Synthesis and Antibacterial Analysis of Analogues of the Marine Alkaloid Pseudoceratidine

Abstract

In an effort to gain more understanding on the structure activity relationship of pseudoceratidine 1, a di-bromo pyrrole spermidine alkaloid derived from the marine sponge Pseudoceratina purpurea that has been shown to exhibit potent biofouling, anti-fungal, antibacterial, and anti-malarial activities, a large series of 65 compounds that incorporated several aspects of structural variation has been synthesised through an efficient, divergent method that allowed for a number of analogues to be generated from common precursors. Subsequently, all analogues were assessed for their antibacterial activity against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. Overall, several compounds exhibited comparable or better activity than that of pseudoceratidine 1, and it was found that this class of compounds is generally more effective against Gram-positive than Gram-negative bacteria. Furthermore, altering several structural features allowed for the establishment of a comprehensive structure activity relationship (SAR), where it was concluded that several structural features are critical for potent anti-bacterial activity, including di-halogenation (preferable bromine, but chlorine is also effective) on the pyrrole ring, two pyrrolic units in the structure and with one or more secondary amines in the chain adjoining these units, with longer chains giving rise to better activities.

Syntheses and Preliminary Biological Evaluations of the Dibromopyrrole‐Containing Marine Natural Products Agesasine A, Agesasine B, Longamide E and Various Congeners

“…The outcomes of the preliminary biological evaluations of the compounds ( S )‐ 1 , ( R )‐ 1 , (±)‐ 1 , ( S )‐ 2 , ( R )‐ 2 , (±)‐ 3 to (±)‐ 6 , (±)‐ 11 to (±)‐ 15 , 16 , (±)‐ 22 , (±)‐ 28 , (±)‐ 29 , (±)‐ 30 and (±)‐ 31 presented in the preceding section reveals an interesting structure activity relationship profile for a significant cross‐section of the family of bromopyrrole‐containing marine natural products. These results reinforce the notion that this scaffold represents something of a privileged structure for the purposes of drug development [7–13] . Again, our work in this area is ongoing and results will be reported in due course.…”

“…Each of these was obtained as a solid and the derived spectral data were not only consistent with the assigned structures but also matched those reported [3] for agesasine A (1). A tabulated comparison of the 13 C{ 1 H} NMR spectral data recorded on the naturally-and synthetically-derived samples of compound (�)-1 is provided in Table 1 below.…”

“…The present route to amide (�)-6 differs from that recently reported by Savic and coworkers [15] who employed a metal-catalyzed cyclization of a proline-derived allene to generate longamide B and thence stylisine D. The spectral data acquired on all these products were in complete accord with the assigned structures and in the case of product (�)-4 matched those reported [14] in our previous study. A comparison of the spectral data acquired on compound (�)-5 with those reported [4] for the natural product longamide F also proved a good match as evident in the comparison of the 13 C { 1 H} NMR data sets shown in Table 5. The same was true for stylisines D/E and compound (�)-6 (see, for example, Table 6).…”

“…A further motivation for undertaking this work was that a number of bromopyrrole alkaloids have served as the inspiration for various drug development programs including ones focused on identifying and optimizing inhibitors of PIM kinases, [7] indoleamine 2,3‐dioxygenase [8] and Aurora B kinase [9] . Others have served as starting points for the development of anti‐fungal agents, [10] the identification of antiprotozoal drugs, [11] of anti‐fouling agents, [12] and of anti‐microbial agents [13] …”

“…[9] Others have served as starting points for the development of anti-fungal agents, [10] the identification of antiprotozoal drugs, [11] of anti-fouling agents, [12] and of anti-microbial agents. [13]…”