Synthesis, Biological Evaluation, and Structure−Activity Relationships for 5-[(E)-2-Arylethenyl]-3-isoxazolecarboxylic Acid Alkyl Ester Derivatives as Valuable Antitubercular Chemotypes

Abstract

Tuberculosis (TB), mostly caused by Mycobacterium tuberculosis (Mtb), is one of the leading causes of death from infectious disease worldwide. Its coinfection with HIV and the emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains have further worsened the TB pandemic. Despite its global impact, TB is considered a neglected disease and no new anti-TB therapeutics have been introduced over the last four decades. The nonreplicating persistent form of TB (NRP-TB) is responsible for the length of the treatment and is the putative cause of treatment failure. Therefore, new anti-TB agents, which are active against both the replicating form of Mtb (R-TB) and NRP-TB, are urgently needed. Herein, we report the synthesis and structure-activity relationships (SAR) of a series of 5-[(E)-2-arylethenyl]-3-isoxazolecarboxylic acid alkyl esters as potent anti-TB agents. Several compounds had submicromolar minimum inhibitory concentrations (MIC) against R-TB and were active against NRP-TB in the low micromolar range, thus representing attractive lead compounds for the possible development of new anti-TB agents.

A High-Throughput Screen To Identify Inhibitors of ATP Homeostasis in Non-replicating Mycobacterium tuberculosis

“…35 However, Pieroni and co-workers synthesized pyrido-benzimidazoles with submicromolar activity against drug resistant replicating mycobacteria. 36 …”

Derivatives of 3-Isoxazolecarboxylic Acid Esters - A Potent and Selective Compound Class against Replicating and Nonreplicating Mycobacterium tuberculosis

“…The excellent anti-TB activity and the satisfactory metabolic profile of 5a, led to the development of a simplified series of compounds bearing a trans-ethenyl linker, in which the quinoline moiety was replaced with a benzene or pyridine ring [19]. Various substituents and substitution patterns in the rings were investigated allowing plausible SAR to be derived for the 5-[(E)-2-arylethenyl]-3-isoxazolecarboxylic acid alkyl ester derivatives (for examples see Table 2, 6a-6d).…”

Novel quinoline and naphthalene derivatives as potent antimycobacterial agents

“…These compounds were screened against M. tuberculosis H37Rv (ATCC 27294) in triplicate at the single concentration of 6.25 mg/mL for inhibitory activity by BACTEC 460 radiometric methods [38,39]. It was found that naphthalene series compounds (22)(23)(24)(25)(26)(27)(28)(29)(30) possess superior anti-TB activity than the quinoline series compounds (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). (Table 2).…”

“…Quinoline-based well-known drug mefloquine is widely used for the prophylaxis of chloroquineresistant Plasmodium falciparum malaria [16,17]. Mefloquine is also known for its antibacterial [18] and anti-tubercular activity [19][20][21][22] (H37Rv MIC range: 8-16 mg/mL or 21.1-42.2 mM) [23] and its analogs have displayed moderate [24] to submicromolar [25] anti-TB activity. Mefloquine and its derivatives are known to act as purine receptor antagonists [26] and it's only prokaryotic target known so far is F 0 F 1 H þ ATPase in Streptococcus pneumoniae [27].…”

“…Thus, we planned to synthesize two series of molecules based on this strategy (Fig. 1), modified quinoline series (compounds [9][10][11][12][13][14][15][16][17][18][19] and modified naphthalene series (compounds [22][23][24][25][26][27][28][29][30]. Ramamurthy et al reported [30] the synthesis and anti-tubercular activity of bioisosters N(2-naphthyl)glycine hydrazide analogs and N-(6-quinolyl)glycine hydrazide, and found that N(2-naphthyl)glycine hydrazide analogs possess potent inhibitory activity against M. tuberculosis H37Rv at concentrations ranging from 0.5 to 10.0 mg/mL whereas N-(6-quinolyl)glycine hydrazide analogs did not show anti-tubercular activity.…”