Synthesis and Antibacterial Activity of Ficuseptine and Its Derivatives: Determination of Structure–Activity Relationships

Abstract

The indolizinium natural product ficuseptine, produced by the tropical fig tree Ficus septica, has been reported to have antibacterial properties. Herein, the synthesis of ficuseptine, ten analogues with differing aryl substituents, and two aryl regioisomers is reported. Despite several previous total syntheses, synthetically prepared ficuseptine has not been subjected to biological testing to confirm its activity. In our hands, ficuseptine was moderately active in Gram-positive B. spizizenii, with an MIC of 32 μg/mL, which was maintained for most aryl substituents. The position of the aryl rings was crucial, however, since regioisomeric ficuseptine analogues, mimicking related natural products, were found to be inactive. Finally, all ficuseptine derivatives were inactive (MIC >128 μg/mL) against Gram-negative E. coli. Understanding these structure–activity relationships (SAR) is helpful for future studies to understand the molecule’s mechanism of action or further develop its antibacterial properties.

Key word

alkaloids - antibiotics - natural products - pyridines - annulation - medicinal chemistry

Publication History

Received: 15 August 2024

Accepted after revision: 27 November 2024

Accepted Manuscript online:
27 November 2024

Article published online:
13 December 2024

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• 27 Ficuseptine (1a): In a 250 mL pressure tube, 4-methoxyphenylacetaldehyde 6a (1.27 g, 8.5 mmol, 2.1 equiv) was dissolved in acetic acid (40 mL, 0.1 M) before 4-aminobutanal dimethyl acetal (0.57 mL, 4.0 mmol, 1.0 equiv) was added. The pressure tube was sealed and heated to 95 °C for 2 days before cooling to rt. 15% NaOH (aq) was added until pH >7 before the solution was transferred to a separatory funnel with Et₂O. The layers were separated and the organic layer was discarded. NaCl was added to the aqueous layer until saturated, and the mixture was extracted five times with CHCl₃. The combined organic layers were dried over anhydrous CaCl₂, filtered, and concentrated. Purification by column chromatography (Biotage® Sfär 25 g cartridge, 3–30% MeOH in CH₂Cl₂) yielded 170 mg 1a (12%) as a brown solid. ¹H NMR (500 MHz, CDCl₃): δ = 10.10 (s, 1 H), 8.16 (s, 1 H), 7.81 (d, J = 9.0 Hz, 2 H), 7.46 (d, J = 8.9 Hz, 2 H), 7.06 (d, J = 8.8 Hz, 2 H), 6.97 (d, J = 8.9 Hz, 2 H), 5.46 (t, J = 7.6 Hz, 2 H), 3.88 (s, 3 H), 3.78 (s, 3 H), 3.57 (t, J = 7.5 Hz, 2 H), 2.54 (p, J = 7.4 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.2, 160.9, 152.9, 140.1, 138.9, 138.1, 138.0, 129.8, 128.9, 126.6, 125.1, 115.1, 114.8, 60.3, 55.5, 55.4, 32.4, 22.3. HRMS: m/z [M]⁺ calcd for C₂₂H₂₂NO₂ ⁺: 332.1651; found: 332.1646.