Structure–Activity Relationships for Amide-, Carbamate-, And Urea-Linked Analogues of the Tuberculosis Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

Abstract

Analogues of clinical tuberculosis drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824), in which the OCH(2) linkage was replaced with amide, carbamate, and urea functionality, were investigated as an alternative approach to address oxidative metabolism, reduce lipophilicity, and improve aqueous solubility. Several soluble monoaryl examples displayed moderately improved (∼2- to 4-fold) potencies against replicating Mycobacterium tuberculosis but were generally inferior inhibitors under anaerobic (nonreplicating) conditions. More lipophilic biaryl derivatives mostly displayed similar or reduced potencies to these in contrast to the parent biaryl series. The leading biaryl carbamate demonstrated exceptional metabolic stability and a 5-fold better efficacy than the parent drug in a mouse model of acute M. tuberculosis infection but was poorly soluble. Bioisosteric replacement of this biaryl moiety by arylpiperazine resulted in a soluble, orally bioavailable carbamate analogue providing identical activity in the acute model, comparable efficacy to OPC-67683 in a chronic infection model, favorable pharmacokinetic profiles across several species, and enhanced safety.

SOLID SiO2-H3PO4 IS AN EFFICIENT CATALYST FOR CYCLIZATION OF ENONES UNDER SOLVENT-FREE CONDITION: SYNTHESIS AND ANTIMICROBIAL ACTIVITIES OF SOME OXAZINE DERIVATIVES

“…Griseofulvin has been taken as the standard drug. The observed antifungal activities of all all 4-(1-naphthyl)-5,6-dihydro-6-(substituted phenyl)-oxazine-2-amines (entries [11][12][13][14][15][16][17][18][19][20][21][22][23] were presented in Table 6 …”

“…These oxazines were medicinally important due to the presence of oxygen, nitrogen heteroatoms along with a double bonds in their structural moieties 3 . The important medicinal activities of these oxazines are anti-bacterial, antifungal [3][4][5] , anti-plasmodial 6 , anti-cancer 7 , anti-depressants 8 , cytotoxicity 9 , anti-osteoplastic 10 , anti-tumour 11 , anti-oxidant 12 , anti-tuberculosis 13 , antineoplastic 14 , antagonists 15 , anti-inflammatory 16 , anti-infectants 17 , IKB kinase beta 18 and PTP-1B inhibition 19 . These oxazine derivatives were applied for improving the super resolution microscope 20 , synthesis of eosinophils 21 , identification and separation of neutrophils 22 .…”

Hydroxyapatite catalyzed cyclization of aryl enones: Solvent-free efficient synthesis of some 4-aryl-5,6-dihydro- 6-(substituted phenyl)-4H-1,3-oxazine-2-amines

“…These oxazines were medicinally important due to the presence of oxygen, nitrogen heteroatoms along with a double bonds in their structural moieties [4]. The important medicinal activities of these oxazines are anti-bacterial, anti-fungal [4][5][6], anti-plasmodial [7], anti-cancer [8], anti-depressants [9], cytotoxicity [10], anti-osteoplastic [11], anti-tumour [12], anti-oxidant [13], anti-tuberculosis [14], anti-neoplastic [15], antagonists [16], antiinflammatory [17], anti-infectants [18], IKB kinase beta [19] and PTP-1B inhibition [20]. These oxazine derivatives were applied for improving the super resolution Microscope [21], synthesis of eosinophils [22], identification and separation of neutrophils [23].…”

Aryl Chalcones as Efficient Precursors for Deriving Oxazine: Solvent-Free Synthesis and Antimicrobial Activities of some Oxazine-2-amines

“…The important medicinal activities of these oxazines are anti-bacterial [2][3][4], anti-fungal [2][3][4], antiplasmodial [5], anti-cancer [6], anti-depressants [7], cytotoxicity [8], anti-osteoplastic [9], anti-tumour [10], anti-oxidant [11], anti-tuberculosis [12], anti-neoplastic [13], antagonists [14], anti-inflammatory [15], anti-infectants [16], IKB kinase beta [17] and PTP-1B inhibition [18].…”