Chlorinated and Fluorinated Derivatives of Methylpyridine ...

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• Classification of methylpyridine and its downstream applications
  

• Analysis of methylpyridine derivatives&#; market and supply

• Introduction to pyridine derivatives related products of Huimeng Bio-Tech

• Outlook of agrochemical industry

Pyridine, known as the &#;chip&#; of pesticides, medicines and veterinary drugs, is critical intermediate. It is mostly used (up to 50% of the production) in the manufacture and synthesis of pesticides and, based on which, over 30 kinds of products can be produced. 

Pesticides containing pyridine moiety are highly efficient with low toxicity and enhanced longevity. They have good environmental compatibility with human beings and organisms, which meet the development requirements and trends of pesticides. Pyridine-containing pesticides are developing rapidly worldwide and are one of the main directions in pesticide innovation.

The whole industrial chain of pyridine compounds shows a tree-like structure, and the pyridine base is the &#;root&#; of the entire pyridine industrial chain. Numerous derivatives and end products can be derived from pyridine intermediates to the back end of the industrial chain.

Early on, it was found that more than 20% of the products in the production of pyridine were methylpyridine compounds, mainly the mixture of 3-methylpyridine, 2-methylpyridine and 4-methylpyridine, and 2-chloro-5-chloromethylpyridine (CCMP). To further promote the development of pyridine industry, people started to research and develop these methylpyridine compounds. After years of development and in-depth exploration, methylpyridine derivatives, especially 3-methylpyridine, are now widely used in the agrochemical industry.

Currently, the pesticide industry has evolved to the fourth generation of pesticides. The first generation is organochlorine pesticides, such as DDT and benzex; the second generation is organophosphorus pesticides, such as methamidophos and parathion; the third generation is pyrethroid pesticides, such as cypermethrin and deltamethrin, and the fourth generation is pyridine pesticides such as haloxyfop-P-methyl, fluazifop-P-butyl, fluazifop-P-butyl, fluazinam, fluopyram and picoxystrobin. Methylpyridine derivatives are mainly used to produce the fourth generation of agrochemical products with high efficacy and low toxicity, and most of the intermediates of the fourth generation of advanced pesticides are fluorine-containing pyridine products.

Commonly used methylpyridine products are CCMP (2-chloro-5-chloromethylpyridine), 2-methylpyridine, 3-methylpyridine, and 4-methylpyridine. These four products belong to the category of pyridine, and are the methylpyridine products with the highest application value in the agrochemical industry.

In terms of the production process, there is not necessarily an upstream or downstream relationship between pyridine and various methylpyridine products. Formerly, pyridine was extracted mainly from coal tar, and now it is primarily obtained through the synthesis method. The aldehyde-ammonia method is the most common chemical synthesis method. Different pyridine compounds can be obtained based on raw material aldehyde and different reaction conditions. For example, acetaldehyde reacts with ammonia to produce pyridine, 2-methylpyridine and 4-methylpyridine; acetaldehyde, formaldehyde react with ammonia to produce pyridine, 3-methylpyridine, etc. CCMP can be obtained from the reaction of 3-methylpyridine downward or from the reaction of dicyclopentadiene (as the starting material) with acrylaldehyde or acrylonitrile.

Derivative products of methylpyridine after chlorination and fluorination

There are many derivatives of methylpyridine products after chlorination and fluorination. The specific derivation modes include adding trichloro or trifluoro in 2-6 positions of pyridine moiety; chloro, fluoro, amino, hydroxyl, bromo or iodo to 2 position; chlorio, fluoro, amino or hydroxyl to 2 and 3 positions. The derived products are 2-trifluoromethyl pyridine, 2-chloro-3-trifluoromethyl pyridine, 2-chloro-4-trichloromethyl pyridine, 2-amino-5-trifluoromethyl pyridine, 2-amino-3-chloro-5-trifluoromethyl pyridine, 2-chloro-6-trifluoromethyl pyridine, etc.

The following three figures show in detail the downstream derivatives and applications of each series of 2-methylpyridine, 3-methylpyridine and 4-methylpyridine.

1. Downstream derivatives of 2-methylpyridine

Downstream derivative of 2-methylpyridine (intermediates in blue and pesticide technicals in green)

2-chloro-6-trichloromethyl pyridine (CTC) is obtained by stepwise deep chlorination of 2-methylpyridine. CTC has a wide range of applications. For example, it can be used to produce chlorfenapyr, a pesticide with certain herbicidal activity and can control cyanobacteria in water.

CTC also has a remarkable effect in the field of nitrogen fertilizer synergists. It can inhibit or regulate the nitrification of ammonia nitrogen in the soil or other plant growth media. The consumption of nitrogen fertilizer can be reduced by 30% by adding 1kg of synergist to 1t of nitrogen fertilizer. At present, nitrogen fertilizer synergists have been widely used in developed areas abroad. The product will have a favorable market development prospect, considering its low use rate in the Chinese market.

CTC is subject to further deep fluorination produces 2-fluoro-6-trifluoromethyl pyridine (FTF). FTF is a key intermediate for the production of pesticides flupyrsulfuron-methyl-sodium, thiazopyr, dithiopyr, bicyclopyrone, sulfoxaflor, etc. 2-amino-6-trifluoromethyl pyridine can be produced by introducing ammonia gas to add amino group.

Another process route is to obtain 2-chloro-6-trifluoromethyl pyridine by fluorination of CTC, and then add the hydroxyl by introducing alkali to produce 2-hydroxy-6-trifluoromethyl pyridine (HTF). HTF can be used to produce picoxystrobin.

2. 3-methylpyridine

Downstream derivatives of 3-methylpyridine

3-methylpyridine is obtained by stepwise chlorination of 2-chloro-3-trichloromethyl pyridine, which is then fluorinated to obtain 2-chloro-3-trifluoromethyl pyridine, an intermediate for the production of flazasulfuron.

3-methylpyridine is chlorinated to 2-chloro-5-methylpyridine and further chlorinated to CCMP, which can be directly used as an intermediate of imidacloprid and acetamiprid. CCMP can also be further fluorinated and chlorinated to produce DCTF, which can be used to produce a variety of pesticides, such as haloxyfop-methyl, haloxyfop-P-methyl, haloxyfop-methyl, chlorfluazuron, and fluazuron. Ammonia gas can be introduced to DCTF to produce 2-amino-3-chloro-5-trifluoromethyl pyridine (ACTF), a key intermediate of fluazinam.

Back to 2-chloro-5-methylpyridine, it is first chlorinated and then fluorinated to obtain 2-chloro-5-trifluoromethyl pyridine (CTF), an intermediate of pyridalyl and fluazifop-butyl series products.

The downstream value of other related derivatives such as 3-trifluoromethyl pyridine and 2-amino-5-trifluoromethyl pyridine is also worth probing.

Among the thirteen pesticide technicals shown in the figure, imidacloprid is currently one of the top three highly effective new insecticides globally. Chinese companies have an annual production capacity of over 10,000 tons for CCMP, an intermediate of imidacloprid. CCMP can be synthesized through two different routes. The first is the route from 3-methylpyridine to 2-chloro-5-methylpyridine and then to CCMP. The second is the route from dicyclopentadiene to CCMP, a more economical and efficient one. Most of the imidacloprid production plants in China use the cyclopentadiene-acrolein process to produce CCMP. The process has a shorter route, costs less and has a better product quality. But it has high pollutant emissions, where every ton of imidacloprid consumes 14~28t of wastewater and generates 1.3~2.9t of waste residues and a large amount of acrolein, acrylonitrile and other toxic gases, which are difficult to treat and cause serious environmental pollution.

Since , China gradually tightened its environmental protection policy, and some small factories with insufficient environmental protection technology and equipment were forced to shut down, decreasing utilization of production capacity of CCMP and imidacloprid, increasing concentration of the industry, and rising product prices.

3. 4-methylpyridine

Downstream derivatives of 4-methylpyridine

The downstream products manufactured with 4-methylpyridine derivatives as an intermediate are mostly high value-added products with excellent development prospects. Besides the well-known 2-chloro-4-trifluoromethyl pyridine obtained by chlorination and fluorination, which is used to produce aminopyralid and flonicamid, 2-amino-4-trifluoromethyl pyridine obtained by chlorination, fluorination and ammonia addition can be used to synthesize the active ingredients of anticancer drugs: MLN and BKM120-AAA, of which the market price can reach several million yuan per ton. As the production of 2-amino-4-trifluoromethyl pyridine involves positioned catalytic chlorination, in-depth chlorination, fluorination and ammonization, and the synthesis is difficult, the product has high technical barriers.

On the whole, pesticide products are still the main direction of downstream development for methylpyridine. The biological activity of pyridine heterocyclic compounds after adding the fluoro is several times that of the original compounds, with less use rate and low residues in the soil, which meet the increasingly stringent environmental requirements. Therefore, the downstream fluorine-containing pyridine pesticides become the mainstay of the latest generation of pesticides. According to incomplete statistics, fluorine-containing compounds account for over 50% of the new pesticides developed in recent ten years.

The market and supply of methylpyridine derivatives

At present, China has a huge production capacity of methylpyridine, distributed mainly in Jiangsu and Shandong. Before , the traditional coal tar separation method was applied to produce pyridine, with a production capacity of less than 200 tons/year, which seriously restricted the development and production of downstream products. Today, the traditional method is replaced by synthetic method, which accounts for over 95% of the total output. The global production capacity of pyridines exceeds 100,000 tons per year. The largest four manufacturers are the USA, Europe, Japan and China, accounting for over 86.75% of the total global output of pyridine compounds.

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Pyridine derivatives involve too many products, and the price correlation is not high and varies. To understand the market and price trends of this category of products, four products widely used in the agrochemical market are selected and analyzed as follows.

1. 2-chloro-5-chloromethylpyridine (CCMP)

In , China&#;s sharp and severe environmental pressure pushed CCMP&#;s price to its highest level in recent years. During -, with more companies satisfying the environmental requirements, the production capacity of CCMP increased and the price gradually fell back. In , the price fell below RMB80,000/t, to the lowest point in recent years. There are two main contributing factors. The first is that the imidacloprid price remained sluggish for a long time in . The second is the vicious competition among CCMP manufacturers in the market, represented by malicious price cuts, with some product prices below the production cost, just for seizing the market share. The second factor is the core reason for the disruption of the CCMP market.

In , the unhealthy market situation gradually returned reasonably due to the rising raw material prices and environmental pressure, and the price rebounded to around RMB94,000/t. With the increase of raw material cost, the CCMP price is still upward. Since the issuance of the national policy on controlling the amount and intensity of carbon emissions in September , some small factories were shut down due to soaring raw material prices. The price of CCMP gradually peaked RMB170,000-190,000/t. By the end of December , the market gradually cooled down, the price of raw materials stabilized, and the price of CCMP was maintained at the level of RMB150,000-160,000/t.

2. 2,3-dichloro-5-trifluoromethyl pyridine (DCTF)

The sudden soaring price did not happen to DCTF when the environmental pressure increased in . But for this reason, the price was maintained at about RMB210,000-220,000/t during -. Since the second half of , the DCTF price dropped to below RMB180,000/t after the price collapse of the upstream intermediate CCMP. The cost of DCTF also experienced sharp rise due to the fluctuation of raw material prices since the issuance of the national policy on controlling the amount and intensity of carbon emissions. By the end of December , the market price of DCTF was about RMB240,000/t. Considering the rising cost of the raw materials of CCMP, the upstream intermediate of DCTF, the price of DCTF is expected to rise accordingly.

3. 2-chloro-5-trifluoromethyl pyridine (CTF)

The price of CTF has been maintained at RMB230,000-240,000/t since the price rise due to the environmental pressure starting from .

4. 2-chloro-6-trichloromethyl pyridine (CTC)

The price of CTC is relatively stable and has been maintained at around RMB110,000/t. CTC can also be used as a nitrogen fertilizer booster &#;which can prolong the effective time of nitrogen fertilizer, reduce damage to crops, reduce soil compaction, and pollution of water bodies.

Production of methylpyridine series products by Huimeng Bio-Tech

Shandong Huimeng Bio-Tech Co., Ltd.(Huimeng Bio-Tech for short) has strong R&D and production capacity of methylpyridine series products, Huimeng is located in Heze City, Shandong Province, China. The company was established in May with a total investment of RMB1 billion and covering an area of 320,000&#;. Huimeng Bio-Tech has lined up the industrial chain from primary raw materials, critical intermediates to pesticide technicals and completed the production line of biological fermentation-based chiral compounds for producing intermediates of methylpyridine derivatives as well as the technical production line.

Huimeng Bio-Tech has three production sites and one R&D base, which are shown in the figure below:

Huimeng Bio-Tech&#;s main intermediate products of methylpyridine are all single products with an annual production capacity of 1,000t level. The annual production capacity will be expanded to 10,000t level for some products. The company&#;s products are listed as follows.

Most of the leading products listed above have an annual production capacity of tons or more. All products listed in the table are in production except Anhe&#;s HPPA and MAQ and Heilong&#;s intermediate, penoxsulam and glufosinate-P projects, which are still under construction. Over 50% of Huimeng Bio-Tech&#;s products are for export, and the destination covers twelve countries. In addition, the company has established a good reputation among international customers and maintained a long-term stable partnership with them.

Industry outlook

With the improvement of pesticide-related laws and regulations worldwide, the backward pesticides with high toxicity and high residue phased out one by one. The increasingly stringent registration requirements have also shifted the focus to a new generation of pesticide products with increased activity, high selectivity, no toxicity or low toxicity, safe for crops and no residues in crops, agricultural products and soil, atmosphere and water after use, or, even if there is a trace residue, it can be degraded in a short time to become non-toxic natural substances and completely be integrated into nature.

There are three categories of compounds that can meet the requirements for future pesticides:

1. Pesticides containing pyridine moiety / pesticides containing fluorine / pesticides containing fluorinated pyridine (high activity and low toxicity), such as the afore-mentioned pyridine downstream products, e.g., haloxyfop-P-methyl, fluazifop-P-butyl, fluazinam, etc.

2. Pesticides of chiral compounds with single optical activity (of which the ineffective part is converted into the effective part, to avoid the ineffective or antagonistic effect of isomers), such as quizalofop-P-ethyl and gibberellins

3. Biological fermentation-based pesticides, with low toxicity, good environmental compatibility, small or no ecological problems, and very safe for non-target plants and animals. Typical products: spinosad, glufosinate-P, etc.

Huimeng Bio-Tech has been committed to R&D innovation for many years. Up to now, four new substances have been successfully synthesized, namely, 2,3,6-trichloro-5-trifluoromethyl pyridine, 3-chloro-5-trifluoromethyl pyridine, 2,5-dichloro-3-trifluoromethyl pyridine, and 2-methoxy-6 chloro-5-trifluoromethyl pyridine.

There are no specific derivatives and downstream application data of these latest compounds but, after years of research, development, production and practice, there is no doubt that pyridine products have a bright future.

The products developed by Huimeng Bio-Tech are only a small portion of this segment. In agrochemicals, the two links that create value and make it bigger lie in R&D and sales. As the competitiveness of a big power depends on manufacturing, the future development of China&#;s agrochemical industry needs the collaboration of all participants from R&D to manufacturing. The current direction of Huimeng Bio-Tech&#;s efforts is highly consistent with the industry&#;s future direction. It is hoped that more Chinese companies can take part in the front end of the industry chain and create more Chinese value for the global agrochemical industry.

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At present more than 250 FDA approved chlorine containing drugs were available in the market and many pharmaceutically important drug candidates in pre-clinical trials. Thus, it is quite obvious to expect that in coming decades there will be an even greater number of new chlorine-containing pharmaceuticals in market. Chlorinated compounds represent the family of compounds promising for use in medicinal chemistry. This review describes the recent advances in the synthesis of chlorine containing heterocyclic compounds as diverse biological agents and drugs in the pharmaceutical industries for the inspiration of the discovery and development of more potent and effective chlorinated drugs against numerous death-causing diseases.

The application of chlorine in medicinal chemistry is one of the fastest growing hot areas in chemistry as its fascinating and instructive role of halogens distribution in the field of drug development. Surprisingly, among four halogens, chlorine (Cl) is the one which is more frequently found in drugs than others, even fluorine (F). Interestingly, in drugs, the elements of sulphur, chlorine, and fluorine were placed as 5&#;7 respectively after C, H, O, and N. The remaining phosphorous (P), bromine (Br), and iodine (I) are the rest of the top 10 elements in approved drugs, and remarkably, the Cl and F are the heavy hitters (Cl > F &#; Br > I) [ [8] , [9] , [10] ].

The properties mentioned above will give rise steric and/or electronic effects of the chlorine substituents and lead to local electronic attraction or repulsion or to steric interference with any amino acid residue surrounding the position of the chlorine atom in the binding pocket of the protein. This in turn may cause a tighter interaction or a loosening of the contacts to the amino acids close to the chlorine or in other parts of the active molecule. Either one may affect the function of the target protein and cause an increase or decrease of biological activity. In other cases however a chlorine substituent may have no specific effect on the primary biological properties of the molecule to which it is attached [ 7 ]. Chlorinated compounds are not necessarily toxic or dangerous. Highly reactive chemicals or polychlorinated compounds cannot be compared with regard to toxicological properties with unreactive compounds having a low degree of chlorination. The chlorine atom, as one of many possible substituents used in synthetic organic chemistry, will remain in the future one of the important tools for probing structure-activity relationships in life science research and as a molecular component in commercialized compounds, in order to provide safer, more selective and more environmentally compatible products with higher activity for medicine and agriculture [ 7 ].

The presence of chlorine atom played a pivotal role in a number of natural products such as the antibiotics clindamycin [ 3 ], vancomycin [ 4 ], chloramphenicol [ 5 ], and griseofulvin. Over the course of time it has been found empirically that the introduction of a chlorine atom into one or more specific positions of a biologically active molecule may substantially improve the intrinsic biological activity [ 6 ]. The properties of the carbon-chlorine bond (C-Cl) in organochlorines have been analysed by Henschler [ 4 , 5 ]. However, in the low-molecular-weight chemicals investigated in that analysis, the electrophilic reactivity of the carbon centre adjacent to the chlorine atom, which facilitates displacement of chlorine by (bio)nucleophiles, determines the observed biological properties [ 4 , 5 ]. The increase of lipophilicity of the whole molecule by a chlorine substituent leads to a higher partitioning of a chlorinated compound into the lipophilic phase of a cell membrane or lipophilic domains of a protein. This causes a higher local concentration of the compound near a biological target site, but, not necessarily a higher biological activity. The most important effect of a non-reactive chlorine atom in the biological activity of many compounds comes from chlorine as a substituent on an aromatic, heteroaromatic or olefinic moiety.

Chlorine is one of the most vital industrial chemicals, which was utilized by various end-users of industries. And it has been tremendous sprite in pharmaceuticals as the major key ingredients in drugs to treat many diseases such as meningitis, cholera, plague, typhoid, bacterial skin infections, respiratory and nervous system problems etc., as per the Business Wire and A Berkshire Hathaway Company reports. The therapeutics and percentage of sales were presented to address the importance of chlorine chemistry in pharmaceutical drugs as what have been reported by HIS Applied Economics, Canada ( ) . In United States, more than 88% of the pharmaceuticals were depended on chlorine chemistry including the drugs those have been used for the treatment of stomach ulcer, cancer, anemia, high cholesterol, depression, and epilepsy. As per statistics, the benefit from the chlorine chemistry was estimated to $450 billion per year. The net gain of the pharmaceuticals in the U.S. and Canada using chlorine is as high as $640 billion per year from the health care system reported by HIS Applied Economics, Canada [ 1 ]. According to the Business Wire and A Berkshire Hathaway Company reports, the estimating chlorine market for the period of &#; is approximately 4.8%. Some of the drugs presented with chemical structures containing chlorine (number of groups are different). One of the studies detailed that, 163 compounds among 233 approved drugs; nearly 73% of them contained single chlorine atom [ 2 ]. Of which, 23% of them possessed by two chlorines, 2.6% of them possessed by three chlorine atoms, 1.4% of them possessed by four chlorines, and 2.5% of them possessed by six chlorines in the compounds. Surprisingly, none of the drugs had been approved with five chlorine atoms yet. Also, among them, 98% were monosubstituted (CCl), only four were disubstituted (CCl 2 ), and none of the approved drugs has trisubstituted (CCl 3 ) groups. This interesting research gap suggests that, chlorine will further continue its industry ruler role to provide and benefit consumers of the pharmaceuticals in the future [ 1 ]. To improve the quality and advantage of chlorinated chemistry, scientists need to an advance understanding of the chlorine in the view of medicinal chemistry in the future (see ).

2.&#;Synthesis and biological applications of chlorinated analogues

2.5. Synthesis of chlorine containing α-glucosidase agents

Diabetes is one of the insistent diseases rising in the world. According to the estimated data obtained in , around 285 million peoples were suffered from diabetes all over the world and it may increase to 439 million by [69,70]. Blood glucose changing due to the insulin resistance is regarded as the feature of being diabetic in 95% of the cases [71] which give raise to several problems like high blood pressure, heart problem, kidney failure, stroke and blindness [72]. Consequently, the inhibition of α-glucosidase (EC. 3.2.1.20), a key carbohydrate hydrolyzing enzyme, could serve as an effective methodology in both preventing and treating diabetes through controlling the postprandial glucose level and suppressing postprandial hyperglycemia [73]. α-Glucosidase specifically performs the hydrolysis of α-glucopyranoside bond, resulting in the production of α -d-glucose from the non-reducing end of the sugar [74]. Several α-glucosidase inhibitors like acarbose, voglibose, and miglitol, have appeared in clinic for the treatment of type II diabetes mellitus [75], however, number and intensity of side effects call for the development of potent, structurally diverse, safe and efficacious drugs for the effective treatment of diabetes mellitus.

Very recently, Javid et al. have developed the synthesis and SAR study of a series of novel thiosemicarbazide compounds. The targeted thiosemicarbazide compounds were synthesized in simple and three steps. First, equimolar amount of commercially available p-chlorobenzaldehyde 260 was treated with thiosemicarbazide 261 in methanol in the presence of catalytic amount of HCl under reflux condition for 3&#;4&#;h to yield compound 262. Then compound 262 was cyclized in the presence of iodine and potassium carbonate in 1,4-dioxane to afford compound 263. Next, compound 263 was reacted with dichloro benzaldehyde in methanol in the presence of catalytic amount of conc. HCl to yield final compound 264 in good yield ( ). Compound 264 was found to be excellent α-glucosidase inhibitory agent with IC50 value of 4.70&#;μM. The presence of electron withdrawing group (Cl) on the phenyl ring highly enhanced the α-glucosidase activity [76].

In , Pirotte et al. have synthesized a series of new 6-chloro-substituted-3-alkylamino/cycloalkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides analogues and tested for their in vitro α-glucosidase activity. The starting material aniline 265 was reacted with chlorosulfonyl isocyanate under the optimal reaction conditions to yield 6-chloro-substituted 3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide 266. Subsequent thionation of the oxo derivatives 266 with phosphorus pentasulfide in pyridine led to the corresponding compound 267. In the next step, compound 268 was prepared from the reaction of thioxo compound 267 with methyl iodide in the presence of sodium hydrogenocarbonate. Finally, compound 268 was treated with isopropyl amine under optimal reaction conditions to obtain final product 269 [77] ( ). The compound 269 was found to be the most potent glucose-induced insulin secretion with RIS value of 13&#;μM per 1&#;μM concentration. The position of the chlorine atom on the benzene ring strongly affected the activity on insulin-secreting cells. Taken as a whole, the rank order of potency of 3-isopropylamino-substituted compounds on pancreatic β-cells was found to be 6-chloro&#;=&#;6,7-dichloro > 7-chloro > 8-chloro > 5-chloro [78].

Taha et al. have synthesized novel imidazole-pyridine hybrids and screened for their in vitro biological activities. These compounds were prepared from commercially available starting materials 5-chloropyridine-2,3-diamine 270. Compound 270 was reacted with substituted aldehydes 271 in the presence of Na2S2O5 with DMF as solvent under reflux conditions to afford desired products 272a-z in high yields ( ). All the newly synthesized derivatives were tested for their in vitro biological activities such as antioxidant, antiglyacation and β-glucuronidase activities. Among them, compound 272a (IC50&#;=&#;240.12&#;μM) was found to be the most potent antiglyacation agent, compound 272b (IC50&#;=&#;29.25&#;μM) showed excellent β-glucuronidase activities and compound 272c (IC50&#;=&#;72.50&#;μM) exhibited promising antioxidant activity [79].

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