Secondary Metabolites in Haplophyllum tuberculatum (Forssk.) A. Juss and Their Biological Significance: A Comprehensive Review

Haplophyllum tuberculatum (Forssk.) A. Juss, a perennial herb of the family Rutaceae, is a medicinally important plant widely distributed across North Africa, the Middle East, and Southwest Asia. It has been extensively used in traditional medicine systems for the treatment of malaria, arthritis, headaches, parasitic infections, and gynecological disorders. The plant is phytochemically rich, producing a diverse array of secondary metabolites including quinoline alkaloids, furoquinoline alkaloids, isoquinoline alkaloids, acridone alkaloids, arylnaphthalene lignans, furanocoumarins, flavonoids, phenolic compounds, terpenoids, saponins, amides, and volatile terpenoids in its essential oils. These secondary metabolites exhibit a broad spectrum of pharmacological activities encompassing antioxidant, antimicrobial, antifungal, antiprotozoal, anti-inflammatory, antidiabetic (α-glucosidase inhibition), anticancer, antiviral, and insecticidal effects. Recent studies have isolated three novel alkaloids from Omani H. tuberculatum as competitive α-glucosidase inhibitors with IC₅₀ values as low as 2.28 µM, significantly exceeding the standard drug acarbose. Lignans such as justicidin A, justicidin B, and tuberculatin have shown potent antiprotozoal activity against Leishmania donovani, Trypanosoma brucei, and Plasmodium falciparum. Essential oils characterized by GC-MS show β-caryophyllene, β-phellandrene, limonene, and myrcene as dominant volatiles with confirmed antifungal and insecticidal properties. This review compiles and critically analyses the current state of knowledge on secondary metabolites of H. tuberculatum and their documented biological significance, highlighting research gaps and future prospects for drug discovery.