Structure−Activity Relationships of Antitubercular Nitroimidazoles. 2. Determinants of Aerobic Activity and Quantitative Structure−Activity Relationships

Abstract

The (S)-2-nitro-6-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines have been extensively explored for their potential use as new antituberculars based on their excellent bactericidal properties on aerobic whole cells of Mycobacterium tuberculosis. An oxygen atom at the 2-position of the imidazole ring is required for aerobic activity. Here we show that substitution of this oxygen by either nitrogen or sulfur yielded equipotent analogs. Acylating the amino series, oxidizing the thioether, or replacing the ether oxygen with carbon significantly reduced the potency of the compounds. Replacement of the benzylic oxygen at the 6-position by nitrogen slightly improved potency and facilitated exploration of the SAR in the more soluble 6-amino series. Significant improvements in potency were realized by extending the linker region between the 6-(S) position and the terminal hydrophobic aromatic substituent. A simple 4-feature QSAR model was derived to rationalize MIC results in this series of bicyclic nitroimidazoles.

Design, synthesis and docking studies of some novel (R)-2-(4′-chlorophenyl)-3-(4′-nitrophenyl)-1,2,3,5-tetrahydrobenzo[4,5] imidazo [1,2-c]pyrimidin-4-ol derivatives as antitubercular agents

“…A C C E P T E D ACCEPTED MANUSCRIPT 4 polar isosteres of isonicotinic acid, which may be due to better penetration of these agents into the cell wall of the mycobacteria [9,10].…”

A QSAR Study of Biphenyl Analogues of 2-Nitroimidazo-[2, 1-b] [1, 3] - oxazines as Antitubercular Agents Using Genetic Function Approximation

“…Among these two moieties, 2-nitroimidazo- [2, 1-b] [1,3]oxazines show excellent pharmacokinetics, tolerability, and safety in clinical trials [7]. The SAR studies reported on this group are also reasonably limited [8][9][10][11]. The studies indicate that bicyclic oxazines, the lipophilic tail and the oxygen substituents are the key components required for activity [10].…”

“…The studies indicate that bicyclic oxazines, the lipophilic tail and the oxygen substituents are the key components required for activity [10]. Replacement of oxygen by sulfur also produces active compounds but replacement with sulfoxide or sulfone or with carbon dramatically reduces the activity [11,12]. Planche et al [13] reported two models for the design and prediction of new antituberculosis agents to overcome resistance of Mycobacterium tuberculosis to the existing drugs.…”

Adsorptive stripping voltammetric determination of nitroimidazole derivative on multiwalled carbon nanotube modified electrodes: influence of size and functionalization of nanotubes

“…2,3 Due to his pharmacological activities, the synthesis of new nitroimidazole compounds remains as a very active area of research. [4][5][6] It is a well known matter that the biological activity of nitroimidazole compounds is related to the redox chemistry of the nitro group. 7 This aspect has motivated a great number of electrochemical studies and consequently, the redox chemistry of different nitro compounds of biological significance is focused to understand how the reduction of the nitro group can play an active role in several aspects as: electroanalytical determinations, free radical generation, stability and reactivity.…”