681492-22-8

Marketed by Otsuka, delamanid was approved in both the European Union and Japan in 2014 as part of combination therapies for multi-drug resistant tuberculosis (TB). Because delamanid exhibited no adverse drug–drug interactions, it has found utility as a combination therapy with standard antiretroviral drugs indicated for TB. Delamanid blocks mycolic acid biosynthesis in Mycobacterium tuberculosis, which allows its cell wall to be penetrated by small molecule antivirals.

Delamanid is a novel anti-tuberculosis medication that inhibits mycolic acid synthesis and shows potent in vitro and in vivo activity against drug-resistant strains of Mycobacterium tuberculosis.

ChEBI: Delamanid is a member of piperidines.

Treatment of multi-drug resistant tuberculosis

Piperidine 81 was concurrently prepared by first generating biaryl ether 79, which arose from a substitution reaction between pyridine N-oxide 77 and phenol 78 that proceeded in 86% yield. Next, removal of the N-oxide functionality by means of catalytic hydrogenation under mild pressure and neutral conditions afforded diaryl ether 80 in excellent yield. Reduction of the pyridine to the corresponding piperidine (81) was affected through the use of catalytic hydrogenation as well, this time under acidic conditions and elevated pressures relative to the N-oxide reduction. At this juncture, subjection of piperidine 81 to Buchwald¨C Hartwig conditions in the presence of diol subunit 82 delivered diol 83. A two-step elimination to deliver enantiopure epoxide 84 set the stage for an interesting cascade reaction to arrive at delamanid (XI) directly?a the initial alkylation of the epoxide by imidazole 85 proceeded under basic conditions with sodium acetate which then underwent an intramolecular nucleophilic substitution reaction by the liberated alcohol on the pendant imidazole chloride in the presence of sodium hydroxide. The reaction sequence proceeded in 73% yield to provide delamanid (XI) as a free base.

Potentially hazardous interactions with other drugs
Analgesics: increased risk of ventricular arrhythmias with methadone
Anti-arrhythmics: increased risk of ventricular arrhythmias with amiodarone and disopyramide
Antibacterials: possible increased risk of ventricular arrhythmias with clarithromycin, erythromycin and moxifloxacin; increased risk of ventricular arrhythmias with pentamidine; concentration reduced by rifampicin
Antidepressants: possible increased risk of ventricular arrhythmias with tricyclics.
Antiepileptics: avoid with carbamazepine.
Antipsychotics: increased risk of ventricular arrhythmias with droperidol, haloperidol, phenothiazines that prolong the QT interval and pimozide.
Antivirals: increased risk of ventricular arrhythmias with saquinavir
Beta-blockers: increased risk of ventricular arrhythmias with sotalol.
Cytotoxics: increased risk of ventricular arrhythmias with arsenic trioxide and possibly vinblastine, vincristine, vindesine, vinflunine and vinorelbine
Domperidone: possible increased risk of ventricular arrhythmias.

Delamanid is mainly metabolised in plasma by albumin and to a lesser extent by CYP3A4. The complete metabolic profile of delamanid has not yet been elucidated. The identified metabolites do not show anti-mycobacterial activity but some contribute to QT prolongation, mainly DM-6705.