Synthesis and evaluation of anti cancer and anti alzheimer activity of hybrid strucsture containing 4 - Aminoquinazoline frame

In addition, quinazoline systems appear to be impotent in 148a, 150a

and 150b when they are linked to Trp286 by many π interactions and H

bonds with Phe295 and / or Ser293 similar to donepezil. On the other hand,

H bonds play an important role in stabilizing 149a and 149b when they

interact strongly with Ser293 and Arg296 of the PAS site via the pyrimidine

ring of quinazoline. All compounds show similar π interactions between

triazoles for Tyr341 and nitro-benzene rings with Tyr337

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efore, the study designed and synthesized new Quinazoline compounds with the goal of inhibiting Tyrosine Kinases and hybridizing these molecules with components that inhibit cancer cells under other mechanisms such as AZT or triazole to Incorporating the unique pharmacological properties of each component into a single hybrid molecule towards the goal of multifunctional inhibition will be a very interesting, new and necessary research issue. In addition, quinazoline and triazole also exhibit acetylcholinesterase inhibiting activity (AChEI) in treating Alzheimer's disease. The combination of AChE-inhibiting components such as quinazoline and triazole to form a single hybrid molecule aims to enhance activity in search of safer cholinesterase inhibitors or multiple-target activity. very necessary. Therefore, the topic "Synthesis and evaluation of anti-cancer 2 and anti-Alzheimer activity of hybrid structure containing 4- aminoquinazoline frame" is a research direction with high scientific and practical significance. 2. Objectives of the dissertation - Synthesis and structural determination of some 4-aminoquinazoline derivatives containing prop-2-yn-1-yloxy substituents at C-6 position. - Research and synthesize and determine the hybrid compound structure containing Quinazoline frame. + Study on synthesis and determination of quinazoline dimer hybrid compound structure. + Study on synthesis and structure of hybrid 4-aminoquinazoline-triazole compounds + Research synthesis and determine the structure of hybrid compounds 4-aminoquinazoline-triazole-AZT - Research on carcinogenic activity and inhibition of acetylcholinesterase enzyme of synthetic compounds. - Studying protein docking and predicting the pharmacokinetic properties of some compounds that inhibit the enzyme acetylcholinesterase. 3. New points of the dissertation - The thesis has successfully designed and synthesized 34 new compounds, including: + 4 new quinazoline derivatives that have changes in position C-4 and C-6 130a-d. + 1 new hybrid compound with quinazoline dimer structure 145. These derivatives may be used to crossbreed with other drugs or active substances 3 Other properties contain azit –N3 intergroup according to click reaction to synthesize compounds new hybrid. + 20 new hybrid compounds between quinazoline and phenylazide via triazole bridge 148-151. + 9 new hybrid compounds between quinazoline and AZT via triazole bridge 153-156 - Evaluated the cytotoxic activity of the new compound on three human cancer cell lines (epithelial, liver, and lung cancer) and acetylcholinesterase enzyme inhibiting activity. The results showed that 14 compounds were capable of carcinogenic carcinogenicity, of which 4 compounds exhibited strong cytotoxic activity with IC50 values <5 µM, 130a, 145, 148d, 149d; There are 7 compounds with the ability to inhibit the enzyme acetylcholinesterase, of which 3 compounds exhibit strong AChE inhibiting activity with IC50 <2.1 µM values of 148a, 149a, 149b. - Two new hybrid compounds have been synthesized with better IC50 values than the Ellipticine reference standard: 149d (IC50 = 0.94 μM (HepG2), and 145 (IC50 = 1.53 μM (KB). good inhibition of acetylcholinesterase enzyme: 148a (IC50 = 2.06 µM), 149a (IC50 = 0.23 µM) and 149b (IC50 = 1.10 µM). - Using docking protein simulation and pharmacodynamic prediction model to explain and predict the acetylcholinesterase inhibitory activity and the ability to develop into a new anti-Alzheimer drug of compounds 148a, 149a- b , 150a-b. 4. Structure of the dissertation The dissertation consists of 137 pages including: Introduction: 3 pages. Chapter 1: Overview 23 pages 4 Chapter 2: Experimental 33 pages. Chapter 3: Results and discussion 60 pages. Conclusion, new points, list of works, references: 18 pages The reference section has 137 documents on the relevant field of the thesis, updated to 2019. The appendix includes 70 pages of spectrum types of synthesized substances. 5. Research methodology The substances were synthesized according to known modern organic synthesis methods, improved and applied appropriately in specific cases. Reaction products were cleaned by column chromatography and recrystallization. The structure of the product was determined by modern spectral methods such as IR, HRMS, ESI-MS, 1 H-NMR, 13 C-NMR, HMBC, HSQC, DEPT. Biological activity was explored according to the method of Mossman on three cancer cell lines, KB, Hep-G2 and Lu-1. Protein docking simulation was used to predict the target activity of synthesized compounds. Inhibiting the activity of acetylcholinesterase enzyme based on Ellman's photometric method. Docking protein uses ICM- Pro Molsoft software 3.8-7. B. CONTENTS OF THE DISSERTATION CHAPTER 1. LITERATURE REVIEW This chapter presents the following contents: - Quinazoline, derivatives and bioactive - Some methods of synthesizing Quinazoline frame compounds. - Quinazoline hybrid compound and biological activity - Protein docking technique and pharmacokinetic parameter prediction. 5 CHAPTER 2. EXPERIMENT The experiment section consists of 33 pages, detailing the research methods, synthesis process, refining process, physical properties of received products such as melting point, shape, color, reaction performance and detailed data of IR, HRMS, 1 H-NMR, 13 C-NMR, HMBC, HSQC, DEPT. CHAPTER 3: RESULTS AND DISCUSSION 3.1. Objectives of the dissertation Diagram 3.1. General strategy of the topic The general strategy of the project is to design successfully synthesize a number of new quinazoline derivatives along the imine path and perform molecular hybridization by click reaction to create quinazoline- triazole and quinazoline- hybrid compounds triazole-AZT and a dimerquinazoline hybrid compound. Compounds were selected to evaluate 6 anticancer activity and inhibitory activity of acetylcholinesterase enzyme. Some well-functioning compounds will be performing docking proteins and predicting pharmacokinetic properties to find the relationship between structure and activity and explain the target orientation and predict the ability to develop into drugs new destination. 3.2. Results of synthesis and structure of some 4-aminoquinazoline derivatives containing prop-2-yn-1-yloxy substituents at C-6 position (130) When looking at studies on the correlation between the structure and biological activity of quinazoline compounds, it was found that the size and nature of aniline radicals decide the selective inhibition of enzyme kinase. The aniline substituents at C-4 quinazoline frame were selected appropriately to inhibit tyrosine kinase enzyme receptors. Meanwhile, the hydrophilic group at C-6 position of quinazoline frame improved the physical properties of pharmacological properties such as solubility. Adding a substituent such as 3-ethynylalinine to the C-4 site or a propargyl substituent at the C-6 site may result in a new bioactive quinazoline derivative and the ability to hybridize with compounds. Other active part. The derivatives 6 (prop-2-yn-1-yloxy) quinazolin-4-amine 130 were synthesized from 5-hydroxy-2-nitrobenzaldehyde 124 according to diagram 3.4 and diagram 3.5. 7 Diagram 3.4. Synthesis of intermediate 127 Diagram 3.5. Synthesis of compounds 130a-d Figure 3. 2. Chemical structure and melting point of 130a-d compounds There for, from the starting material, 5-hydroxy-2nitrobenzaldehyde has 8 successfully synthesized 4 new quinazoline derivatives that have been changed at C-6 and C-4 position and capable of hybridizing with active components other high biology. 3.3. Result of synthesizing and determining the structure of quinazoline dimer hybrid compound (145) Derived from the molecule erlotinib and with the goal of creating a more active dimer hybrid compound, we performed a synthetic design of a compound containing two 4-aminoquinazoline frames in the molecule via a - O group. -propylene- at position C-6. This dimer compound contains two groups of ankyne so it will be the material to perform the "click" reaction. The compound 6.6 'dimer - (propane-1,3-diylbis (oxygen)) bis (N- (3- ethynylphenyl) quinazolin-4-amine) 145 is synthesized according to Figure 3.8. Analysis data of IR, 1 H-NMR, 13 C-NMR, MS spectrum of compound 145 were obtained as follows: IR (KBr), νmax: 3290; 2955; 1625; 1575; 1530; 1506; 1484; 1425; 1367; 1231; 1064; 969; 834; 779 cm-1. 1 H-NMR (DMSO-d6, 500 MHz) δ (ppm): δ 9.65 (1H, s), 8.54 (1H, s), 8.02 (1H, s), 7.98 (1H, d, J = 2 Hz), 7.92 (1H, dd, J = 5 Hz, J = 1 Hz), 7.75 (1H, d, J = 9.5 Hz), 7.55 (1H, dd, J = 9 Hz, J = 2.5 Hz), 7.41 (1H, t, J = 8 Hz), 7.23 (1H, d, J = 7.5 Hz), 4.42 (2H, t, J = 6 Hz, OCH2), 4.18 (1H, s, C≡CH), 2.41 (1H, quin, J = 6 Hz, OCH2CH2CH2O). 13 C-NMR (DMSO-d6), 125MHz) (ppm): 156.7, 156.6, 152.2, 145.1, 139.5, 129.5, 128.8, 126.6, 124.9, 124.4, 122.8, 121.7, 115.6, 102.8, 83.4, 80.5, 65.1, 28.6. 9 HRMS-ESI: Found (m/z) 563.2156 [M+H] + , Calc. for: C35H26N6O3: 563.2117. Diagram 3.8. Synthesis quinazoline dimer compound 145 On the high-resolution mass spectrometry HRMS-ESI of compound 145 detected pionic ion peak pic m / z: 563,2156 [M + H] + , the calculation is 563,2117 corresponding to the formula C35H27N6O2 + . This proves that the 145 synthesized product is a symmetrical structure dimer. Thus, based on data 1 H-NMR and MS, MS spectroscopy proved the structure of compound 145 is correct. 3.4. Results of synthesis and structure of hybrid compounds 4-aminoquinazoline-triazole 3.4.1. Results of synthesis and structure of hybrid compounds 4-aminoquinazoline-triazole (148-151) The triazole component has many valuable activities such as anti- cancer, strong antimicrobial and antifungal, inhibits AChE due to the special 10 structure of the pentacycular aromatic ring with 3 nitrogen atoms with high dipole moment, easy to join. involved in forming hydrogen bonds and bipolar interactions with DNA, proteins or cells. The replacement of the acetylene group at the C-6 branched position in the original quinazoline molecule by a triazole nucleus can harden the structure of the resulting molecule, thereby increasing the hydrogen bond between the triazole ring and the peptide chain of EGFR receptors thus improve the inhibitory activity of the resulting hybrid compounds. For the above reasons, in this thesis, the click reaction with copper (I) catalyst is connected to the important 130a-d alkynequinazoline with nitrophenylazide and trifluoromethylphenylazide to create 4-anilinoquinazolin-triazole hybrid compounds 148-151 with 70-90% efficiency. The reaction was conducted at room temperature between quinazoline 130a-d and 1.1 azide 123 equivalent in CuI catalyst THF (0.2 equivalent) and DIPEA (12 equivalent) for one to two days. according to the diagram 3.10. The expected structure of 148-151 hybrid compounds was confirmed by their IR, MS, 1 H-NMR and 13 C-NMR spectral data. Diagram 3.10. Synthesis of hybrid compounds 148-151 11 Reaction between compound 130c and azide derivatives for different products. Specifically, the reaction between the compound 130c and 2-nitro-, 3-nitro- and 3-cyano-4-trifluoromethylphenylazide forms a product containing two triazole 151a, b, d rings, while the reaction between 130c and 4- nitrophenylazide received only triazole closed product at position C-6 of quinazoline 151c frame. Although various reaction conditions have been changed such as increasing the azide equivalence, increasing the reaction temperature to THF reflux boiling point, extending the reaction time ... the main product received is still a compound. 151c. 3.4.2. Results of synthesis and structure of hybrid quinazoline dimer - triazole compounds (152) The synthesized dimer compound exhibits typical cytosine inhibitory activity typical of the quinazoline class. By combining two separate pharmacological properties in one molecule, it is possible to expand the drug's activity spectrum while reducing resistance to resistance in cancer patients. Therefore, in this experimental part, we have synthesized a number of hybrid compounds containing two components, quinazoline dimer and 1,2,3-triazole in the same molecule, in search of substances with higher biological activity. Besides, many studies have shown that both quiazoline and triazole components can have AChE inhibitory activity. Therefore, the creation of quinazoline-triazole hybrid compounds in the desire to find new cholinesterase inhibitors safer with minimal side effects or multi-goal activity is essential. Hybrid components of dimmer 145 with phenyl azide 123 follow the diagram in 3.12. 12 Diagram 3.12. Synthesis of hybrid compounds 152a-d The structure of 152d hybrid compound is proved by IR, NMR, HSQC, HMBC, DEPT spectra. The expected structure of 152a-f hybrid compounds was similarly confirmed by their IR, 1 H-NMR and 13 C-NMR spectral data. Thus, by click reaction, we have successfully synthesized 20 new compounds with quinazoline-triazole structure (148-151) or quinazoline- triazole dimer (152) from materials such as quinazoline (130), dimer ( 145) and phenylazides (123) in the presence of CuI catalyst. Reaction efficiency of about 55-80%. 3.5. Results of synthesis and structure of hybrid 4-aminoquinazoline compounds - triazole-AZT (153-156) 13 Phase I studies of the maximum tolerated dose of Zidovudine intravenously in combination with 5-fluorouracil and Leucovorin in patients with metastatic colorectal cancer showed significant activity of AZT in cancer treatment. It is therefore expected to synthesize new quinazoline- triazole-AZT hybrid compounds by click reaction targeting the potential of generating cytotoxic agents and adding other interesting biological activities. We first synthesized hybrid compounds between erlotinib and AZT by click reaction. The result was compound 143 with 85% efficiency. The structure of compound 153 is demonstrated by 1 H NMR, 13 C NMR and MS. Crown ether quinazoline compounds 120a-c have been synthesized and published by the research team showing high anti-cancer activity in the cell lines of epithelial, liver and lung cancer. In the interest of finding a more reactive hybrid compound, we performed the hybridization of quinazoline 120a-c crown ether compound with AZT in THF solvent at room temperature in the presence of CuI catalyst and base DIPEA receives 154a-c hybrid compounds with 80-90% efficiency. The structure of 154a-c hybrid compounds was determined by their 1 H-NMR, 13 C-NMR and MS (ESI) spectra. The click reaction between AZT and quinazoline derivatives 130a-c receives 155a-c hybrid compounds. The reaction between compound 130d and AZT only receives the main product which is the triazole ring product at C6 position of quinazoline 155d frame. 14 Diagram 3.15. Synthesis of 154a-c compound Similarly, the reaction between dimer 145 and AZT only receives the main product that closes the triazole at one end of the dimer showing the effect of spatial effect and the large size of the AZT component so only the product is obtained. major 156. Thus, by click reaction, combining quinazoline-triazole-AZT components to create 9 new hybrid compounds from materials such as quinazoline(erlotinib (119), circular ether) (120), derivatives (130) , dimer (145) and AZT. Reaction efficiency of about 60-90%. 15 Figure 3.28. Chemical structure and melting temperature of compounds 153-156 3.6. Survey The results of the anti-cancer activity and acetylcholinesterase inhibitory activity. 3.6. 1. Test results for anti-cancer activity All four new quinazoline derivatives containing substituents at positions C-6, C-4 (130a-d) can exhibit toxic activity on at least one cancer cell line KB and Hep-G2, Lu-1 and two compounds with inhibitory activity of AChE. The 130d compound shows a strong cytotoxic activity on all three cancer cell lines, stronger than erlotinib with an IC50 value of 7.48 to 10.06 µM. 16 Table 3.6. Anticancer activity of quinazoline and hybrid compounds T T Compounds IC50 (KB), µM IC50 (HepG2), µM IC50 (Lu), µM 1 130a 62.03 ±2.65 321.25 4.16 2 148a 232 ± 2.05 340 >264 3 148d 3.70 ± 0.8 27.53 ±1.05 15.03±0.9 4 130b 59.72 ± 2.30 220 ± 0.79 5 149a 42.69 ± 3.40 >200 6 149b >200 94.08 ± 1.35 7 149d 19.24 ±0.48 0.94 ± 1.34 9 155b 30.96± 1.28 >200 9 130c >200 142.5 ±1.07 >200 10 130d 7.48± 0.48 9.12 10.06 11 151b 92.32± 1.05 > 204 > 204 12 151d 26.53± 2.18 45.14± 3.48 72.00± 0.78 13 155d 30.45±2.24 53.39±4.23 9.04±0.76 14 145 1.53 11.28 15 152a >128 >128 16 152b >128 >128 17 156 >128 >128 18 154b 124.29±9.68 92.00±5.63 13.40±0.89 19 AZT > 400 > 400 29.94 20 Erlotinib.HCl 49.62 14.17 31.15 21 Ellipticine 1.95 2.72 1.38 17 The quinazoline 145 dimer hybrid compound has a higher cytotoxic activity than erlortinib, especially its high inhibition with KB epithelial cancer cell line with IC50 = 1.53 µM, higher than the ellipticine control. Ethynylaniline substituents at C-4 position 130d and dimer 145 are more cytotoxic than other substituents. Some of the hybrid compounds have increased activity compared to the non-hybrid compound such as 148a, 148d, 149d, of which 149d inhibits liver cancer cells best, stronger than the control with IC50 is 0.94 µM . The 154b and 155d compounds with quinazoline-tricazole-AZT hybrid structure have relatively good activity on all 3 cancer cell lines, especially for Lu-1 non-small cell lung cancer with IC50 value = 9-13 µM, higher than the control substance erlotinib hydrochloride. Figure 3.34. Some 4-aminoquinazoline compounds have good activity 18 3.6.2. Test results against Alzheimer's activity The bioactive test results demonstrate that some hybrid compounds containing the quinazoline frame and their quinazoline-triazole hybrid compounds have the ability to inhibit the enzyme AChE (IC50 = 0.2-83.9 µM). These are potential substances to develop into drugs that treat Alzheimer's disease (AD). Table 3.7. AChE inhibitory activity of quinazoline-triazole hybrid compounds TT Compounds IC50 (AChE) µM 1 148a 2.06 ± 0.19 2 130b 47.73 ± 0.81 3 149a 0.23 ± 0.15 4 149b 1.10 ± 0.27 5 130c 83.90 ± 1.06 6 150a 37.38 ± 2.01 7 150b 15.79 ± 0.18 8 Doneperil 0.12 ± 0.36 Some hybrids exhibit strong inhibitory activity against AChE with different IC50 values. The data in Table 3.7 show that the best AChEI activity is obtained from compound 149a (IC50 = 0.23 µM) compared to donepezil as reference drug (IC50 = 0.12 µM). This 149a compound has benzylamine connected to the C-4 position of the quinazoline frame and 2- nitrophenyl connected to 1,2,3-triazole rings. Changing the nitro group to the meta position resulted in a decrease in the AChEI activity of compound 19 149b with IC50 = 1.10. However, 149c compound with a nitro group in the parapositionlost AChEI activity (IC50> 200 µM). Figure 3.38. AChE structure and activity of some compounds Comparison of the activities of 148a-b, 149a-b and 150a-b hybrid compounds with quinazoline 130a-c compounds on AChEI activity showed that the hybrid can greatly increase activity when combining compounds. fraction 1,2,3-triazole and quinazoline into a single hybrid molecule. 3.6.3. Protein docking results and predictive pharmacokinetic parameters Some substances show good inhibitory activity against the AChE enzyme, such as 148a, 149a-b, 150a-b. To find out how it works and how it binds quinazoline-triazole hybrid compounds to AChE enzyme activity centers, we have used the docking protein model. Compounds 148a, 149a and 149b show strong interactions with the Trp86 aromatic side chain of the choline CAS binding site, while compounds 150a and 150b lack those stacking interactions. Compared to 149a and 149b, piperazyls in 150a and 20 150b can be associated with residues at PAS more smoothly through a stacking interaction with Trp286. Figure 3.37. Conformations of the docked compounds 148a, 149a-b, and 150a-b in the active site of human AChE. In addition, quinazoline systems appear to be impotent in 148a, 150a and 150b when they are linked to Trp286 by many π interactions and H bonds with Phe295 and / or Ser293 similar to donepezil. On the other hand, H bonds play an important role in stabilizing 149a and 149b when they interact strongly with Ser293 and Arg296 of the PAS site via the pyrimidine ring of quinazoline. All compounds show similar π interactions between triazoles for Tyr341 and nitro-benzene rings with Tyr337. The connection point is estimated by ICM pack for 148a, 149a and 149b from -24.71 to - 26.07 kCal / mol similar to donepezil calculation. Meanwhile, the affinity of 150a and 150b is only -16.83 and -17.02 kCal / mol, indicating that the 21 affinity of these compounds for AChE is lower than that of donepezil (Figure 3.40). Table 3. Predicted pharmacokinetic properties of synthesized compounds Cpd. Ro 51 Tox. Rule2 Solubility 3 (mg/ml) Caco-2 permeability class4 BBB5 distributio n P-gp6 substr ate Cytochrome P4507 148a 1 Low 1.97e-3 High High No 1A2, 3A4 149a 0 Moderate 2.27e-03 Moderate Moderate No 2C9, 2C19, 3A4 149b 0 Moderate 2.25e-03 Moderate Moderate No 2C9, 2C19, 3A4 150a 1 Low 2.26e-02 High High No 2C9, 3A4 150b 1 Low 2.24e-02 High High No 2C9, 3A4 1Number of Lipinski’s Rule of Five violations [104]; 2in vivo toxicological rule of Hughes et al [105]; 3intrinsic solubility at 25°C calculated by ESOL equation of Delaney [106]; 4Caco-2 cell permeability classification using 3Prule [107]: High class if Papp ≥ 16×10 6cm/s, Moderate class if 0.7×10-6 ≤ Papp < 16×10-6cm/s; 5Blood-Brain Barrier distribution classes based on Castillo-Garit et al [108]; 6P-glycoprotein efflux inhibition state identified via online server [109]; 7metabolisms via CYP enzymes identified via admetSAR 1.0 approach [110] Our molecular assembly study showed that compounds 148a and 149a-b are linked to both the catalytic anion (CAS) and peripheral anion (PAS) sites in the active site of the AChE enzyme. Note that these compounds may act as double bonding inhibitors. Furthermore, compounds 148a, 149a-b and 150a-b are not cytotoxic and they also show appropriate physicochemical properties as well as pharmacokinetic profiles to be developed as anti-AD drug candidates. new. This result shows that our combined strategy allows us to explore promising new structures. On the other hand, optimizing structures based on 22 this class of substance to obtain compounds with better biological activity needs to be further considered for future research. CONCLUSION 1. Successfully designed 34 compounds containing the new 4- aminoquinazoline framework. Include: *4 new 4-aminoquinazoline derivatives contain prop-2-yn-1-yloxy substituents at C-6 position of 130a-d, the reaction efficiency reaches 60-75%. *1 quinazoline dimer structure hybrid 145, efficiency reaches 65% *20 quinazoline-triazole two-component hybrid compounds 148-151, reaction efficiency of 50-85% *9 quinazoline-triazole-AZT three-component hybrid compounds, reaction efficiency reaches 55-75%. 2. Proved the structure of 34 synthetic compounds by modern spectroscopicmethods such as infrared (IR), nuclear magnetic resonance spectroscopy (1HNMR, 13C-NMR, HMBC, HSQC) and mass spectrometry high resolution (HRMS). 3. Tried the cytotoxic activity of new lines of hybrid compounds 130, 148 151, 153-156 on three human cancer cell lines, KB cell (epithelial cancer) and HepG2 cell ( liver cancer) and lung cancer cells (Lu-1). Some compounds 130a-c and 148-150 were tested for the enzyme inhibiting activity of acetylcholinesterase. Results showed that many 4- aminoquinazoline and hybrid compounds have very good anticancer activity, especially 149d compounds (IC50= 0.94 μM (HepG2) and 145 (IC50 = 1.53 μM (KB) with IC50 value lower than the ellipticine standard 23 in simultaneous testing Some hybrid compounds have the ability to inhibit the enzyme acetylcholinesterase: 148a (IC50 = 2.06 µM), 149a (IC50 = 0.23 µM) or 149b (IC50 =1.10 µM). 4. Using docking protein simulation and pharmacodynamic prediction model to predict the target activity of compounds 148a, 149a-b, 150a- b, contribu

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