Synthetic approaches and pharmaceutical applications of ...

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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].

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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].