Synthesis, in vitro antibacterial activity against Mycobacterium tuberculosis, and reverse docking‐based target fishing of 1,4‐benzoxazin‐2‐one derivatives

Abstract

Seventeen 1,4‐benzoxazin‐2‐ones bearing the enaminone moiety and three of their analogs were tested for the antibacterial activity against Mycobacterium tuberculosis (H37Rv). Minimal bactericidal concentrations (MBCs) were determined after 41 days of incubation by BACTEC. 1,4‐Benzoxazin‐2‐ones bearing the unsubstituted benzo moiety showed the most promising activities (MBC = 5.00 µg/ml). For most active compounds, antibacterial activities were determined daily during the 41 days. The most promising compound showed a bacteriostatic effect at a concentration of 0.31 µg/ml on Day 4 of incubation, 0.62 µg/ml on Day 6, 2.50 µg/ml on Day 9, and 5.00 µg/ml on Day 41. All studied compounds, along with some of their reported analogs, were docked to 35 proteins of M. tuberculosis to find their potent targets in these organisms. As a result of reverse docking, aspartate 1‐decarboxylase, panD, was selected as the most appropriate target. Docking of the most active compounds to mutant panD from pyrazinamide‐resistant strains of M. tuberculosis implies that they would not be active against these strains. Considering that most of pyrazinamide clinical resistance cases are due to loss‐of‐function mutations in pyrazinamidase, pncA, compounds from this study could be useful drugs for the treatment of some cases of pyrazinamide‐resistant tuberculosis.

Synthesis of (1,4-benzoxazinones-3-yl)malonate derivatives via cross-dehydrogenative-coupling reactions under ball-milling conditions

“…In the 1 H NMR spectra, presence of two doublets around 4.5 ppm with large coupling constants of about 15 Hz was the indication for the presence of the benzylic fragment in the structure of the products, while the two doublets at about 4.9 and 3.7 ppm were in accordance with the substitution of the malonate moieties at the 3 position of the benzoxazine rings. In addition, the 13 C NMR spectra showed exactly the expected numbers of the signals for each structure.…”

“…With FeCl3 (entry 4), various copper salts (entries 5-10) or CoCl2.6H2O (entry 11) the yield dropped partially. Similarly, no improvement was observed by replacing DDQ with other oxidants (entries [12][13][14][15][16][17][18][19].…”

“…FT-IR spectra are recorded using KBr disks on a Bruker Vector-22 infrared spectrometer and absorptions are reported as wave numbers (cm -1 ). 1 H NMR (500 MHz) and 13 C NMR (125 MHz) spectra are obtained on a FT-NMR Bruker Ultra Shield TM instrument as CDCl3 solutions and the chemical shifts are expressed as units using Me4Si as the internal standard. Mass spectra are obtained on a Finnigan Mat 8430 apparatus at ionization potential of 70 eV.…”

“…12 A few related important molecules, exemplifying various applications, are depicted in Figure 1. [13][14][15][16] Therefore, the development of new methods for the synthesis and derivatization of 1,4benzoxazinones is of continuous interest. [17][18][19][20] Iron is one of the most abundant elements on Earth and iron salts act as catalyst for several chemical transformations, 21 while they are inexpensive and nonharmful to humans and the environment.…”

New Approach to Biologically Active Indolo[2,3‐b]quinoxaline Derivatives through Intramolecular Oxidative Cyclodehydrogenation

“…To understand the mechanism of antimycobacterial activity clearly, the reverse docking strategy has been performed. [11] For this purpose, the library of potential targets of Mycobacterium tuberculosis H 37 Rv that is based on literature data has been applied (Table 3). [12]…”