Synthesis and bioactivity of novel 2-(1,2-benzisothiazol-3-yloxy)- N -(1-aryl-3-cyanopyrazol-5-yl) acetamides

Nine novel types of 2-(1,2-benzisothiazol-3-yloxy)- N -(1-aryl-3-cyanopyrazol-5-yl)-acetamides were synthesized, and their inhibition effects on selected bacteria (heterotrophic bacteria) and algae (marine chlorella) were evaluated. Results showed that 2-(1,2-benzisothiazol-3-yloxy)- N -(3-cyano-1-(2,4-dimethylphenyl)pyrazol-5-yl) acetamide achieved the highest yield of 81% with good bioactivity against heterotrophic bacteria and marine chlorella.

Crystallographic data for the structure reported in this paper have been deposited n the Cambridge data center with deposition number CCDC 980925.
Biological assay: Batch antimicrobial experiments were conducted in six parallel samples, and the average results are listed in Table 6.Heterotrophic bacteria and marine chlorella were selected as typical targets for their normal existence in bodies of water, and are important parameters reflecting water quality.The results showed that the target compounds exert good inhibition against the tested organisms.

Conclusions
This study demonstrated the synthesis and antimicrobial activities of 2-(benzisothiazol-3-yloxy)-N-(3-cyano-1aryl-5-yl) acetamides.Bioactivity testing showed that the compounds exert satisfactory inhibition effects against heterotrophic bacteria and marine chlorella, with rates more than 58.9% and 60.29% for heterotrophic bacteria and marine chlorella at a dosage of 25 ppm, respectively.The highest yield obtained was 81%, indicating that compounds with an aryl-pyrazole and a benzisothiazolone spliced together have high biological activities and low toxicities and represent a new direction for further structural optimization and biological studies on such synthetic acetamides.

Experimental Section
General.All chemicals used in this study were commericallly available.Melting points were recorded on a X-4 binocular spectra melting apparatus.IR spectra in KBr were recorded on a PerkinElmer PE-683 IR spectrometer.
The 1 H NMR spectra were determined using TMS as an internal reference with a Avance Bruker-500 instrument operating at 500 MHz or an Avance Bruker-300 instrument operating at 400 MHz.Elemental analyses were performed by an Elementer Vario EL III elementary analysis instrument.Compounds were synthesized in accordance the method described in our previous work. 21nzisothiazolinone sodium salt.A mixture of benzisothiazol-3(8H)-one (6) (0.01 mol) and NaH (0.011 mol) in MeOH (40 mL) was stirred and heated at refluxed for 2 h.The remaining MeOH was evaporated under negative pressure.The crude product was washed with MeOH and dried to obtain benzisothiazolin-3-one sodium salt (7)   as a white solid, mp >300 ℃.
3-Cyano-5-amino-1-(substituted-phenyl)pyrazoles.Ethyl 2,3-dicyanopropanoate (0.01 mol), NaOAc (0.03 mol), and EtOH (50 mL) were mixed in a 150 mL round-bottomed flask.Then, the mixture was added to a substituted aniline diazonium salt within 20 min and stirred at 5 ℃ for 8 h, after which, the mixture was extracted with CH 2 Cl 2 (3 x 30 mL).Ammonia was then added to the combined organic extracts to adjust the pH to 9-10.After addition, the mixture was stirred at rt for 3 h.The organic phase was washed and then concentrated.After cooling, the crude product precipitated, was filtered off, washed with EtOH, dried, and then recrystallized from toluene to afford the 3-cyano-5-amino-1-(substituted-phenyl)pyrazole (4).

Table 4 .
Intramolecular and intermolecular hydrogen bonds of 8g

Table 6 .
Comparison of the bioactivity of synthesized compounds 8 against heterotrophic bacteria and marine chlorella