A series of biphenyl analogues of the new tuberculosis drug PA-824 was prepared, primarily by coupling the known (6S)-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-ol with iodobenzyl halides, followed by Suzuki coupling of these iodides with appropriate arylboronic acids or by assembly of the complete biaryl side chain prior to coupling with the above alcohol. Antitubercular activity was determined under both replicating (MABA) and nonreplicating (LORA) conditions. para-Linked biaryls were the most active, followed by meta-linked and then ortho-linked analogues. A more detailed study of a larger group of para-linked analogues showed a significant correlation between potency (MABA) and both lipophilicity (CLOGP) and the electron-withdrawing properties of terminal ring substituents ( summation operatorsigma). Selected compounds were evaluated for their efficacy in a mouse model of acute Mycobacterium tuberculosis infection. In vivo activity correlated well with the stability of compounds to microsomal metabolism. Three compounds bearing combinations of lipophilic, electron-withdrawing groups achieved >200-fold higher efficacies than the parent drug.

New heterocyclic analogues of the potent biphenyl class derived from antitubercular drug PA-824 were prepared, aiming to improve aqueous solubility but maintain high metabolic stability and efficacy. The strategy involved replacement of one or both phenyl groups by pyridine, pyridazine, pyrazine, or pyrimidine, in order to reduce lipophilicity. For para-linked biaryls, hydrophilicities (ClogP) correlated with measured solubilities, but highly soluble bipyridine analogues displayed weak antitubercular activities. A terminal pyridine or proximal heterocycle allowed retention of potency and provided solubility improvements, particularly at low pH, with examples from the latter classes displaying the better in vivo efficacies, high metabolic stabilities, and excellent pharmacokinetics. Five such compounds were >100-fold better than the parent drug in a mouse model of acute Mycobacterium tuberculosis infection, and two orally bioavailable pyridine analogues (3-4-fold more soluble than the parent at low pH) were superior to antitubercular drug OPC-67683 in a chronic infection model.

Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alternatively contact researchonline@lshtm.ac.uk.Available under license: http://creativecommons.org/licenses/by-nc-nd/2.5/ 7-Substituted 2-nitro-5,6-dihydroimidazo [2,1-b] [1,3] that was present in 6-nitroimidazooxazole 5. This was equivalent to a one carbon expansion of the oxazole ring between C-2 and C-3 ( Figure 2). The rationale for this design concept stemmed from initial evidence 21 that delamanid (5) was highly stable towards metabolism, as well as from a report 22 that 7-methyl derivatives of 6 retained excellent antitubercular potency, suggesting that such an approach merited investigation.Serendipitously, we soon discovered 23 that this novel "7-substituted oxazine" class not only showed considerable promise for TB (as later confirmed by others 24,25 ), it also displayed potent antileishmanial activity, comparable to the 6-nitroimidazooxazoles in early screening assays. Therefore, following the success with 4, this new series was similarly repositioned for VL as part of an extensive backup program, run in collaboration with DNDi. In this paper, we first highlight some critical VL hit to lead assessments on the original subset of compounds that had been prepared for TB. We then detail the findings of our lead optimisation study directed at developing backups to 4 having an improved physicochemical/pharmacological profile and better safety, which culminated in the selection of a new preclinical candidate for VL. Finally, in light of these encouraging results and the excellent activities of this novel 7-substituted 2-nitroimidazooxazine class against both TB and Chagas disease, we point to related analogues that might be worthy of further assessment for the latter applications. 5 CHEMISTRYIn order to rapidly access some initial examples, the racemic 7-H and 7-methyl alcohol intermediates, 13 and 20, were first sought (Scheme 1A). These could be obtained in very good overall yield (62-79%) via similar 5 step reaction sequences, starting with base catalysed alkylation of 2-bromo-4-nitroimidazole (8) For more efficient synthesis of 7-H biaryl analogues having a proximal 3-pyridine ring, an epoxide-opening strategy (Scheme 3A) was preferred over the Mitsunobu route described above. Epoxide 67 was obtained in 72% optimised yield from 2-chloro-4-nitroimidazole (40), via alkene 66; in this case, the slow epoxidation step was best achieved under non-buffered conditions at higher concentration (with initial cooling). Ring opening of 67 with 6-bromopyridin-3-ol (68) (K2CO3, MEK, 81-82 °C) gave mainly alcohol 69 (51% using 2 equiv for 35 h, or 57% from 4 equiv and 14 h), together with small amounts of the oxazine 70 (6-12%). Ring closure of purified 69 (NaH, DMF, 0-20 °C) then gave additional 70 in excellent 7 yield (91%). Comparable results were obtained for scale-up of 39 from 67 (62%), as well as for reaction of epoxide 42 with pyridinol 68 and ring closure, leading to oxazine 89 (Scheme 3D). As expected, br...