Repositioning Antitubercular 6-Nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazoles for Neglected Tropical Diseases: Structure–Activity Studies on a Preclinical Candidate for Visceral Leishmaniasis

Abstract

Phenotypic screening of representative examples against kinetoplastid diseases unexpectedly led to the identification of DNDI-VL-2098 as a potential first-in-class drug candidate for visceral leishmaniasis (VL). Additional work was then conducted to delineate its essential structural features, aiming to improve solubility and safety without compromising activity against VL. While the 4-nitroimidazole portion was specifically required, several modifications to the aryloxy side chain were well tolerated e.g., exchange of the linking oxygen for nitrogen (or piperazine), biaryl extension, and replacement of phenyl rings by pyridine. Several less lipophilic analogues displayed improved aqueous solubility, particularly at low pH, although stability towards liver microsomes was highly variable.Upon evaluation in a mouse model of acute Leishmania donovani infection, one phenylpyridine derivative (37) stood out, providing efficacy surpassing that of the original preclinical lead.3

7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis

“…Here, new synthesis was directed at the optimisation of solubility, efficacy, and safety, primarily through the incorporation of heterocycles to reduce compound lipophilicity 11 (estimated by CLogP data derived from ACD LogP/LogD software, version 12.0; Advanced Chemistry Development Inc., Toronto, Canada). Kinetic aqueous solubility measurements were conducted on dry powder forms of particular examples that were being considered for further evaluation.…”

“…40 Assessments of cytotoxicity were concurrently conducted on both human lung fibroblasts (MRC-5 cells; the host for T. cruzi) and primary peritoneal mouse macrophages (the host for L. inf), which revealed that the compounds were generally nontoxic (MRC-5 IC50s >55 µM except for 117: IC50 35 µM), as confirmed for TB (VERO assay 41 IC50s >128 µM for 71 of 72 compounds). Table 3) was not notable in comparison to the results for rac-4 (99% at 6.25 mg/kg), 11 suggesting that further optimisation of the side chain would be necessary. Indeed, while 28 showed good stability on exposure to mouse liver microsomes (MLM: 75% remaining after 1 h, Table 3) and gave a mouse pharmacokinetic (PK) profile comparable to rac-4 (Table 4 and Supporting Information, Figures S1 and S2), it was very hydrophobic (CLogP 5.14) and displayed poor solubility (~58 ng/mL at pH 7, Table 3; 62-fold lower than for rac-4 11 ).…”

“…These featured two design elements that had proven most advantageous for enhancing in vivo efficacy in early studies of 4 and 6, namely, biaryl extension, and methylation adjacent to the ring oxygen. 11,30,58 From this larger dataset, it was observed that 7-methyl congeners (e.g., 21, 23, 44, and 47)…”

“…10, 11 Our opening assignment with TB Alliance had been to prepare and evaluate novel nitroheterobicyclic analogues of the tuberculosis (TB) drugs delamanid (5) and pretomanid (PA-824, 6), 12,13 seeking a possible third active scaffold for the construction of a backup series. However, amongst the fused 5/6 ring systems examined, only the metabolically labile 2-nitroimidazothiazines retained significant antitubercular potency, 14 returning our attention to the original oxazine class where we uncovered heterobiaryl derivatives of 6 with better efficacy (e.g., TBA-354, 7).…”

Development of a Scalable Process for the Synthesis of DNDI-VL-2098: A Potential Preclinical Drug Candidate for the Treatment of Visceral Leishmaniasis

“…The Auckland medicinal chemistry group had synthesized multigram quantities of the racemate using a route shown in Scheme 1 that had been employed in initial work at the University of Auckland. 4 Pure enantiomers needed for preliminary efficacy and pharmacokinetic evaluation were prepared at the University of Auckland using a route similar to that shown in Scheme 2 below, but using 2-chloro-4-nitroimidazole in place of 2-bromo-4-nitroimidazole in step 3. This route was based on methods published by Otsuka Pharmaceuticals 5 for the synthesis of analogues of 2 .…”