Development of Urea-Bond-Containing Michael Acceptors as Antitrypanosomal Agents Targeting Rhodesain

Abstract

Human African Trypanosomiasis (HAT) is a neglected tropical disease widespread in sub-Saharan Africa. Rhodesain, a cysteine protease of Trypanosoma brucei rhodesiense , has been identified as a valid target for the development of anti-HAT agents. Herein, we report a series of urea-bond-containing Michael acceptors, which were demonstrated to be potent rhodesain inhibitors with K i values ranging from 0.15 to 2.51 nM, and five of them showed comparable k 2nd values to that of K11777, a potent antitrypanosomal agent. Moreover, most of the urea derivatives exhibited single-digit micromolar activity against the protozoa, and the presence of substituents at the P3 position appears to be essential for the antitrypanosomal effect. Replacement of Phe with Leu at the P2 site kept unchanged the inhibitory properties. Compound 7 (SPR7) showed the best compromise in terms of rhodesain inhibition, selectivity, and antiparasitic activity, thus representing a new lead compound for future SAR studies.

Structure-based lead optimization of peptide-based vinyl methyl ketones as SARS-CoV-2 main protease inhibitors

“…With this approach, the peptide backbone was initially synthesized from C - to N -terminus, and the warheads were introduced in the last step ( Scheme 1 ). Indeed, the Weinreb amide at the C -terminal portion is well suited to be reduced in the corresponding aldehyde, which by Wittig reaction provided the desired final compounds, as we recently reported [ 38 ]. The commercially available ester 3 was hydrolyzed in alkaline conditions and the resulting acid 4 was coupled with N , O -dimethylhydroxylamine hydrochloride in the presence of TBTU and NMM as coupling reagent and base, respectively.…”

Next Generation of Fluorometric Protease Assays: 7‐Nitrobenz‐2‐oxa‐1,3‐diazol‐4‐yl‐amides (NBD‐Amides) as Class‐Spanning Protease Substrates

“…The authors have cited additional references within the Supporting Information [27,41,47,52–54,56,64–89] …”

Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis

“…After the purification, the ester portion of intermediates 3a-j was hydrolyzed with LiOH, and the inner salts 4a-j were obtained after crystallization and re-crystallization with 1 M HCl and from methanol, respectively. On the other hand, the hPhe-warhead fragment 8 was synthesized starting from commercially available Boc-hPhe-OH, which was coupled with N,O-dimethylhydroxylamine chloride as recently reported [56], and the Weinreb amide 5 was reduced yielding the corresponding aldehyde 6 using LiAlH 4 . The methyl vinyl ester portion was inserted by Wittig reaction using methyl (triphenylphosphoranylidene)acetate as reagent, and the subsequent Boc-removal with 30% TFA in DCM provided the hPhe-warhead portion 8 as trifluoroacetate.…”

“…13 (S)-2-((4-methoxybenzyl)ammonio)-3-phenylpropanoate (4c) 1 H NMR (500 MHz) in D 2 O, δ = 2.76 (dd, J = 13.5, 6.9 Hz, 1H), 2.82 (dd, J = 13.2, 6.8 Hz, 1H), 3.24 (t, J = 6.9 Hz, 1H), 3.34 (d, J = 12.4 Hz, 1H), 3.52 (d, J = 12.6 Hz, 1H), 3.57 (s, 3H), 6.72 (d, J = 8.6 Hz, 2H), 7.02 (d, J = 7.5 Hz, 2H), 7.13-7.07 (m, 3H), 7.17 (t, J = 7.2 Hz, 2H). 13 (S)-tert-butyl (1-(methoxyamino)-1-oxo-4-phenylbutan-2-yl)carbamate (5) The Weinreb amide 5 was obtained as we have recently reported [56].…”