Generation and exploration of new classes of antitubercular agents: The optimization of oxazolines, oxazoles, thiazolines, thiazoles to imidazo[1,2-a]pyridines and isomeric 5,6-fused scaffolds

Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46656, USA.
Bioorganic & medicinal chemistry (Impact Factor: 2.79). 02/2012; 20(7):2214-20. DOI: 10.1016/j.bmc.2012.02.025
Source: PubMed


Tuberculosis (TB) is a devastating disease resulting in a death every 20s. Thus, new drugs are urgently needed. Herein we report ten classes of compounds-oxazoline, oxazole, thiazoline, thiazole, pyrazole, pyridine, isoxazole, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine and imidazo[1,2-c]pyrimidine-which have good (micromolar) to excellent (sub-micromolar) antitubercular potency. The 5,6-fused heteroaromatic compounds were the most potent with MIC's as low as <0.195 μM (9 and 11). Overall, the imidazo[1,2-a]pyridine class was determined to be most promising, with potency similar to isoniazid and PA-824 against replicating Mtb H(37)Rv, clinically relevant drug sensitive, multi- and extensively resistant Mtb strains as well as having good in vitro metabolic stability.

Download full-text


Available from: Sanghyun Cho,
  • Source
    • "Based on our previous results, we designed a series of 1-aryl-6-benzyl-7-hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidine-5(1H)-ones (Rządkowska et al., 2009). The rationale of the study may be summarized as follows: (a) the designed compounds fulfilled both non-classical opioid receptor pharmacophore models presented in Fig. 2 as well as the model for serotoninergic activity depicted in Fig. 3; (b) the designed series is aimed to determine the effect of the second aromatic moiety on the antinociceptive activity; (c) the designed compounds were expected to have favorable values of lipohilicity and ADMET parameters for the activity in central nervous system; (d) the imidazo[1,2-a]pyrimidine scaffold is present in many biologically active compounds which have been reported to exhibit not only central nervous system activity (Blackaby et al., 2006; Goodacre et al., 2006; Jensen et al.,2005; Matosiuk, et al., 1996; Tully et al., 1991) but also anti-inflammatory and analgesic (Abignente et al., 1994; Freeman et al.,1978; Sacchi et al., 1997; Vidal et al.,2001), antibacterial (Al-Tel and Al-Qawasmeh, 2010; Moraski et al.,2012; Rival et al., 1992; Steenackers et al., 2011a, b), antiviral (Gueiffier et al., 1996), antifungal (Rival et al., 1991, 1993), insecticidal, acaricidal and nematocidal (Dehuri et al., 1983), hormonal (Sasaki et al., 2002), mutagenic (Turner et al., 1978), anticancer (Guo et al., 2011; Lin et al., 2012; Linton et al.,2011), and cardiovascular (Okabe et al., 1983) activity; (e) the set of substituents was similar to those in previously reported series (Fig. 1) which turned out to exhibit the expected profile of pharmacological activity. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A series of 24 1-aryl-6-benzyl-7-hydroxy-2,3-dihydroimidazo[1,2-a]pyrimidine-5(1H)-ones was designed as antinociceptive compounds acting through opioid receptors with additional serotoninergic activity. The compounds, similarly as previously published series, lack the protonable nitrogen atom which is a part of classical opioid receptor pharmacophore and is necessary to interact with the conserved Asp(3.32) in the opioid receptor binding pocket. The compounds were obtained in one-step cyclocondensation of 1-aryl-4,5-dihydro-1H-imidazol-2-amines diethyl 2-benzylmalonate or diethyl 2-(2-chlorobenzyl)malonate under basic conditions. Almost all the tested compounds exerted strong antinociceptive activity, but surprisingly, it was not reversed by naloxone; thus, it is not mediated through opioid receptors. It makes it possible to conclude that addition of one more aromatic moiety to the non-classical opioid receptor pharmacophore results in the compounds which are not opioid receptor ligands. The lack of activity of one of the tested compounds may be attributed to low blood–brain barrier permeation or unfavorable distribution of electrostatic potential and HOMO and LUMO orbitals. Electronic supplementary material The online version of this article (doi:10.1007/s00044-014-0993-1) contains supplementary material, which is available to authorized users.
    Medicinal Chemistry Research 09/2014; 23(9):4221-4237. DOI:10.1007/s00044-014-0993-1 · 1.40 Impact Factor
  • Source
    • "e derivatives of this scaffold show a variety of therapeutic properties such as agonist of benzodiazepine receptor [4], GABA A í µí»¼í µí»¼2/í µí»¼í µí»¼3 binding site agonists [5], ligand for detecting í µí»½í µí»½-amyloid [6] and also constitute orally active nonpeptide bradykinin B 2 receptor antagonists [7]. ese derivatives have been found to possess antibacterial [8], antiviral [9] [10], anti-in�ammatory [11], antiulcer [12], antitubercular [13], anticancer [14], antiparasitic [15], and antiprotozoa [16] activities, and so forth Moreover, it is also a core structure of several drugs such as zolimidine (1) (antiulcer), alpidem (2) (anxiolytic), and zolpidem (3) (selective benzodiazepine receptor agonist, for the treatment of insomnia) [17] (Figure 1) which are currently available in the market. As a result, various methods for the preparation of imidazo[1,2-a]pyridine derivatives were developed [18– 20]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Imidazo[1,2-íµí±Žíµí±Ž]pyridine-based tosylhydrazone was prepared and treated with K 2 CO 3 in dioxane at 110 ∘ C to generate the corresponding carbene in situ. It was coupled with a variety of aryl alcohols in one pot to obtain a series of imidazo[1,2-íµí±Žíµí±Ž]pyridine derivatives possessing aryl ether moiety at C-3 position.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: TB is a global public health emergency in which new drugs are desperately needed. Herein we report on the synthesis of a diverse panel of 41 aryl allylic azides, thiocyanates, isothiouronium salts, and N,N'-diacetylisothioureas that were evaluated for their in vitro activity against replicating and non-replicating Mycobacterium tuberculosis (Mtb) H(37)Rv and toxicity to VERO cells. We found a selective group of new and promising compounds having good (micromolar) to excellent (sub-micromolar) potency against replicating Mtb H(37)Rv. Allylic thiocyanates bearing halophenyl (halo=2-Br, 4-Br, 4-Cl, 4-F), 4-methylphenyl and 2-naphthyl moieties were the most active as antitubercular agents. In particular, the 2-bromophenyl-substituted thiocyanate showed MIC=0.25μM against replicating Mtb, MIC=8.0μM against non-replicating Mtb and IC(50)=32μM in the VERO cellular toxicity assay.
    Bioorganic & medicinal chemistry letters 08/2012; 22(20):6486-9. DOI:10.1016/j.bmcl.2012.08.048 · 2.42 Impact Factor
Show more