Cyclopeptide alkaloids from the Greek shrub <i>Paliurus spina</i>-<i>christi</i> and their <i>in silico</i> binding affinity to Dipeptidyl Peptidase IV

A new cyclopeptide alkaloid, spinachristene A (1), along with two previously described, sanjoinenine (2) and oxyphylline C (3), were isolated from the fruits of Paliurus spina-christi Mill. All three metabolites are being isolated for the first time from the genus Paliurus. A model for the in silico binding affinity of compounds 1-3 to Dipeptidyl Peptidase IV (DPP4), which is related to type 2 diabetes (T2D), was developed. According to our model, compounds 1-3 were ranked in positions 9/12, 11/12 and 8/12, respectively and are predicted to exhibit significant affinity to DPP4, in the range of low 2-digit μΜ.</p

Novel Lipophilic Acetohydroxamic Acid Derivatives Based on Conformationally Constrained Spiro Carbocyclic 2,6-Diketopiperazine Scaffolds with Potent Trypanocidal Activity

We describe novel acetohydroxamic acid derivatives with potent activity against cultured bloodstream-form <i>Trypanosoma brucei</i> and selectivity indices of >1000. These analogues were derived from conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds by attaching acetohydroxamic acid moieties to the imidic nitrogen. Optimal activity was achieved by placing benzyl groups adjacent to the basic nitrogen of the 2,6-DKP core. <i>S</i>-Enantiomer <b>7d</b> was the most active derivative against <i>T. brucei</i> (IC₅₀ = 6.8 nM) and <i>T. cruzi</i> (IC₅₀ = 0.21 μM)

EC₅₀ against LACV and ZIKV replication.

EC50 against LACV and ZIKV replication.</p

Representative structures of RFVF inhibitors.

(A) Inactive and active troponoid natural products, illustrating preference for oxygen triad, along with common nuclease inhibition mode for αHTs. (B) Synthetic αHTs with activity under 10 μM against RVFV, demonstrating broad substitution tolerance. (C) Representative examples of alternative scaffolds with activity against RFVF.</p

Antiviral effect of compounds on bunyavirus replication.

Vero cells were infected with either RVFV ZH501 (A) or LACV (B) then treated with decreasing concentrations of antiviral compound. Viral growth was measured by FFA. Data represents three independent experiments completed with biological replicates. Error bars represent standard deviation.</p

EC₅₀ against RVFV replication.

EC50 against RVFV replication.</p

Top antiviral hits.

Top antiviral hits.</p

Experimental methods for compound generation and validation of compounds.

(PDF)</p

EC₅₀ value against RVFV.

(XLSX)</p

Structures of all confirmed hit compounds.

(PDF)</p