Synthesis and Biological Activities of (4-Arylpiperazinyl)piperidines as Nonpeptide BACE 1 Inhibitors

Poojary, Boja; Won, Sun-Woo; Suh, Dong Hoon; Chu, Jeonghyun; Park, Woo Kyu; Lim, H.

doi:10.5012/bkcs.2011.32.4.1249

Cited by 8 publications

(8 citation statements)

References 16 publications

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“…As noted above, phenylpiperazine and phenylpiperidine are soluble bioisosteres for biphenyl, and these moieties are now appearing in many new drug candidates. 60,61 Here, 57 and 58 were respectively 61and 11-fold more soluble than 8 at neutral pH and formed nicely soluble hydrochloride salts at low pH (19−23 mg/mL), in line with their calculated pK a values of 5.9 and 7.3. Finally, on the basis of previous success with an arylpiperazine carbamate analogue of 4 for TB, 41 carbamate 59 was studied, but the additional carboxy group proved detrimental for VL (8.5-fold potency loss).…”

Section: ■ Chemistrysupporting

confidence: 72%

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

et al. 2016

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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

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Section: ■ Chemistrysupporting

confidence: 72%

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

et al. 2016

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“…More structurally diverse targets ( 142 , 144 , 147 , 149 , 152 , 154 , 157 , 159–161 , 170 , and 178 ; Table 2 ) were designed on the premise that arylated cyclic amines can be effective bioisosteres for biphenyls, thus facilitating substantial boosts in solubility. 51 , 52 Several side chains of this type have previously shown promise for TB and/or VL, 11 , 18 including in the recent development of antileishmanial aminopyrazole ureas. 53 It was initially encouraging to see four examples (arylpiperazine 142 , aryloxypiperidines 152 and 154 , and arylpiperazine carbamate 161 ) exhibiting reasonable potencies in the L. don screen (IC 50 s 0.19–0.45 μ M), with 142 and 152 displaying a markedly better solubility profile than 49 (10–49 μ g/mL at pH 7, 15–21 mg/mL at low pH).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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

et al. 2017

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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...

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“…Conversion of the bromobenzophenone 137 51 into the novel methyl congener 138 (94% by Negishi coupling with dimethylzinc 52 ) enabled access to the simple benzophenone derivative 60, following free-radical bromination and reaction of chiral alcohol 95 with the crude bromide product mixture (mostly 139) under the standard alkylation conditions (Scheme Subsequent bromination of the derived alcohol 155 required more forcing conditions (concd HBr, 80 °C, 16 h), but reaction of the crude (dried) bromide 156 with alcohol 95 was surprisingly effective (53% yield over 2 steps). Methylation of this coupled product (70) (MeI/K 2 CO 3 /acetone) also provided the tertiary amine derivative (71) in good yield (68%). Synthesis of related aryloxymethyl compounds (72,73) and substituted benzyloxybenzyl analogue 75 commenced by alkylation of substituted phenols [or 6-(trifluoromethyl)pyridin-3-ol] with bromides 91 or 166, respectively, while a pyridine analogue (74) was built up using a high-yielding Mitsunobu reaction on the known 55 monoprotected diol 162 (Scheme 5C,D).…”

Section: ■ Chemistrymentioning

confidence: 99%

Synthesis and Structure–Activity Relationships for Extended Side Chain Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

et al. 2015

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Novel extended side chain nitroimidazooxazine analogues featuring diverse linker groups between two aryl rings were studied as a potential strategy to improve solubility and oral activity against chronic infection by Mycobacterium tuberculosis. Both lipophilic and highly polar functionalities (e.g., carboxamide, alkylamine, piperazine, piperidine, but not sulfonamide) were well tolerated in vitro, and the hydrophilic linkers provided some solubility improvements, particularly in combination with pyridine rings. Most of the 18 compounds further assessed showed high microsomal stabilities, although in the acute infection mouse model, just one stilbene (6-fold) and two pyridine-containing acetylene derivatives (5-fold and >933-fold) gave in vivo efficacies notably superior to the clinical stage compound pretomanid (PA-824). The most efficacious analogue also displayed outstanding in vivo activity in the stringent chronic model (up to 24-fold better than the drug delamanid and 4-fold greater than our previous best phenylpyridine candidate), with favorable pharmacokinetics, including good oral bioavailability in the rat.

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Synthesis and Biological Activities of (4-Arylpiperazinyl)piperidines as Nonpeptide BACE 1 Inhibitors

Cited by 8 publications

References 16 publications

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

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

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

Synthesis and Structure–Activity Relationships for Extended Side Chain Analogues of the Antitubercular Drug (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)

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