Domenico Armenise

4H-1,4-Benzothiazine, Dihydro-1,4-benzothiazinones and 2-Amino-5-fluorobenzenethiol Derivatives: Design, Synthesis and In Vitro Antimicrobial Screening

As part of our studies focused on the design and synthesis of new antimicrobial agents a series of 7‐fluoro‐3,4‐dihydro‐2H‐1,4‐benzothiazine derivatives (4a–4f, 4h) and 7‐fluoro‐2H‐1,4‐benzothiazin‐3(4H)‐one analogues (4j–4o) were synthesized and evaluated for their in vitro inhibitory activity against a representative panel of Gram‐positive and Gram‐negative bacteria strains and also toward selected fungi species. These compounds were prepared in one step from chloro‐substituted‐2‐amino‐5‐fluorobenzenethiol 6a–6c. The biological screening identified in compounds 4a, 4j and 4l the most promising results of both series showing an interesting antimicrobial activity. Our antibiotic investigation was also completed by testing the key intermediates 6a–6c. Surprisingly, 6a–6c emerged as the compounds exhibiting the highest antimicrobial activity by possessing a remarkable antibacterial effect against the Gram‐positive strains with MIC (minimal inhibitory concentration) values between 2 and 8 µg/mL and the fungi panel with MIC values between 2 and 8 µg/mL. These results may prove useful in the design of a novel pool of antimicrobial agents.

Synthesis and Antimicrobial Activity of Some Pyrrolo[1,2,3‐de]‐1,4‐benzothiazines, Part 2

Acid catalyzed cyclization reactions of both 3‐alkyl‐ and 3‐aryl‐substituted N‐/2,2‐dialkoxyethyl)‐3,4‐dihydro‐2H‐1,4‐benzothiazines (2) lead to 2,3‐dihydro‐pyrrolo[1,2,3‐de]‐1,4‐benzothiazines (3). The pyrrolobenzothiazine structure was deduced on the basis of 2D 1H NMR‐NOESY experiments and fully determined by X‐ray data. Compounds 3a‐c showed poor antibacterial activity. However, the 3‐phenyl‐N‐(2,2‐dimethoxyethyl)‐3,4‐dihydro‐2H‐1,4‐benzothiazine (2b′) showed antifungal activity against Aspergillus niger 16‐fold greater than miconazole.

Synthesis and Antimicrobial Evaluation of a New Series of N-1,3-Benzothiazol-2-ylbenzamides

Enterococcus faecalis is a Gram-positive commensal inhabitant of the intestinal tract of humans, animals, and insects. However, it is also an opportunistic pathogen and has emerged as a leading cause of hospital-acquired extraintestinal infections. Fluoroquinolones have been frequently used to treat E. faecalis infections, and the emergence of fluoroquinolone-resistant E. faecalis strains has recently been reported in several countries. Thus, the identifications of new antibiotics specifically directed to E. faecalis may be envisaged. In this paper, a new series of N-1,3-benzothiazol-2-ylbenzamides have been designed, synthesized, and evaluated for their in vitro antimicrobial activities. Among the tested compounds, 3i was active against E. faecalis.

Enhanced solubility and antibacterial activity of lipophilic fluoro-substituted N-benzoyl-2-aminobenzothiazoles by complexation with β-cyclodextrins

Some lipophilic fluoro-substituted N-benzoyl-2-aminobenzothiazole antibacterial agents have been evaluated for their activity in the presence of cyclodextrins (CDs) containing aqueous solutions where CDs are adopted as solubilizing excipients for improving the poor water solubility of these compounds. For such purpose both the natural β-CD and one of FDA/EMA approved CDs for parenteral use (i.e. HP-β-CD) have been employed. The solubility rank order observed was accounted for by thermal analysis (Differential Scanning Calorimetry) and FT-IR spectroscopy. The most promising compound was subjected to further NMR spectroscopic studies and molecular modelling simulations to verify the interactions between the guest molecule and the CD cavity. The assessment of the antibacterial activity of such compounds against selected Gram positive and Gram negative bacterial strains clearly showed that their antimicrobial effectiveness may, quite in all instances, be positively affected by complexation with β-CD and HP-β-CD. These results, which are in some ways in contrast with those already reported in the literature, are herein discussed on the basis of plausible mechanisms. Moreover, this investigation also reveals that the described methodology of complexing both lipophilic and hydrophilic antimicrobial agents with CDs may be an useful approach to enhance their effectiveness as well as a promising strategy to overcome even the microbial resistance problem.

Antiproliferative Activity Evaluation of a Series of N-1,3-Benzothiazol-2-ylbenzamides as Novel Apoptosis Inducers

A series of N-1,3-benzothiazol-2-ylbenzamide derivatives were studied for their antiproliferative activity on human liver hepatocellular carcinoma (HepG2) and human breast cancer (MCF-7) cell lines. Most of them were found to show a prominent inhibitory effect on cell growth. Among the most active compounds, 1k emerged for its proapoptotic effect that is particularly evident towards MCF-7 cancer cell lines.