Substituted benzaldehydes and acetophenones to yield derivatives

synthesisa

1. WELLCOME TO ALL

2. CATALYTIC SYNTHESIS, CHARACTERIZATION, DOCKING STUDY AND ADMET PARAMETERS OF SOME HETEROCYCLIC DERIVATIVES AS POTENT ANTIOXIDANT AGENTS Presented by G PRABAKARAN Dr. S. MANIVARMAN Assistant Professor, Department of Chemistry Government Arts College, C.Mutlur , Chidambaram – 608 102

3. INTRODUCTION

4. Numerous manufactured medications and colours , as well as various chemicals including alkaloids, antibiotics, vital amino acids, vitamins, haemoglobin , or hormones, all have heterocyclic rings as their major structural components Chalcons have bactericidal, antifungal, insecticide activity, and are reported to be antimutagenic chalcones their biological activity is also employed with a variety of heterociclic molecules, including flavones, flavonols , pyrazol , isoxazole , thiazine , Oxopyrimidine , and thiopyrimidine . Therefore, chalcones are considered the most significant synthesis molecules for a number of heterocyclic systems

5. Numerous pyrazoline compounds are said to have a variety of biological properties, including antibacterial, anti-depressant, neuroprotective , anticonvulsant, anti-inflammatory, analgesic, antitiscin , local anaesthetic , hypoglycemia, hypotensive , insecticide, herbicide, and molluscicidal effects Pharmaceutical and agrochemical agents, five member heterocycles such as isoxazoline were widely used. The synthesis of isoxazoline derivatives as a source of new antibacterial agents has been given increasing attention in recent years.

6. Pyrimidines are acknowledged as particularly essential heterocycles due to their biological characteristics and therapeutic significance. It has been shown from the literature studies above that the main attraction for researchers in the fields of synthetic organic chemistry are five component heterocyclics , especially isoxazoline , pyrazolins , pyrimidine and related compounds.

7. LITERATURE SURVEY

8. Anti-inflammatory Insecticidal Antiepileptic Antitumor Anticancer Antiviral Herbicidal AntiHIV Based on Literature survey Chalcone , Pyrazoline , isoxazoline and pyrimidine derivatives show following biological activities Antibacterial A ntifungal Antidiabetic Antipyeretic Antioxidant Antitubercluosis Antimalarial Analgesic

9. EXPERIMENTAL METHODS This chapter provides information to experimental methods, All chemicals were obtained from commercial sources and used without any further purification. All the melting points were determined by digital melting point apparatus. IR spectra were recorded in Shimadzu FT-IR-8400 instrument using KBr pellet method. The 1H NMR spectral data were recorded on Bruker AV 400 MHz in DMSO and CDCl3 using TMS as an internal standard. The purity of the synthesized compounds was ascertained by TLC using iodine vapour as visualizing agents

10. RESULTS AND DISCUSSION

11. SYNTHESIS AND CHARACTERIZATION OF HYDRAZIDE DERIVATIVE General procedure for the synthesis (E)-N'-(1-(5-chlorothiophen-2-yl) ethylidene )furan-2-carbohydrazide The solution of isonicotinic acid hydrazide (0.01 mol) and appropriate substituted acetophenone (0.01 mol) in ethanol was refluxed for 4–5 h. The precipitates obtained were filtered off, washed, and recrystallized from ethanol.

12. SYNTHESIS AND CHARACTERIZATION OF ALDEHYDE DERIVATIVE General procedure for the synthesis of 3-(5-chlorothiophen-2-yl)-1- (furan-2- carbonyl)-2,3-dihydro-1H-pyrazole-4-carbaldehyde (E ) - N‘ - ( 1-( 5-chloro thiophen-2-yl) ethylidene ) furan-2-carbohydrazide ) (3 mmol ) was added to the Vilsmeier-Haack reagent made from DMF (10 mL ) and POCl3 (1.1 mL ), which was then agitated at 60–65 oC for 2.5 hours before being emptied into ice cold water. The NaHCO3 solid that separated after neutralisation was filtered, water rinsed off of it, and column chromatography was used to purify it.

13. SYNTHESIS AND CHARACTERIZATION OF CHALCONE DERIVATIVE Synthesis of (E)-3-(3-(5-chlorothiophen-2-yl)-1-(furan-2-carbonyl)-2,3- dihydro-1H-pyrazol-4-yl)-1-(substituted)prop-2-en-1-one (6a-g) A solution of 3-(5-chloro thiophen-2-yl)-1-(furan-2-carbonyl)-2,3-dihydro- 1H-pyrazole-4-carbaldehyde (1mmol) and Acetyl substituted compounds (1mmol), sodium hydroxide (0.5g) and 10 ml of ethanol in the presence of TiO2- ZnS nanocatalyst were shaken occasionally for 15 min. After the completion of the reaction, the mixture was cooled at room temperature. The resulting precipitate was filtered and washed with cold water.

14. In order to get effective results, the reaction conditions were optimized. For this purpose, 1-benzoyl-3-(thiophen-2-yl)-2,3-dihydro-1h-pyrazole-4- carbaldehyde (4) and thiophen-2-carbohydrazide (5b) were used as the model substrate for the synthesis of substituted chalcone CATALYTIC STUDIES USING TiO 2 -ZnS NANOPARTICLES

15. The polar solvents produced better results than non - polar ones and achieved the best results in ethanol, which most efficiently managed to eliminate the desired product by means of the TiO2- ZnS nanoparticles catalyst. All reactions were carried out smoothly and within 15 min the reaction was finished to provide good yields (85– 89 percent). EFFECT OF SOLVENT

16. SUPERIORITY OF TIO 2 -ZnS NANOPARTICLES OVER SOME OTHER METAL OXIDE NANOPARTICLES Different catalysts were used to determine the catalyst's capability and efficiency. Initially, in the absence of any catalyst the model reaction was performed, and the response was very slow and the expected product was very small. When Bare TiO2, commercial TiO2, bulk TiO2 and bare ZnS , the reaction was examined with nanoparticles with 7 mol% of each catalyst separately, the reaction took longer time for completion with higher yield. The reaction with TiO2-ZnS nanoparticles has been speeded up and the desired product yield has been maximized.

17. EFFECT OF CATALYST LOADING The effect of catalyst loading on the model reaction synthesis was investigated with a variation of 3 to 12 mol %. In order to achieve optimum results in less response time, it was found that 7 mol% of the catalyst was necessary, while less than 7 mol% of the catalyst increased the response times and reduced yield

18. REUSABILITY OF CATLYST The catalyst had been regenerated with filtering, washed with dichloromethane and methanol and dried at 150 C for 4 hours after completion of the model response at a certain period of time, and then used for the following cycle. The results indicate that the catalyst has shown up to five cycles of good catalytic activity.

19. PHYSICAL PROPERTIES OF SYNTHESIZED CHALCONE DERIVATIVES (6a-g)

20. The strong absorption stretching frequency band appeared at 1660 cm-1 is due to C=O of chalcone moiety and a stretching frequency band strongly appeared at 1462 cm-1 is due to CH=CH of the chalcone . The stretching frequency band present in the region of 1595 cm-1 is due to C=N bond. Stretching frequency range at 3049 cm-1 is reveals that the presence of aromatic C-H group. The absence of aliphatic C-H stretching frequency range at 2900 cm-1 is confirmed the reactant was totally converted into the product. IR SPECTRUM OF COMPOUND 6a

21. The strong singlet appeared at 8.12 ppm is due to ring CH proton. The H-α and H-β protons of chalcones occur as two doublets in the ranges 7.54 ppm (H- α) and 7.91 ppm (H- β) in the 1H NMR spectra. 1H NMR SPECTRUM OF COMPOUND 6a

22. The carbonyl carbon of the chalcones usually appears δ 188.7 in its 13C NMR spectrum. The α- and β- carbon atoms with respect to the carbonyl group give rise to characteristic signals in between δ 126.4 and δ 137.4 respectively. Phenyl ring aromatic carbon signals are appeared from 111.7-158.7ppm . IR, 1HNMR, 13 C N MR spectrum of other compounds also taken and discussed in the thesis. 13C NMR SPECTRUM OF COMPOUND 6a

23. The majority of the compounds had moderate to good antioxidant activity when compared to that of common compounds (ascorbic acid). All of the other compounds under investigation, with the exception of compound 6a (IC50 >150 g/ mL ), were found to be moderately active, with IC50 values ranging from 76.5 to 119.1 g/ mL. Antioxidant activity of compounds 6a-g

24. Of these, compound 6f ( methylenedioxy group) showed almost equal activity (IC50 =82.8 g/ mL ), when compared to compounds with compound 6g. Therefore, the hetero atom of oxygen has been significantly involved in the suppression of antioxidant function. The activities of all the compounds were compared to those of the positive control, ascorbic acid (IC50 = 34.51 g/ mL ).

25. Auto Dock 4.2.6 is used perform docking analysis . Auto Dock Tools (ADT) is used to prepare protein. All water and hetero- molecules were removed from protein preparation. Other essential ions were introduced. Kollman charges were used. Synthesized derivatives were docked with the active site of α- glucosidase (PDB ID: 2ZEO) and cyclin -dependent kinase 2 (PDB ID: 1HCK) enzymes. The SWISS ADMET predictor was used to conduct the ADMET investigation . DOCKING STUDIES

26. Docking studies' findings suggest that molecules 6c and 6f have binding energy(- 7.8and7.6kcal.mol-1 ). Contrarily , compound 6a has a lower binding energy (-6.2) than compound 6c due to the substituent effect, which lowers the binding energy. Additionally, the binding energy of the fluorine substituted molecule 6b is -7.0 kcal.mol-1. DOCKING EXPERIMENTS WITH THE 1HCK RECEPTOR (6a-g)

27. Docking results of synthesized chalcone derivatives with 1HCK receptor

28. Docking results of synthesized chalcone derivatives with 1HCK receptor

29. Binding score and ic50 value of chalcone derivatives (6a-g) with 1HCK protein receptor

30. According to the findings of docking experiments, molecules 6a and 6e have a binding energy of -8.3 kcal.mol-1 for the 2ZE0 receptor. Compound 6d also has a binding energy of -7.8 kcal.mol-1 DOCKING EXPERIMENTS WITH THE 2ZE0 RECEPTOR (6a-g)

31. Docking results of synthesized chalcone derivatives with 2ZE0 receptor

32. Docking results of synthesized chalcone derivatives with 2ZE0 receptor

33. Binding score and ic50 value of chalcone derivatives (6a-g) with 2ZE0 protein receptor

34. The in vitro PPB affinity values in the range of 100.00% confirm that they are with poor binding capability towards the plasma proteins, compared to the ascorbic acid The %HIA identified is competent with as they are in the range of 96.67 to 99.90 and are better than standard ascorbic acid with 33.15% and assures their interactions with the reactive species in the expecting target of domains. partition co-efficient ( logP ) values ranging from 3.08 to 5.45 which are less than 5. These results confirm that 6a-g are with good pharmaceutical parameters with zero Lipinski property violations. TPSA have calculated the total polar surface area and the obtained values are ranging from 62.55 to 78.01 which are less than 140, number of rotatable bonds are ranging from 5 which are less than 10 authorizes them as potent molecules with zero Veber property violations to interact with the target cells. ADMET,QSAR AND BIOACTIVITY PROPERTIES OF SYNTHESIZED DERIVATIES 6a-g

35. ADMET PROPERTIES OF SYNTHESIZED DERIVATIES 6a-g

36. QSAR PROPERTIES OF SYNTHESIZED DERIVATIES 6a-g

37. BIOACTIVITY PROPERTIES OF SYNTHESIZED DERIVATIES 6a-g

38. The other properties like Van der Waals volume ranging from 330.68 to 354.6 and solubility ranging from poor to moderate supports the interaction of ligand molecules with the hosting receptors and their competent affinity towards the target cells within the binding domain. In the toxicity risk assessment, we have evaluated the drug-likeness and drug score properties and found that all the compounds are in the range of 5.46 to 6.35 of the drug-likeness property and is comparable with the standard ascorbic acid having 0.02 of drug-likeness property. Similarly, the drug score is in the range of 0.78 to 0.87 which are in comparable to the standard with 0.75 of drug score. ADMET,QSAR AND BIOACTIVITY PROPERTIES OF SYNTHESIZED DERIVATIES 6a-g

39. Acknowledgments I T hank My Research Guide Dr. S. MANIVARMAN Assistant Professor, Department of Chemistry Government Arts College, C.Mutlur , Chidambaram – 608 102

40. THANK YOU