Phenothiazine: A Better Scaffold against Tuberculosis

Abstract

The incidence of Tuberculosis (TB) is baffling in developing countries due to the increase in multidrug-resistant and extensively drug-resistant TB. Therefore, drugs acting through different mechanisms are in dire need to counter the resistant strains. Various chemical scaffolds are being investigated against tuberculosis, among them the molecules containing phenothiazine nucleus are found to be more effective against both susceptible and resistant strains of M. tuberculosis. In addition, the efficacy of first-line drugs has been found to be enhanced on supplementary treatment with phenothiazines. The present review provides an overview of the phenothiazine based molecules which were investigated during the last ten years for their anti-tubercular activity.

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

“…In particular, the imidazo [1,2-a] pyridine amides (IPAs) class is surprisingly highly selective to mycobacteria [ 48 , 50 ], and the most advanced derivatives showed MICs in the nanomolar range. The discovery of Q203 (Telacebec, Figure 8 ) [ 51 ], the most advanced compound of this class, has prompted many to lead optimization programs around the IPA scaffold providing elaborated SARs: 6- or 7-Cl groups at the R 2 position enhance both the activity and the metabolic stability with respect to the unsubstituted compounds [ 52 , 53 , 54 ]; the ethyl group at R 1 appears to be the most favorable [ 52 , 53 , 54 ]; a lipophilic side chain is pivotal for the activity, regardless of chain length and linearity [ 52 ]; the substituted N -benzyl group at the side chain is important but not critical for the activity [ 53 , 54 , 55 , 56 , 57 ]; 4-trifluoromethoxy-phenyl-piperidino group is the best one at the side chain, but can be replaced by other nitrogen heterocycles to improve PK properties [ 55 , 58 ]; generally, scaffold switching is not a good option since that of the imidazo [1,2-a] pyridine-3-carboxamides is optimal for potency and ADME properties [ 59 ], but there are a few exceptions [ 60 , 61 , 62 ]; the presence of -NH in the carboxamide group at 3 is critical for the activity, as well as the carbonyl group [ 53 , 54 ]; switching the position of the carboxamide from 3 to 2 results in less effective derivatives. …”

“…6- or 7-Cl groups at the R 2 position enhance both the activity and the metabolic stability with respect to the unsubstituted compounds [ 52 , 53 , 54 ];…”

“…a lipophilic side chain is pivotal for the activity, regardless of chain length and linearity [ 52 ];…”

“…Indeed, it showed activity in the nanomolar range against Mtb (MIC 50 = 2.7 nM) that was conserved for MDR and XDR clinical isolates; likewise, a safety profile of the drug was recorded since it did not inhibit either CYP450 targets or the hERG (human ether-à-go-go related gene) potassium channel. In addition, despite the high lipophilicity (LogP: 7.64) [ 56 ], Q203 was well-tolerated during acute and long-term administration in mice, and the PK profile (low volume of distribution with a drug concentration in lungs 2-3-fold higher than in serum, bioavailability of 90% and a terminal half-life of 23.4 h) was even more reassuring than in BDQ [ 52 ]. Pre-clinical studies confirmed the high efficacy of Q203 as an anti-TB drug, and Phase 1 clinical study showed it is well-tolerated in healthy human subjects.…”

Targeting the cytochrome bc1 complex for drug development in M. tuberculosis: review

“…In this regard, Q203 is the sole member of this family with good efficacy against MDR and XDR and a favorable safety profile since it does not inhibit either CYP450 targets or the hERG potassium channel [94]. Q203 was well-tolerated during long-term administration in mice models with better PK profile like bioavailability of 90% and a terminal half-life of 23.4 h [95]. Q203 was also shown to be well-tolerated in the pre-clinical study [96] and effective as an anti-TB medication in healthy human volunteers in phase 1 clinical trial [97].…”