SQ109

SQ109 is a novel antitubercular drug with IC50 value of 0.2 μg/ml on XDR [1].
Tuberculosis is a serious infection disease caused by Mycobacterium tuberculosis (Mtb). It is the leading single-agent killer with highest fatality rate. About more than three million lives were killed by tuberculosis every year. Even so, the existed drugs for TB treatment are facing many challenges including the side effects and the development of multidrug-resistant tuberculosis (MDR-TB). As a novel antitubercular drug, SQ109 has a distinguished mechanism of action and improved potency. The target of it is the mycolic acid transporter MmpL3 required for the synthesis of mycolic acid in cell wall of Mtb [1 and 2].  
SQ109 was screened out from a big chemical library designed around the active pharmacophore of ethambutol (EMB). Even so, SQ109 had different chemical structure, potency and mechanism with EMB. Among the top 27 candidates, SQ109 showed the highest selectivity index value and lowest IC50 value in vitro of 16.7 and 0.78 μg/ml, respectively. SQ109 displayed potent activity against all the substrains of Mtb including XDR- and MDR-TB clinical strains with IC50 values of 0.2 μg/ml. Besides that, SQ109 also showed significant effects on other pathogenic Mycobacteria with MIC values in the range of 4 to 16 μg/ml [1].
SQ109 showed low oral bioavailability in PK studies. The carbamate prodrug of it with improved oral bioavailability (from 21.4% to 91.4 %) exerted a high tissue distribution in rats. In the infected mice, treatment of SQ109 at dose of 10 mg/kg significantly attenuated the symptom of weight loss. In the chronic TB model in mice, 10 mg/kg of SQ109 showed better potency than EMB at dose of 100 mg/kg. Besides that, it was reported that the combination treatment of SQ109 and bedaquiline demonstrated a durable cure in infected mice model [1 and 3].
References:
[1] Sacksteder K A, Protopopova M, Barry C E, et al. Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action. Future microbiology, 2012, 7(7): 823-837.
[2] Meng Q, Luo H, Liu Y, et al. Synthesis and evaluation of carbamate prodrugs of SQ109 as antituberculosis agents. Bioorganic & medicinal chemistry letters, 2009, 19(10): 2808-2810.
[3] SQ109 (2008) SQ109. Tuberculosis (Edinb) 88, 159–161.
[4] Reddy V M, Dubuisson T, Einck L, et al. SQ109 and PNU-100480 interact to kill Mycobacterium tuberculosis in vitro. Journal of antimicrobial chemotherapy, 2012: dkr589.

Activity of moxifloxacin and linezolid against Mycobacterium tuberculosis in combination with potentiator drugs verapamil, timcodar, colistin and SQ109.[Pubmed:28162983]

Int J Antimicrob Agents. 2017 Mar;49(3):302-307.

Current treatment for tuberculosis (TB) is complicated by the emergence of multidrug resistant TB (MDR-TB). As a result, there is an urgent need for new powerful anti-TB regimens and novel strategies. In this study, we aimed to potentiate a moxifloxacin + linezolid backbone as treatment for MDR-TB with the efflux pump inhibitors verapamil and timcodar as well as with drugs that act on mycobacterial cell wall stability such as colistin and SQ109. Using a time-kill kinetics assay, the activities of moxifloxacin, linezolid, verapamil, timcodar, colistin and SQ109 as single drugs against Mycobacterium tuberculosis were evaluated. In addition, the activity of the moxifloxacin + linezolid backbone in combination with one of the potentiator drugs was assessed. As little as 0.125 mg/L moxifloxacin achieved 99% killing of M. tuberculosis after 6 days of exposure. Linezolid showed moderate killing but 99% killing was not achieved. Verapamil, timcodar and colistin only resulted in killing with the highest concentrations tested but 99% killing was not achieved. SQ109 resulted in complete elimination after 1 day of exposure to 256 mg/L and in 99% elimination after 6 days of exposure to 1 mg/L. Furthermore, colistin added to the moxifloxacin + linezolid backbone resulted in increased elimination, whereas verapamil, timcodar and SQ109 showed no added value to the backbone. This finding that colistin potentiates the activity of the moxifloxacin + linezolid backbone against M. tuberculosis suggests its potential role in further studies on the applicability of a moxifloxacin + linezolid treatment of MDR-TB.

Inhibition of Leishmania mexicana Growth by the Tuberculosis Drug SQ109.[Pubmed:27458218]

Antimicrob Agents Chemother. 2016 Sep 23;60(10):6386-9.

We report that the tuberculosis drug SQ109 [N-adamantan-2-yl-N'-((E)-3,7-dimethyl-octa-2,6-dienyl)-ethane-1,2-diamine] has potent activity against the intracellular amastigote form of Leishmania mexicana (50% inhibitory concentration [IC50], approximately 11 nM), with a good selectivity index (>500). It is also active against promastigotes (IC50, approximately 500 nM) and acts as a protonophore uncoupler, in addition to disrupting Ca(2+) homeostasis by releasing organelle Ca(2+) into the cytoplasm, and as such, it is an interesting new leishmaniasis drug hit candidate.

High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial.[Pubmed:28100438]

Lancet Infect Dis. 2017 Jan;17(1):39-49.

BACKGROUND: Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis. METHODS: We did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15-20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15-20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0.05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186). FINDINGS: Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1.78; 95% CI 1.22-2.58, p=0.003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3-5 adverse events, with similar proportions in each arm. INTERPRETATION: A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost. FUNDING: The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC).

Design and Synthesis of 1-((1,5-Bis(4-chlorophenyl)-2-methyl-1H-pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N-Adamantan-2-yl-N'-((E)-3,7-dimethylocta-2,6-dienyl)ethane-1,2-diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria.[Pubmed:26907951]

J Med Chem. 2016 Mar 24;59(6):2780-93.

Novel pyrroles have been designed, synthesized, and evaluated against mycobacterial strains. The pyrroles have originally been designed as hybrids of the antitubercular drugs BM212 (1) and SQ109 (2), which showed common chemical features with very similar topological distribution. A perfect superposition of the structures of 1 and 2 revealed by computational studies suggested the introduction of bulky substituents at the terminal portion of the pyrrole C3 side chain and the removal of the C5 aryl moiety. Five compounds showed high activity toward Mycobacterium tuberculosis, while 9b and 9c were highly active also against multidrug-resistant clinical isolates. Compound 9c showed low eukaryotic cell toxicity, turning out to be an excellent lead candidate for preclinical trials. In addition, four compounds showed potent inhibition (comparable to that of verapamil) toward the whole-cell drug efflux pump activity of mycobacteria, thus turning out to be promising multidrug-resistance-reversing agents.

SQ109 is a potent inhibitor of the trypomastigote form of the parasite, with IC50 for cell killing of 50±8 nM. SQ109, targets MmpL3, is an antitubercular agent.

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