Synthesis of non-purine analogs of 6-aryl-9-benzylpurines, and their antimycobacterial activities. Compounds modified in the imidazole ring

Abstract

Purine analogs modified in the five-membered ring have been synthesized and examined for antibacterial activity against Mycobacterium tuberculosis H(37)Rv in vitro employing the microplate alamar blue assay (MABA). The 9-deaza analogs were only found to be weak inhibitors, but the 8-aza-, 7-deaza- and 8-aza-7-deazapurine analogs studied displayed excellent antimycobacterial activities, some even substantially better than the parent purine. In the 7-deazapurine series, MIC values between 0.08 and 0.35 μM, values comparable or better than the reference drugs used in the study (MIC rifampicin 0.09 μM, MIC isoniazid 0.28 μM and MIC PA-824 0.44 μM). The five most active compounds were also examined against a panel of drug-resistant Mtb strain, and they all retained their activity. The compounds examined were significantly less active against M. tuberculosis in a state of non-replicating persistence (NRP). MIC in the low-oxygen-recovery assay (LORA) ≥ 60 μM. The 7-deazapurines were somewhat more toxic towards mammalian cells, but still the selectivity indexes were excellent. The non-purine analogs exhibit a selective antimycobacterial activity. They were essentially inactive against Staphylococcus aureus and Escherichia coli.

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

“…A follow‐up optimisation campaign identified MMV687170 ( 419 ) as a promising lead, which maintained its activity inside infected macrophages . A series of related studies which appeared simultaneously assisted in developing a thorough understanding of the SAR of this class, with only compound 420 representing a substantial improvement in in vitro biological activity …”

Chemotherapeutic Interventions Against Tuberculosis

“…The five most active compounds of the series were also evaluated against a panel of drug-resistant Mtb strains, where all of them retained activity. However, these compounds did not show good activity against non-replicating Mtb [76]. A series of dihydropyrimidines was examined by Trivedi et al in 2010.…”

Antimycobacterial activity of pyrazinoate prodrugs in replicating and non-replicating Mycobacterium tuberculosis

“…The low-oxygenrecovery assay (LORA) [3] is a method considered adequate to identify hits and lead compounds active in this subpopulation. Several examples of bioactive compounds were identified using this approach, such as quinolines [4], quinoxalines [5], arylbenzylpurines, aza-and deaza-purines [6] and aminothiazoles [7].…”