1131005-00-9Relevant academic research and scientific papers
The R enantiomer of the antitubercular drug PA-824 as a potential oral treatment for visceral leishmaniasis
Patterson, Stephen,Wyllie, Susan,Stojanovski, Laste,Perry, Meghan R.,Simeons, Frederick R. C.,Norval, Suzanne,Osuna-Cabello, Maria,De Rycker, Manu,Read, Kevin D.,Fairlamb, Alan H.
, p. 4699 - 4706 (2013)
The novel nitroimidazopyran agent (S)-PA-824 has potent antibacterial activity against Mycobacterium tuberculosis in vitro and in vivo and is currently in phase II clinical trials for tuberculosis (TB). In contrast to M. tuberculosis, where (R)-PA-824 is inactive, we report here that both enantiomers of PA-824 show potent parasiticidal activity against Leishmania donovani, the causative agent of visceral leishmaniasis (VL). In leishmania-infected macrophages, (R)-PA-824 is 6-fold more active than (S)-PA- 824. Both des-nitro analogues are inactive, underlining the importance of the nitro group in the mechanism of action. Although the in vitro and in vivo pharmacological profiles of the two enantiomers are similar, (R)-PA-824 is more efficacious in the murine model of VL, with≥99% suppression of parasite burden when administered orally at 100 mg kg of body weight-1, twice daily for 5 days. In M. tuberculosis, (S)-PA-824 is a prodrug that is activated by a deazaflavin-dependent nitroreductase (Ddn), an enzyme which is absent in Leishmania spp. Unlike the case with nifurtimox and fexinidazole, transgenic parasites overexpressing the leishmania nitroreductase are not hypersensitive to either (R)-PA-824 or (S)-PA-824, indicating that this enzyme is not the primary target of these compounds. Drug combination studies in vitro indicate that fexinidazole and (R)-PA-824 are additive whereas (S)-PA-824 and (R)-PA-824 show mild antagonistic behavior. Thus, (R)-PA-824 is a promising candidate for late lead optimization for VL and may have potential for future use in combination therapy with fexinidazole, currently in phase II clinical trials against VL. Copyright
Substrate specificity of the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis responsible for the bioreductive activation of bicyclic nitroimidazoles
Gurumurthy, Meera,Mukherjee, Tathagata,Dowd, Cynthia S.,Singh, Ramandeep,Niyomrattanakit, Pornwaratt,Tay, Jo Ann,Nayyar, Amit,Lee, Yong Sok,Cherian, Joseph,Boshoff, Helena I.,Dick, Thomas,Barry III, Clifton E.,Manjunatha, Ujjini H.
, p. 113 - 125 (2012)
The bicyclic 4-nitroimidazoles PA-824 and OPC-67683 represent a promising novel class of therapeutics for tuberculosis and are currently in phase II clinical development. Both compounds are pro-drugs that are reductively activated by a deazaflavin (F420) dependent nitroreductase (Ddn). Herein we describe the biochemical properties of Ddn including the optimal enzymatic turnover conditions and substrate specificity. The preference of the enzyme for the (S) isomer of PA-824 over the (R) isomer is directed by the presence of a long hydrophobic tail. Nitroimidazo-oxazoles bearing only short alkyl substituents at the C-7 position of the oxazole were reduced by Ddn without any stereochemical preference. However, with bulkier substitutions on the tail of the oxazole, Ddn displayed stereospecificity. Ddn mediated metabolism of PA-824 results in the release of reactive nitrogen species. We have employed a direct chemiluminescence based nitric oxide (NO) detection assay to measure the kinetics of NO production by Ddn. Binding affinity of PA-824 to Ddn was monitored through intrinsic fluorescence quenching of the protein facilitating a turnover-independent assessment of affinity. Our results indicate that (R)-PA-824, despite not being turned over by Ddn, binds to the enzyme with the same affinity as the active (S) isomer. This result, in combination with docking studies in the active site, suggests that the (R) isomer probably has a different binding mode than the (S) with the C-3 of the imidazole ring orienting in a non-productive position with respect to the incoming hydride from F 420. The results presented provide insight into the biochemical mechanism of reduction and elucidate structural features important for understanding substrate binding.
Structure-activity relationships of antitubercular nitroimidazoles. 1. structural features associated with aerobic and anaerobic activities of 4 - And 5-nitroimidazoles
Kim, Pilho,Zhang, Liang,Manjunatha, Ujjini H.,Singh, Ramandeep,Patel, Sejal,Jiricek, Jan,Keller, Thomas H.,Boshoff, Helena I.,Barry III, Clifton E.,Dowd, Cynthia S.
supporting information; experimental part, p. 1317 - 1328 (2009/12/07)
The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis(Mtb)while 5-nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4 - and 5-nitroimidazoles and explor
