Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines

Protopopova, Marina; Hanrahan, Colleen F.; Никоненко, Б. В.; Samala, Rowena; Chen, Ping; Gearhart, Jackie; Einck, Leo; Nacy, Carol A.

doi:10.1093/jac/dki319

Cited by 349 publications

(252 citation statements)

References 10 publications

Supporting

Mentioning

248

Contrasting

Unclassified

Order By: Relevance

“…The comparison between the intracellular activity of compound SCAR05 and rifampin (Table 4) showed a higher activity in the new compound. Additionally, the intracellular activities of compounds SCAR01-05 are better than those of 26 synthesized compounds from a combinatorial library of 1,2-ethylenediamines, and comparable to SQ 109 (4.72 mM ¼ 99% intracellular inhibition), (2)eRueP (1) 99.25(9) which is the best compound in this library [27]. On the other hand, the compound SCAR06 showed low intracellular activity at 1.29 mM (19.40%), compared to the similar compound SCAR01, with 55.10%…”

Section: In Vitro Infection Modelmentioning

confidence: 88%

“…The MICs of complexes SCAR01-05 are comparable to or better than those of some "second" and "first" line drugs used in current therapy [6,25,26]. SQ 109, an antitubercular compound derived from ethambutol, with MIC of 1.56 mM [27], and TMC 207, a diarylquinoline with MIC of 0.81 mM [28], both of which are new promising drug candidates, presently in the human clinical trial phase, are examples of in vitro activity comparable to the ruthenium complexes presented here. Even though the complex SCAR06 showed the worst inhibitory result among the tested compounds, it had activity comparable to or better than the "second" line drugs [25].…”

Section: Anti-m Tuberculosis Activity Assaymentioning

confidence: 98%

See 1 more Smart Citation

Ruthenium(II) phosphine/diimine/picolinate complexes: Inorganic compounds as agents against tuberculosis

Pavan

Poelhsitz

Barbosa

et al. 2011

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

Section: In Vitro Infection Modelmentioning

confidence: 88%

Section: Anti-m Tuberculosis Activity Assaymentioning

confidence: 98%

Ruthenium(II) phosphine/diimine/picolinate complexes: Inorganic compounds as agents against tuberculosis

Pavan

Poelhsitz

Barbosa

et al. 2011

European Journal of Medicinal Chemistry

View full text Add to dashboard Cite

“…Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9)(10)(11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1).…”

mentioning

confidence: 99%

Antiinfectives targeting enzymes and the proton motive force

Feng

Zhu

Schurig-Briccio

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

147

169

View full text Add to dashboard Cite

There is a growing need for new antibiotics. Compounds that target the proton motive force (PMF), uncouplers, represent one possible class of compounds that might be developed because they are already used to treat parasitic infections, and there is interest in their use for the treatment of other diseases, such as diabetes. Here, we tested a series of compounds, most with known antiinfective activity, for uncoupler activity. Many cationic amphiphiles tested positive, and some targeted isoprenoid biosynthesis or affected lipid bilayer structure. As an example, we found that clomiphene, a recently discovered undecaprenyl diphosphate synthase inhibitor active against Staphylococcus aureus, is an uncoupler. Using in silico screening, we then found that the anti-glioblastoma multiforme drug lead vacquinol is an inhibitor of Mycobacterium tuberculosis tuberculosinyl adenosine synthase, as well as being an uncoupler. Because vacquinol is also an inhibitor of M. tuberculosis cell growth, we used similarity searches based on the vacquinol structure, finding analogs with potent (∼0.5-2 μg/mL) activity against M. tuberculosis and S. aureus. Our results give a logical explanation of the observation that most new tuberculosis drug leads discovered by phenotypic screens and genome sequencing are highly lipophilic (logP ∼5.7) bases with membrane targets because such species are expected to partition into hydrophobic membranes, inhibiting membrane proteins, in addition to collapsing the PMF. This multiple targeting is expected to be of importance in overcoming the development of drug resistance because targeting membrane physical properties is expected to be less susceptible to the development of resistance.T here is a need for new antibiotics, due to the increase in drug resistance (1, 2). For example, some studies report that by 2050, absent major improvements in drug discovery and use, more individuals will die from drug-resistant bacterial infections than from cancer, resulting in a cumulative effect on global gross domestic product of as much as 100 trillion dollars (3, 4). To discover new drugs, new targets, leads, concepts, and implementations are needed (5, 6).Currently, one major cause of death from bacterial infections is tuberculosis (TB) (7), where very highly drug-resistant strains have been found (8). Therapy is lengthy, even with drug-sensitive strains, and requires combination therapies with four drugs. Two recent TB drugs/drug leads (9-11) are TMC207 [bedaquiline (1); Sirturo] and SQ109 (2) (Fig. 1). Bedaquiline (1) targets the Mycobacterium tuberculosis ATP synthase (9) whereas SQ109 (2) has been proposed to target MmpL3 (mycobacterial membrane protein large 3), a trehalose monomycolate transporter essential for cell wall biosynthesis (12). SQ109 (2) is a lipophilic base containing an adamantyl "headgroup" connected via an ethylene diamine "linker" to a geranyl (C 10 ) "side chain," and in recent work (13), we synthesized a series of 11 analogs of SQ109 (2) finding that the ethanolamine (3) was more potent th...

show abstract

“…42,43 sQ109 SQ109 is a 1,2-ethylenediamine that was derived from the pharmacophore of ethambutol. 44 However, SQ109 has a distinct mechanism of action from ethambutol, and it maintains activity against ethambutol-resistant strains of M. tuberculosis. SQ109 exerts antimycobacterial activity by interfering with cell wall assembly by targeting the transport molecule MmpL3.…”

Section: Pretomanidmentioning

confidence: 99%

Novel Treatments for Drug-Resistant Tuberculosis

Clain

Escalante

2016

Clinical Medicine Insights: Therapeutics

View full text Add to dashboard Cite

Drug resistance has emerged as a major obstacle to global control of tuberculosis (TB). Treatment with currently available medications requires prolonged courses of numerous drugs, many of which are associated with significant adverse effects. New drugs are urgently needed to meet the challenge posed by drug-resistant TB, in order to relieve the burden that drug resistance has placed on individual patients and health systems. Fortunately, many new drugs have been developed for the treatment of drug-resistant TB in recent years. The new antimycobacterial agents are derived from various medication classes, work by means of an assortment of mechanisms of action, and are at differing phases of development. This review provides a survey of the most promising new agents, in order to promote familiarity with these emerging drugs and compounds.

show abstract

Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines

Cited by 349 publications

References 10 publications

Ruthenium(II) phosphine/diimine/picolinate complexes: Inorganic compounds as agents against tuberculosis

Ruthenium(II) phosphine/diimine/picolinate complexes: Inorganic compounds as agents against tuberculosis

Antiinfectives targeting enzymes and the proton motive force

Novel Treatments for Drug-Resistant Tuberculosis

Contact Info

Product

Resources

About