Bicyclic peptidomimetics targeting secreted aspartic protease 2 (SAP2) from Candida albicans reveal a constrained inhibitory chemotype

Identification of constrained peptidomimetic chemotypes as HIV protease inhibitors

“…A further hydrogenebonding interaction was established between the hydroxyl group of the alaninol moiety and the side chain of Asp30. Interestingly, hydrogenbonding at position 2 of the scaffold with the flap region of the protease was in agreement with similar binding mode found for hit compounds of this library towards Sap2 protease [21], confirming a structural similarity between the two aspartic proteases.…”

“…This approach enabled the development of tripeptide mimetics by introducing an additional side-chain analogue at position 3 of the scaffold. Accordingly, compounds 1À3 and 56À71 (Table 2) were obtained using leucine, norleucine and isoleucine methyl esters as the starting materials to build the bicyclic scaffold, as previously reported [20,21] (Scheme 1). Further manipulation of diesters E or F allowed for introducing an additional aliphatic moiety by amidation of the a-amino acid moiety at position 3 of the scaffold (Scheme 1).…”

“…demonstrated this class of bicyclic peptidomimetics being useful as a new template for the development of HIV-1 protease inhibitors. Compound 30, which was selected as a hit Sap2 inhibitor for the treatment of C. albicans infections [20,21], possessed inhibition capability also towards the viral enzyme. It is worth nothing the discrepant inhibitory activities of compounds 25 and 30.…”

“…-yl)-2-oxo-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-carboxylate (Est-70) was obtained as a yellow solid from isoleucine methyl ester and D-tartaric acid derivative, as reported[20,21] 1. H NMR (400 MHz, CDCl 3 ) d 5.93 (s, 1H), 4.95 (s, 1H), 4.90 (d, J ¼ 10.7 Hz, 1H), 4.69 (s, 1H), 3.79 (s, 3H), 3.72 (s, 3H), 3.63 (dd, J ¼ 12.4, 2.2 Hz, 1H), 3.19 (d, J ¼ 12.4 Hz, 1H), 2.00e1.93 (m, 1H), 1.38e1.30 (m, 1H), 1.09e1.00 (m, 1H), 0.94e0.86 (m, 6H) ppm.…”

“…ppm. ESI-MSMS m/z (ES þ ) 369.24 [(Mþ1) þ , 14.9], 337.02 [ 93.00], 318.94 [100], 308.93 [45.7], 290.Est-65) was obtained as a yellow solid from isoleucine methyl ester and L-tartaric acid derivative, as reported[20,21]. 1 H NMR (400 MHz, CDCl 3 ) d 5.93 (d, J ¼ 1.9 Hz, 1H), 4.95 (s, 1H), 4.88 (d, J ¼ 10.7 Hz, 1H), 4.70 (s, 1H), 3.79 (s, 3H), 3.71 (s, 3H), 3.52 (d, J ¼ 12.2 Hz, 1H), 3.37 (dd, J ¼ 12.2, 2.4 Hz, 1H), 1.97e1.89 (m, 1H), 1.45e1.35 (m, 1H), 1.11e1.02 (m, 1H), 0.95e0.88 (m, 6H) ppm.…”