Alkaloids from Waltheria spp. (Malvaceae): Chemosystematic Aspects, Biosynthesis, Total Synthesis, and Biological Activities

Abstract

Waltheria, a genus within the Malvaceae family, is abundantly distributed in tropical and subtropical areas worldwide. Many species of this genus are widely utilized in various ways, including chewing, in folk medicine, acting as an anti-inflammatory agent, and treating gastrointestinal disorders, rheumatism, and asthma, among other conditions. These applications are largely due to their secondary metabolites, primarily quinolone alkaloids and cyclopeptides. Several biological activities have been reported for Waltheria species, including antifungal, anticancer, trypanocidal, acetylcholinesterase inhibitory, potential anti-HIV, antinociceptive, analgesic, anti-inflammatory, antibacterial, antioxidant, and leishmanicidal activities. This review not only presents information on isolated alkaloids and their biological activities but also delves into biosynthetic, chemosystematic, medicinal chemistry, and total synthesis aspects. Additionally, the manuscript highlights other applications of alkaloids of the genus, such as a study on their herbicidal activity, which shows significant potential for agricultural use.

Keywords: Waltheria; alkaloids; antidesmone; natural products; waltheriones.

Figure 1

Degradation reaction of the alkaloids melicopine (2), melicopidine (3), and melicopicine (4), resulting in the formation of 1-methyl-4-quinolone (5). The corresponding acid, 1-methyl-4-quinolone-3-carboxylic acid (1), represents the first compound in the quinolone group (Adapted from Crow and Price, 1949 [14]).

Figure 2

Examples of 4-quinolone alkaloids: phenyl-terminal open chain (waltherione G (6)), methyl-terminal open chain (antidesmone (7)), and cyclized (waltherione A (8)).

Figure 3

4-quinolone alkaloids melochinone (9) and melovinone (10).

Figure 4

Basic structure of cyclopeptide alkaloids (adapted from Gehm et al., 2022 [36]).

Figure 5

Pandamine (17) isolated from Panda oleosa (Pandaceae).

Scheme 1

Formation of the 4-quinolone nucleus (23) via anthranyl-CoA (18) and malonyl-CoA (19) (adapted from Dewick, 2009 [43]).

Scheme 2

Melochinone biosynthesis proposal (adapted from Kapadia et al., 1975 [17]).

Scheme 3

Antidesmone (7) biosynthesis (adapted from Bringmann et al., 2000 [19]).

Figure 6

Lasiodine A (38) (adapted from Marchand et al., 1969 [46]).

Scheme 4

Probable precursors of cyclopeptide alkaloids. Curved arrows (red) indicate probable formation of the macrocycle (adapted from Warnhoff, 1971; Bhat et al., 1987 [47,48]).

Figure 7

p-phenylenedialanine (42) and its dihydrogenated counterpart (43) (adapted from Schmidt et al., 1985 [49]).

Scheme 5

Kaufman and Larghi’s total synthesis of waltherione F (44).

Scheme 6

Kaufman and Larghi’s total synthesis of melovinone (10).

Scheme 7

Cox’s total synthesis of waltherione F (44).

Scheme 8

Pabbaraja and Mehta’s total synthesis of waltherione F (44).

Scheme 9

Nakagawa-Goto’s total synthesis of waltherione A (8).

Figure 8

Design strategy of the target compounds: 120 by the introduction of the ester group (orange) and pyrazole ring (lilac); compounds 121 and 122 by the introduction of an aromatic amide group (green); compounds 123 and 124 combining pyrazole ring (lilac) and piperazine-amide groups (yellow).

Figure 9

Design strategy of target compounds 125, 126, and 127 by the introduction of the acethydrazide group (pale pink) and varying the presence of methyl in the quinoline ring.