Synthesis and evaluation of the 2,4-diaminoquinazoline series as anti-tubercular agents

Abstract

The 2,4-diaminoquinazoline class of compounds has previously been identified as an effective inhibitor of Mycobacterium tuberculosis growth. We conducted an extensive evaluation of the series for its potential as a lead candidate for tuberculosis drug discovery. Three segments of the representative molecule N-(4-fluorobenzyl)-2-(piperidin-1-yl)quinazolin-4-amine were examined systematically to explore structure-activity relationships influencing potency. We determined that the benzylic amine at the 4-position, the piperidine at 2-position and the N-1 (but not N-3) are key activity determinants. The 3-deaza analog retained similar activity to the parent molecule. Biological activity was not dependent on iron or carbon source availability. We demonstrated through pharmacokinetic studies in rats that good in vivo compound exposure is achievable. A representative compound demonstrated bactericidal activity against both replicating and non-replicating M. tuberculosis. We isolated and sequenced M. tuberculosis mutants resistant to this compound and observed mutations in Rv3161c, a gene predicted to encode a dioxygenase, suggesting that the compound may act as a pro-drug.

Tuberculosis: Still a Way to go ahead for a Lead- A Review

“…this versatile series has an attention drawing microbiological profile with bactericidal activity against replicating and non-replicating M. tuberculosis encouraging for the development of the series for bacterial viability [66].…”

Activation of 2,4-diaminoquinazoline in Mycobacterium tuberculosis by Rv3161c, a putative dioxygenase

“…A high throughput screening campaign led to the discovery of a series of diaminoquinazoline (DAQ) compounds that was active against Mycobacterium tuberculosis with minimum inhibitory concentrations (MIC) in the sub-micromolar range (3). We carried out a structure activity relationship analysis to evaluate the potential of the DAQ series and identified a number of analogs with improved anti-tubercular activity and good exposure in rat pharmacokinetic studies (4). DAQ compounds had bactericidal activity against replicating and non-replicating bacteria (4).…”

“…We carried out a structure activity relationship analysis to evaluate the potential of the DAQ series and identified a number of analogs with improved anti-tubercular activity and good exposure in rat pharmacokinetic studies (4). DAQ compounds had bactericidal activity against replicating and non-replicating bacteria (4). The target for the DAQ series is not known, but DAQ-resistant isolates have mutations in Rv3161c, a putative dioxygenase (4).…”

“…DAQ compounds had bactericidal activity against replicating and non-replicating bacteria (4). The target for the DAQ series is not known, but DAQ-resistant isolates have mutations in Rv3161c, a putative dioxygenase (4). Since Rv3161c is not essential, and we predict that the mutation would lead to reduced or lower activity, it is unlikely that this is the intracellular target of the series.…”

“…In our previous work, we had only determined the MIC on solid medium using the serial proportion method (8). For compound IDR-0010006, the MIC 99 for wild-type was 6.25 μM, but for the resistant mutants was 25 μM (a 4-fold shift) (4). In order to run metabolite identification studies, we determined the MICs for the wild-type and resistant strains in Middlebrook 7H9 liquid medium supplemented with 10% v/v OADC (oleic acid, albumin, dextrose, catalase) and 0.05% w/v Tween 80.…”