Whole cell screen based identification of spiropiperidines with potent antitubercular properties (original) (raw)
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Journal of Medicinal Chemistry, 2018
Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the Spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogs. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome. Parameter 1 Mtb H37Rv MIC90 (µM) 0.30 Mtb MIC90 (µM) (108 strains) 0.60 Intracellular H37Rv MIC80 (µM) 0.25 Antibacterial panel IC50 (µM) ≥16 Mammalian cell (HepG2) Tox50 (µM) 36 clogP 2.99 CLint (mL/min•g) mouse microsomes >30 CLint (mL/min•g) human microsomes 25 Solubility CLND (µM) 266 The compound's intra-macrophage activity, selectivity for mycobacteria vs. other bacterial species, and potency against a broad panel of clinical isolates including MDR and XDR strains, in vitro-cidal behavior and a low frequency of spontaneous resistance 13a suggested a highly promising antitubercular profile. The low microsomal stability was a concern and required improvement. In this paper, we report our efforts to optimize this family of compounds through the synthesis of analogs aimed at retaining the antitubercular potency while improving the overall profile for the series. RESULTS AND DISCUSSION Synthesis and In Vitro Evaluation of Analogs Aiming to explore the chemical space of the series, a library of novel compounds was synthesized and evaluated. The compounds were isolated either as free amines or as salts (hydrochloride or
PLoS ONE, 2013
Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. As part of our efforts towards the discovery of new anti-tubercular leads, a number of potent tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide (THPP) and N-benzyl-69,79-dihydrospiro[piperidine-4,49-thieno[3,2-c]pyran] (Spiro) analogues were recently identified against Mycobacterium tuberculosis and Mycobacterium bovis BCG through a high-throughput whole-cell screening campaign. Herein, we describe the attractive in vitro and in vivo anti-tubercular profiles of both lead series. The generation of M. tuberculosis spontaneous mutants and subsequent whole genome sequencing of several resistant mutants identified single mutations in the essential mmpL3 gene. This 'genetic phenotype' was further confirmed by a 'chemical phenotype', whereby M. bovis BCG treated with both the THPP and Spiro series resulted in the accumulation of trehalose monomycolate. In vivo efficacy evaluation of two optimized THPP and Spiro leads showed how the compounds were able to reduce .2 logs bacterial cfu counts in the lungs of infected mice. Citation: Remuiñ án MJ, Pérez-Herrán E, Rullás J, Alemparte C, Martínez-Hoyos M, et al. (2013) Tetrahydropyrazolo[1,5-a]Pyrimidine-3-Carboxamide and N-Benzyl-69,79-Dihydrospiro[Piperidine-4,49-Thieno[3,2-c]Pyran] Analogues with Bactericidal Efficacy against Mycobacterium tuberculosis Targeting MmpL3. PLoS ONE 8(4): e60933.
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According to WHO report, globally about 10 million active tuberculosis cases, resulting in about 1.6 million deaths, further aggravated by drug-resistant tuberculosis and/or comorbidities with HIV and diabetes are present. Incomplete therapeutic regimen, meager dosing, and the capability of the latent and/or active state tubercular bacilli to abide and do survive against contemporary first-line and second line antitubercular drugs escalate the prevalence of drug-resistant tuberculosis. As a better understanding of tuberculosis, microanatomy has discovered an extended range of new promising antitubercular targets and diagnostic biomarkers. However, there are still no new approved antitubercular drugs of routine therapy for several decades, except for bedaquiline, delamanid, and pretomanid approved tentatively. Despite this, innovative methods are also urgently needed to find potential new antitubercular drug candidates, which potentially decimate both latent state and active state my...
Spiro acenapthene derivatives are structurally diverse group of compounds that show the wide range of antituberculosis activity. The computational evaluation of spiro acenapthene derivatives as rpoB protein from Mycobacterium tuberculosis inhibitor has been performed. The gene rpoB encodes the β–subunit of RNA polymerase. Since no crystal structure was available for the rpoB protein, the three–dimensional structure of rpoB protein from Mycobacterium tuberculosis has been modeled to see the drug interactions,thus allowing us to predict the mutations D435V, H445Y, S450L in the modeled structure. The docking analysis was performed by PyRx software using Autodock 4. The study provides the base for further in vitro and in vivo study of the spiro acenapthene derivatives as rpoB protein inhibitor
An atom economic synthesis and antitubercular evaluation of novel spiro-cyclohexanones
Bioorganic & Medicinal Chemistry Letters, 2009
The 1,3-dipolar cycloaddition of azomethine ylides derived from acenaphthenequinone and a-amino acids viz. sarcosine, phenylglycine, 1,3-thiazolane-4-carboxylic acid and proline to a series of 2,6-bis[(E)-arylmethylidene]cyclohexanones afforded novel spiro-heterocycles chemo-, regio-and stereoselectively in quantitative yields. These compounds were screened for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) using agar dilution method. Two compounds, 4-(2,4-dichlorophenyl)-5-phenylpyrrolo(spiro[2.2 00 ]acenaphthene-1 00 -one)spiro[3.2 0 ]-6 0 -(2,4-dichlorophenylmethylidene)cyclohexanone (4i) and spiro[5.2 00 ]acenaphthene-1 00 -onespiro[6.2 0 ]-6 0 -(2,4-dichlorophenylmethylidene)cyclohexanone-7-(2,4-dichlorophenyl)tetrahydro-1H-pyrrolo[1,2-c][1,3]thiazole (5i) display maximum activity in vitro with a MIC value of 0.40 lg/mL against MTB and were 4 and 15.6 times more potent than ethambutol and pyrazinamide, respectively. Tuberculosis (TB) caused by Mycobacterium tuberculosis bacteria (MTB) is one of the most prevalent diseases, responsible for the death of about one billion people during the last two centuries. 1 TB remains a serious public health problem in India accounting for nearly one-third of the global burden, and it has been estimated that 3.5 million of the population are infected with TB. 1,2 In the last 50 years, only a few drugs have been approved by the Food and Drug Administration (FDA) to treat TB, which reflects the inherent difficulties in the discovery and clinical testing of new agents and the lack of pharmaceutical industry research in this area. 3 Hence, the discovery of fast-acting new drugs to effectively combat TB is imperative.
Design, synthesis, antitubercular and antiviral properties of new spirocyclic indole derivatives
Monatshefte für Chemie - Chemical Monthly
A series of indole-based spirothiazolidinones have been designed, synthesized and evaluated, in vitro, for their antitubercular, antiviral, antibacterial, and antifungal activities. The structures of the new compounds were established by IR, 1 H NMR, 13 C NMR (proton decoupled, APT, and DEPT), electrospray ionization mass spectrometry, and microanalysis. Compounds bearing a phenyl substituent at position 8 of the spiro ring, exhibited significant antitubercular activity against Mycobacterium tuberculosis H37Rv ATCC 27294 at concentrations of 3.9 and 7.8 µM. Still, some of the tested compounds displayed activity on mycobacteria with MIC values of 16 and 31 µM. Four of the indole-spirothiazolidinone derivatives were found to be moderately active against Punta Toro virus, yellow fever virus or Sindbis virus in Vero cells. The antiviral EC 50 values were in the range of 1.9-12 µM and the selectivity index (ratio of cytotoxic to antivirally effective concentration) was above 10 in some cases. The most potent effect was seen with the compound that is methylated at positions 2 and 8 of the spirothiazolidinone system.
Targeting Dormant Tuberculosis Bacilli: Results for Molecules with a Novel Pyrimidone Scaffold
Chemical Biology & Drug Design, 2014
Our inability to completely control TB has been due in part to the presence of dormant mycobacteria. This also renders drug regimens ineffective and is the prime cause of the appearance of drug-resistant strains. In continuation of our efforts to develop novel antitubercular agents that especially target dormant mycobacteria, a set of 55 new compounds belonging to the pyrimidone class were designed on the basis of CoMFA and CoMSIA studies, and these were synthesized and subsequently tested against both the dormant and virulent BCG strain of M. tuberculosis. Some novel compounds have been identified which selectively inhibit the dormant tuberculosis bacilli with significantly low IC 50 values. This study reports the second molecule after TMC-207, having the ability to inhibit tuberculosis bacilli exclusively in its dormant phase. The synthesis was accomplished by a modified multicomponent Biginelli reaction. A classification model was generated using the binary QSAR approach -recursive partitioning (RP) to identify structural characteristics related to the activity. Physicochemical, structural, topological, connectivity indices, and E-state key descriptors were used for generation of the decision tree. The decision tree could provide insights into structure-activity relationships that will guide the design of more potent inhibitors.