, desolvation, electrostatic, total internal, torsional free energy, and energy of an unbound system.[24] As visualized in Figure 6, the residual amino acids around the most stable conformation c examined as hydrophobic acids: Cys–423 and Ile–421 The Cys–423 formed one hydrogen bond with atom oxygen of the P=O double bond The residual hydrophilic amino acids were observed like Gly– 422, Gly–424, Arg–528, Lys–425, Asn–476, Asp–474, Asp–445, Arg–475, Asn–444, Tyr–628, Asn–446, Gln–443, Thr–427, and 6343 © 2020 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim ChemistrySelect Full Papers doi.org/10.1002/slct.202000855 Figure 11 The binding sites of the most stable conformation h with the active site of 3ET5, one hydrogen bond from residual amino acids of 3ET5 to the best docking pose of conformation h Figure 13 The IC50 values of entries, a–j against breast cancer cell lines, MCF–7 in vitro Figure 14 The IC50 values of entries, a–j against small lung cancer cell lines, A–549 in vitro Figure 12 The ligand map indicated the secondary interactions, which included the hydrogen bonds, steric, and overlap interactions between the best docking pose h and 3ET5 Thr–426 The Gly–422, Gly–424, Lys–425, and Thr–426, the hydrophilic amino acids bound to atom oxygen of P=O double and atom oxygen of O–ethyl group via hydrogen bonds (green lines), respectively Other interactions showed the van der Waals, carbon-hydrogen, halogen, unfavorable positive–positive, pi–cation, alkyl, and pi–alkyl All interactions in Figure determined the total amount of minimum energy of the best conformation c for docking As shown in Figure and Table 1, the docking pose c formed four hydrogen bonds with the receptor 6TZM (6TZM: PDB, the crystal structure of Candida albicans) All those hydrogen bonds started from active sites of residual amino acids as Glyn–422, Gly–424, Lys–425, and Thr– ChemistrySelect 2020, 5, 6339 – 6349 426 of A chain of protein structure, 6TZM to atom oxygen of the double bond of P=O (3 hydrogen bonds) and atom oxygen of the O-ethyl group It demonstrated that the phosphonate group in c formed in the K.F reaction, which conducted excellent inhibition against the receptor of Candida albicans fungus The bond lengths of all most hydrogen bonds, which created from ligand c to receptor were shorter than them forming from standard drug to the same receptor It proved that a shorter length of hydrogen bonds, stronger strength of bonds they formed The ligand map exposed the extra secondary interactions such as the hydrogen bonds, steric, and overlaps Those interactions implied the strength of ligand c and receptor 6TZM interactions The green lines noted effect steric, which conducted the conformation of the molecular binding process The size of yellow and green circles on atoms 6344 © 2020 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim ChemistrySelect Full Papers doi.org/10.1002/slct.202000855 Figure 18 The percentage of inhibition of entries, a–j against Hela in vitro in the range of concentrations from 5–100 #M Figure 15 The IC50 values of entries, a–j against cervical cancer cell lines (HeLa) in vitro Table The significant results of a docking pose c and drug–Fluconazole to Candida albicans fungus, code 6TZM[a] Figure 16 The percentage of inhibition of entries, a–j against cancer cell lines, MCF–7 in vitro in the range of concentrations from 5–100 #M Figure 17 The percentage of inhibition of entries, a–j against cancer cell lines, A–549 in vitro in the range of concentrations from 5–100 #M ChemistrySelect 2020, 5, 6339 – 6349 Entry DG[b] Ki[c] Hydrogen bond[d] Property and bond length[e] 3c -7.03 6.98 Drug[f] -5.09 185.6 A:Gly422:H–3 c:O (2.25) A:Gly424:H–3 c:O (2.03) A:Lys425:H–3 c:O (2.48) A:Thr426:H–3 c:O (2.10) A:Thr426:O–drug:N (2.69) A:Asn444:N–drug:N (3.12) A:Asp445:N–drug:N (2.75) A:Asn476:N–drug:N (3.10) Drug:H–Asp445:O (2.12) [a] The crystal structure of Candida albicans was received from the protein data bank [b] The free energy of binding, receptor-ligand presented in the unit of kcal.molÀ1 and calculated by AutoDockTools-1.5.6rc3 package [c] The inhibition constant calculated by AutoDockTools-1.5.6rc3 package and reported in the unit of #M [d] The number of hydrogen bonds was indicated by Discovery Studio 2019 Client package [e] They have visualized in Discovery Studio 2019 Client package and the unit of Angstrom, respectively [f] The structure of Fluconazole was conducted the optimal energy of molecule by Avogadro package via the MMFF94 method and docking calculations identified the strength of overlap interactions and contributed to steric hindrance as shown in Figure As shown in Figure and Table 2, the best docking pose of h against S cerevisiae, 3ET5 has calculated the values of inhibition constant and the free energy of binding of docking, which obtained 0.094 #M and –9.59 kcal.molÀ1, respectively They have compared their values to the values of the standard drug The h indicated a stronger inhibitor against Saccharomyces cerevisiae fungus than Fluconazole, owing to the value of lower negative free energy of binding and the inhibition constant, Ki of the most stable conformation h with a receptor benchmarking with the values of Fluconazole in Table 2, respectively As exposed in Figure 2, the compound h showed a higher inhibitor against Saccharomyces cerevisiae at a concentration of 200 #g.mLÀ1 (455.38 #M) than a drug at a concentration of mg.mLÀ1 (3265 #M) because of both the IC50 of h and the value of free 6345 © 2020 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim Full Papers doi.org/10.1002/slct.202000855 ChemistrySelect Table The remarkable results of docking pose h and drug, Fluconazole to Saccharomyces cerevisiae fungus, 3ET5 [a] Table The important docking poses b and ampicillin to Bacillus megaterium bacterium, 6NVW code [a] Entry DG Ki Hydrgen bond Property and bond length Entry DG Ki Hydrgen bond Property and bond length 3h Drug[b] -9.59 -5.90 0.094 47.0 C:Ser164:O–3 h:O (3.10) C:Arg147:H–drug:F (2.24) C:Ser164:H–drug:O (2.25) C:Val165:H–Drug:O (1.76) Drug–C:Val165:O (2.04) 3b -8.03 1.30 Drug[b] -8.19 0.99 B:Arg381:H–3 b:O (2.23) b:H–B:Gln23:O (2.42) B:Arg266:H–drug:O (2.45) B:Arg381:H–drug:O (2.20) Drug:H–B:Gln23 (2.15) Drug:H–B:Gln23:O (2.26) Drug:H–B:Gln23:O (2.32) Drug:H–B:Asn462 (2.14) [a] The crystal structure of Saccharomyces cerevisiae fungus took from the protein data bank [b] The structure of Fluconazole was performed the optimal energy of molecule by Avogadro package via force field methodMMFF94 and docking calculations energy of binding of docking pose h and the receptor–3ET5 in silico docking were lower those of Fluconazole as shown in Table Only one hydrogen bond formed from atom oxygen of Ser–164 to atom oxygen of P=O double bond with a bond length of 3.10 Å as shown in Figure 11 and Table It proved the phosphonate group in h showed excellent inhibition against a receptor of Saccharomyces cerevisiae The active site atoms at the active sites of a receptor, 3ET5, and ligand h were conducted on a 2D diagram in Figure 10, which visualized one hydrogen bond (from atom oxygen of Ser–164 of C chain of receptor to atom oxygen of O=P double bond of h and other bonds were non-bonding like the Van der Waals, carbonhydrogen bond, pi–donor–hydrogen bond, pi–sigma, alkyl, and pi–alkyl All those interactions established the minimum negative energy of interaction system between ligand h and receptor 3ET5 as shown in Table and led to the most stable conformation h for good docking at active sites of the protein All residual amino acids made contacts with the active sites of h, which were relative to C chain except for Asn–363 of B chain The ligand map identified extra interactions between h and receptor, 3ET5 in Figure 12 like the hydrogen bonds, steric, and overlap interactions, which controlled the strength of conformation ligand h and receptor 3ET5 The green lines (13 steric interactions) determined the formation of confirmation of h The Van der Waals radius of atoms varied from 1.70 to 2.08 Å that controlled the strength of overlap interactions and participants of steric hindrance in Figure 12 The entry h pointed out an excellent activity inhibitor against Saccharomyces cerevisiae fungus at a concentration of 200 #g.mLÀ1 or 455.38 #M and compared with the entry g in our former article.[5] The g at a concentration of 25 #M showed higher activity than h at a concentration of 455.38 #M against Saccharomyces cerevisiae It was explained based on docking poses and differential structures Entries h and g bound to hydrogen and fluorine atom of the phenyl group, respectively, and the h had no atom halogen bond In the best conformation g with a receptor in a 2D diagram, the fluorine atom made unfavorable bonds The halogen bonds with residual amino acids nearby like Gln–353, Glu–277, and Asn–350, which led to g was a stronger inhibitor than h at a low concentration, 25 #M As shown in Table 3, the values of b compared to those of standard drug, Ampicillin against Bacillus megaterium, 6NVW indicated that the best conformaChemistrySelect 2020, 5, 6339 – 6349 [a] The crystal structure of Bacillus megaterium bacterium was downloaded from the protein data bank [b] The structure of Ampicillin was calculated the optimal energy of molecule by Avogadro package via force field method- MMFF94 and docking calculations tion b made a weaker inhibitor than a drug, owing to the values of calculated inhibition constant and free energy of binding of the most conformation b with receptor–6NVW presented lower than those of a drug as shown in Table As shown in Table and Figure S.1.13, the docking pose b formed hydrogen bonds, one from Arg–381 of B chain to atom oxygen of P=O double bond and another from atom hydrogen of secondary amine b to atom oxygen of Gln–23 of B chain From the results of docking poses of c, h, and b were briefly presented in Table 1–3 that proved all those hydrogen bonds formed from the active sites on receptors to O=P(OEt)2 groups or hydrogen atom of HN of secondary amine groups via K.F reaction It was very significant to design structures having bioactivities In vitro, a concentration of b against Bacillus megaterium was 388 #M, which was compared to a concentration of Ampicillin of 5724.0 #M was lower than that of Ampicillin, but the diameter of the inhibition zone of b was identical to that of ampicillin drug, which led to inhibition ability of b at a concentration of 200 mg.mLÀ1 (388 #M) was a potential inhibitor The entry j as shown in Figure 4, indicated moderate activity against B cereus at all concentrations without explanations a docking model for this conformation Anticancer activities The notable results of docking of entries, a–j against three cancer cell lines like MCF–7 (6VNN), A–549 (4ADS), and HeLa (5HES) have been briefly presented in Tables and 6, and other information were reported in supporting information With MCF–7 cancer cell lines 6VNN, based on the calculated results of docking pose of the most stable conformations a–j, the docking abilities of the best conformations a–j were determined and presented in order i > c > h > Drug > f > g > j > b > d > e > a, owing to values of the maximum negative free energy of binding between the docking poses and a receptor of cancer cell lines 6VNN, the inhibitor constants and abilities of formed hydrogen bonds In vitro, the results of test compounds also showed that c, h, and a exposed excellent cytotoxicity activity against MCF–7 6346 © 2020 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim Full Papers doi.org/10.1002/slct.202000855 ChemistrySelect Table The docking poses of entries a–j to active sites of a receptor of breast cancer cell line, MCF–7(6VNN)[a] Table The docking poses of entries a–j to activities sites of a receptor of cervical cancer cell lines, HeLa.[a] Entry DG Ki Hydro-gen bond Property and bond length Entry DG Ki Hydro-gen bond Property and bond length 3a 3b 3c -7.79 -8.53 -9.39 1.94 0.562 0.132 3a 3b 3c -9.60 -9.29 -8.96 0.092 0.154 0.207 0 3d 3e 3f 3g 3h -9.03 -8.56 -9.93 -9.73 À8.92 0.239 0.530 0.052 0.074 0.289 0 1 No hydrogen bond b:H–A:Asp473:O (2.04) C:Ala430:N–3 c:O (2.83) C:Ser433:O–3 c:O (2.62) No hydrogen bond No hydrogen bond C:Ser433:O–3 f:O (2.89) C:Ser433:O–3 g:O (2.84) h:H–C:Ser433:O (2.21) D:Lys472:N–3 h:O (2.76) C:Ser433:O–3 h:O (2.67) C:Arg412:N–3 i:F (3.21) C:Ser433:O–3 i: N(3.00) i:H– C:Ser433:O(2.09) j:H - C:Asp426:O(2.43) C:Ser433:O–drug:N (2.80) D:Phe461:N–drug:O(3.12) D:Leu462:N–drug:O (2.74) 3d 3e -8.95 -7.68 0.275 2.36 3f -10.11 0.039 3g 3h 3i -9.60 -9.53 -9.87 0.092 0.104 0.059 3j Drug[b] -8.88 -9.11 0.308 0.208 No hydrogen bond No hydrogen bond A:Gly23:N–3 c:O (2.92) c:H–A:Asp92:O (2.18) A:Lys135:N–3 d:O (2.65) A:Tyr84:O–3 e:O (2.57) A:Tyr84:O–3 e:O (2.69) A:Tyr84:O–3 e:O (2.83) B:Arg284:N–3 e:O (3.03) B:Cys285:N–3 f:N (1.81) f:H–A:Tyr84:O (2.43) No hydrogen bond h:H–A:Arg137:O (2.25) A:Lys135:N–3 i:F (3.18) A:Arg137:N–3 i:F (2.75) A:Arg137:N–3 i:F (3.16) No hydrogen bond A:Thr82:O–drug:O (2.99) Drug:H–A:Thr82:O (2.03) 3i -9.51 0.107 3j Drug[b] -9.58 -8.90 0.096 0.298 [a] The crystal structure of 6VNN (6VNN: PDB,1.63 Å, and DOI: 10.2210/ pdb6VNN/pdb) was downloaded from the protein data bank The most important values were calculated by AutoDockTools-1.5.6rc3 and visualized by DSC The others were indicated in supporting information, Table S.4 [b] The standard drug was Camptothecin Table The docking poses of entries a–j to active sites of a receptor of lung cancer cell, A–549 [a] Entry DG Ki Hydro-gen bond Property and bond length 3a 3b 3c 3d -8.83 -9.86 -9.47 -10.24 0.335 0.059 0.145 0.031 0 3e 3f -8.68 -8.54 0.434 0.550 3g -8.69 0.425 3h -8.47 0.612 3i -8.49 0.597 3j Drug[b] -9.21 -9.38 0.178 0.133 No hydrogen bond No hydrogen bond c:H– A:Leu840:O (2.32) A:Val899:N–3 d:O (2.99) A:Asp1046:N –3 d:N (2.91) No hydrogen bond A:Asn923:N–3 f:O (2.56) A:Asn923:N–3 f: O (2.70) A:Asp1052:N–3 f:N (2.71) f:H–A:Leu840:O (2.16) A:Asn923:N–3 g:O (2.98) g:H–A:Leu840:O (2.05) A:Asn923:N–3 h:O (3.18) h:H–A:Leu840:O (2.15) A:Tyr1082:O–3 i:F (2.80) i:H–A:His1026:O (2.09) No hydrogen bond A:Cys919:N–Drug:O (2.58) [a] The crystal structure of 4ASD (4ASD: PDB, 2.03 Å, and doi.org/10.2210/ pdb4ASD/pdb) was downloaded from the protein data bank The most significant values were performed by AutoDockTools-1.5.6rc3 and visualized by DSC The others were indicated in supporting information in Table S.4 [b] The standard drug was Camptothecin The calculated results of docking pose conducted that the remarkable hydrogen bonds formed from the residual amino acids of a receptor, 6VNN to an oxygen atom of P = O double bond, an oxygen atom of ethoxy groups, hydrogen, and nitrogen atoms of N–H group via K.F’s reaction as shown in Table For docking poses of the most stable conformations of ligands a–j to a receptor 4ASD as shown in Table 5, the ChemistrySelect 2020, 5, 6339 – 6349 [a] The crystal structure of 5HES (5HES: PDB, 2.14 Å, and doi.org/10.2210/ pdb5HES/pdb) was received from the protein data bank The most fundamental values were conducted by AutoDockTools-1.5.6rc3 and visualized by DSC The others were indicated in supporting information in Table S.4 [b] The standard drug was Camptothecin sequence of the most stable conformations, which docked to a receptor described as d > c > drug > g > f > i > h > b > j > a > e To compare the results of the docking model and test in vitro, the h and c are the best solutions and the h has been given to explain the good quantitative structure-activity relationship in the concepts of an inhibitor constant, Ki of 0.61 #M (in silico docking model) and the IC50 value of 2.29 #M (in vitro) as shown in Table and Table For anticancer against cervical cancer cell lines, HeLa, 5HES, the trends of docking poses were indicated as expression, f > i > h > drug > c > d > e > a > b > g > j in Table Based on docking poes, the docking abilities presented as f > i > c and compared to compounds, which showed potential inhibitions in vitro like f > c > i The f has Table The IC50 values of entries against MCF–7, A–549, HeLa, and drug– Camptothecin in vitro Entries Cancer cell lines IC50[a] MCF-7 A549 HeLa 3a 3b 3c 3d 3e 3f 3g 3h 3i 3j Drug[b] 9.78 Ỉ 0.93 45.94 Ỉ 0.66 9.39 Ỉ 0.64 124.78 Ỉ 0.63 613.99 Æ 0.39 44.45 Æ 1.45 120.96 Æ 1.27 6.38 Æ 022 41.61 Ỉ 0.23 22.14 Ỉ 0.04 2.84 Ỉ 1.33 88.40 Ỉ 0.36 629.56 Ỉ 2.45 7.32 Ỉ 0.07 767.03 Æ 2.35 3.82 Æ 0.01 10486.9 Æ 2.31 52922.39 Æ 1.61 2.29 Ỉ 0.02 123.07 Ỉ 0.05 27.58 Ỉ 0.81 0.58 Ỉ 0.17 22.41 Ỉ 0.35 23.89 Ỉ 0.40 5.98 Æ 0.02 16.59 Æ 0.20 18.47 Æ 0.31 5.16 Æ 0.04 102.90 Ỉ 048 16.33 Ỉ 0.26 7.19 Ỉ 0.02 115.89 Ỉ 0.31 2.15 Ỉ 0.32 [a] The values were in #M [b] The standard drug was Camptothecin 6347 © 2020 Wiley-VCH Verlag GmbH & Co KGaA, Weinheim ChemistrySelect Full Papers doi.org/10.1002/slct.202000855 explained the equivalent result in vitro and in silio docking model Except for a style of hydrogen bonds as explaining above, with the most stable conformation i, three hydrogen bonds formed from Lys 135, Arg 137 of A chain of a receptor, 5HES to F atoms of CF3 group, which bound to a phenyl group at 3-position as shown in Table Conclusions The new analog +–amino phosphate series were performed the green synthesis by PEG–400 as a green catalyst via Kabachnik– Fields reaction based on carbazole screened antimicrobial and cytotoxicity activities and conducted in silico molecular docking model The yield of reactions obtained from 85–91% (after completion of chromatography column) in a few hours by the effectively green catalyst and isolated entries The entry c and h exposed excellent inhibition against Candida albicans and Saccharomyces cerevisiae fungi at the same concentration of 200 #g.mLÀ1 and obtained higher inhibitors than Fluconazole at mg.mLÀ1 The entry b showed moderate activity against Bacillus megaterium bacterium at a concentration of 200 #g.mLÀ1 The results of docking study of some active compounds indicated the reasonable explanations between the bioactivities in vitro of c, h, and b and their docking poses to receptors as activity expresses for antifungal activity: c and h > Fluconazole, for antibacterial activity: b < Ampicillin The entry c gave an excellent inhibitor against Candida albicans in vitro and in silico molecular docking that was a new result The h made benchmarking with g for antifungus, Saccharomyces cerevisiae in our former article.[5] The h made a weaker inhibitor than g This molecular docking model proved that the hydrogen bonds also formed from active sites of receptors to a diethyl phosphate group or an atom hydrogen of the N–H bond of secondary a amine group, which was established by K.F’s reaction It was fundamental to design activity structures The compounds c, f, and i pointed out excellent cytotoxicity against HeLa cancer cell lines and reported the new results in vitro The IC50 value of f against HeLa cancer cell lines in vitro and an inhibitor constant, Ki was equivalent among the highest activity compounds In docking study against cancer cell lines, the novel docking results exposed the hydrogen bonds only formed from almost the residual amino acids of receptors to an oxygen atom of O=P double bond, an oxygen atom of an ethoxy group, and a nitrogen or hydrogen atom of N–H group of (N–HP=O (OEt)2 group), which yielded via K.F reaction, or they formed from the residual amino acids of receptors to fluorine atoms of CF3 groups in i The a, c, and h showed excellent cytotoxicity against MCF–7 cancer cell lines The c, e, and h indicated highest inhibitions against A-549 cancer cell lines in vitro The next article will design, synthesize, screen in vitro and in silico bioactivities of new +-amino phosphate derivatives via Kabachnik-Fields using PEG–400 as a green media ChemistrySelect 2020, 5, 6339 – 6349 Supporting Information Summary The supporting information contains procedures of synthetic compounds of target compounds 3a-j, intermediate compounds, 1–2, and brief procedure to reuse PEG-400 catalyst The IR, 1H, 13C, and 31P NMR of compounds were presented in figures and explained spectral data The bioactivities assays were performed and the results of antimicrobial activities were shown in tables The procedure of molecular docking was briefly presented and the calculated results of a docking pose of structure 3b, the standard drug-Fluconazole, and Ampicillin with receptors were found, visualized, and indicated the key results in tables and figures Acknowledgments This research was an institute project that was supported by the research fund from Industrial University of Ho Chi Minh City, Ho Chi Minh City Vietnam (20/1.5 CNH03) Conflict of Interest The authors declare no conflict of interest Keywords: Amino acids · Antiproliferation · Green chemistry · Multicomponent reactions · Supramolecular chemistry [1] a) R Engel, Chem Rev 1977, 77, 349–367; b) B C Ranu, A Hajra, U Jana, Org Lett 1999, 1,1141–1143 [2] a) K Moonen, I Laureyn, C V Stevens, Chem Rev 2004,104,177–216; b) A B Smith, C M Taylor, S J Benkovic, R Hirschmann, Tetrahedron Lett 1994, 35, 6853–6856; c) 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Trang 147 Hình 43 Phổ 1H NMR 3c, giãn rộng: 3 .40 –5.20 ppm Trang 148 Hình 44 Phổ 1H NMR 3c, giãn rộng: 6.20–8.70 ppm Trang 149 Hình 45 Phổ 13C NMR 3c Trang 150 Hình 46 Phổ 31P NMR 3c, δ = 24. 265... Fluconazole Trang 116 Hình Sự tương tác amino acid lại, Thr -42 6, Asn -44 4, Asp -44 5 Asn -47 6 6TZM với Fluconazole Hình Các tương tác nguyên tử hoạt tính receptor (6TZM) cấu dạng bền (Fluconazole) sơ đồ
