Synthesis, COX-1/2 inhibition activities and molecular docking study of isothiazolopyridine derivatives.

One of the main challenges for nowadays medicine is drugs selectivity. In COX-1 and COX-2, the active sites are composed of the same group of amino acids with the exception of the only one residue in position 523, in COX-1 is an isoleucine, while in COX-2 is a valine. Here, we presented a series of isothiazolopyridine/benzisothiazole derivatives substituted differently into an isothiazole ring, which were synthesized and investigated for their potencies to inhibit COX-1 and COX-2 enzymes by colorimetric inhibitor screening assay. All the tested compounds inhibited the activity of COX-1, the effect on COX-2 activity was differential. The mode of binding was characterized by a molecular docking study. Comparing biological activity of the investigated compounds, it was observed that compounds sharing the most similar position to flurbiprofen and meloxicam, representing the two main enzyme subdomains, achieved higher biological activity than others. It is directly related to the fit to the enzyme's active site, which prevents too early dissociation of the compounds.

Synthesis of novel isothiazolopyridines and their in vitro evaluation against Mycobacterium and Propionibacterium acnes.

In this paper we describe synthesis, structures and some physicochemical properties of 20 isothiazolopyridines 8-13 substituted differently into an isothiazole ring as well as their in vitro antibacterial assays against Mycobacterium tuberculosis H37Rv, Mycobacterium fortuitum PCM 672 and Propionibacterium acnes PCM 2400. Compound 13a was found to be the most active derivative against M. tuberculosis H37Rv, demonstrating 100% growth inhibition of microorganisms in the primary screen (minimum inhibitory concentration [MIC] 6.25µg/mL). Nineteen of the prepared compounds were evaluated against M. fortuitum PCM 672 and P. acnes PCM 2400 and only compounds 9 and 12d exhibited excellent activity against individual strains of microorganisms with MIC90 <1µg/mL. The inhibitory action of the remaining isothiazolopyridines towards the tested strains of the microorganism was low, absent, or a non-linear correlation prohibited accurate determination of MIC values. Unexpectedly, seven of the remaining isothiazolopyridines tested against M. fortuitum and P. acnes stimulated growth of the microorganisms in the range 10-50% or even more (10b) under experimental conditions.

Isothiazolopyridine Mannich bases and their antibacterial effect.

BACKGROUND: Infections caused by multidrug-resistant (MDR) strains, i.e., strains resistant to at least 1 antibiotic of the 3 groups of antibacterial agents, are among the most difficult to treat. New compounds with an antimicrobial action are being sought in order to avoid the complete resistance of bacteria to drugs and the spread of MDR strains. OBJECTIVES: The aim of the research was to determine the antimicrobial activity of the new isothiazolopyridine derivatives. MATERIAL AND METHODS: All chemicals used were purchased from commercial suppliers. The 1H NMR spectra were recorded on a Bruker 300 MHz NMR spectrometer. Infrared (IR) spectra were run on a Perkin-Elmer Spectrum Two UATR FT-IR spectrometer (Perkin-Elmer, Waltham, USA). Elemental analyses were carried out on a Carlo Erba NA 1500 analyzer (Carlo Erba Reagents SAS, Val de Reuil, France). Melting points were determined with a Mel-Temp II apparatus (Laboratory Devices, Holliston, USA). The bacteria panel, including Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 700603 (MDR), Acinetobacter baumannii ATCC 19606, Pseudomonas aeruginosa ATCC 27853, and multidrug-resistant Staphylococcus aureus ATCC 43300 (MRSA) were cultured in Muller-Hinton broth (MHB) at 37°C overnight. Colistin, Polymyxin B, Vancomycin, and Daptomycin were used as controls of bacterial inhibitors. Inhibition of bacterial growth was determined visually and was recorded at 32 µg/mL; 100% inhibition was identified. RESULTS: The new dimethylisothiazolopyridines were prepared by the Mannich reaction. The structures of the isothiazolopyridines were determined based on spectral data analysis, such as IR and 1H NMR. The antimicrobial screening of new compounds was performed. In the primary screen, 2 compounds showed antimicrobial activity (minimum inhibitory concentration (MIC) ≤32 µg/mL). CONCLUSIONS: Taking into account the obtained results, it should be stated that the examined compounds did not exceed the activity of reference drugs and, therefore, further research should be carried out in the group of isothiazolopyridine derivatives.