Pretomanid

Pretomanid

Names
IUPAC name (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine
Identifiers
CAS Number	187235-37-6
3D model (Jmol)	Interactive image Interactive image
ChEMBL	ChEMBL227875
ChemSpider	401693
MeSH	PA+824
PubChem	456199
InChI InChI=1S/C14H12F3N3O5/c15-14(16,17)25-10-3-1-9(2-4-10)7-23-11-5-19-6-12(20(21)22)18-13(19)24-8-11/h1-4,6,11H,5,7-8H2/t11-/m0/s1 Key: ZLHZLMOSPGACSZ-NSHDSACASA-N InChI=1/C14H12F3N3O5/c15-14(16,17)25-10-3-1-9(2-4-10)7-23-11-5-19-6-12(20(21)22)18-13(19)24-8-11/h1-4,6,11H,5,7-8H2/t11-/m0/s1 Key: ZLHZLMOSPGACSZ-NSHDSACABQ
SMILES [O-][N+](=O)c1cn2C[C@@H](COc2n1)OCc3ccc(OC(F)(F)F)cc3 C1[C@@H](COC2=NC(=CN21)[N+](=O)[O-])OCC3=CC=C(C=C3)OC(F)(F)F
Properties
Chemical formula	C14H12F3N3O5
Molar mass	359.258 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Pretomanid^[1] (PA-824) is an experimental anti-tuberculosis drug.^[2][3] Pretomanid is a bicyclic nitroimidazole-like molecule with a very complex mechanism of action. It is active against both replicating and hypoxic, non-replicating Mycobacterium tuberculosis. Microarray analysis of the mode of action of pretomanid showed a puzzling mixed effect both on genes responsive to cell wall inhibition (like isoniazid) and respiratory poisoning (like cyanide). The aerobic killing mechanism of this drug appears to involve inhibition of cell wall mycolic acid biosynthesis through an as yet unknown molecular mechanism.The respiratory poisoning through nitric oxide release seemed to be a crucial element of anaerobic activity by pretomanid. The effect of pretomanid on the respiratory complex under hypoxic non-replicating conditions was also manifested in a rapid drop in intracellular ATP levels, again similar to that observed by cyanide treatment.^[4] Pretomanid recently was shown to be safe, well tolerated, and efficacious at doses of 100–200 mg daily in a dose-ranging study among drug-sensitive, sputum smear–positive, adult pulmonary TB patients ^[5]

PA-824 was developed at Pathogenesis Corporation ^[6] and later transferred to the TB Alliance, where it is currently undergoing Phase III clinical trials. ^[7]

See also

• Tuberculosis treatment#Treatment of MDR-TB
• Delamanid, a related drug

References

1. "PA-824 has a New Generic Name: Pretomanid". Retrieved 12 March 2015.
2. Ginsberg AM, Laurenzi MW, Rouse DJ, Whitney KD, Spigelman MK (September 2009). "Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects". Antimicrob. Agents Chemother. 53 (9): 3720–5. doi:10.1128/AAC.00106-09. PMC 2737845. PMID 19528280.
3. Stover CK, Warrener P, VanDevanter DR, et al. (2000). "A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis". Nature. 405 (6789): 962–6. doi:10.1038/35016103. PMID 10879539.
4. Manjunatha U; Boshoff IM Helena; Barry CE (May–Jun 2009). "The mechanism of action of PA-824". Commun Integr Biol. 2 (3): 215–218. PMC 2717523. PMID 19641733.
5. "PA-824 | Pipeline Report". Retrieved 12 March 2015.
6. http://www.bloomberg.com/research/stocks/private/snapshot.asp?privcapId=343534. Retrieved 1 March 2015. Missing or empty |title= (help)
7. http://www.tballiance.org/. Retrieved 1 March 2015. Missing or empty |title= (help)