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. 2025 Jul 3;16(9):3959–3981. doi: 10.1039/d5md00473j

Unveiling the therapeutic potential of prenyl motif-containing derivatives: a key structural fragment for designing antidepressant compounds

Md Jawaid Akhtar a,✉, Khalid Al Balushi a, Bushara Al Sabahi a, Shah Alam Khan a, Afrah Al Tamimi a
PMCID: PMC12264708  PMID: 40677840

Abstract

Depression is a complex mental disorder, and consequently, the successful treatment of the depressive disorder remains challenging. The available medications often show limitations in terms of both safety and efficacy. In this case, the presence of the prenyl motif in pharmaceutical compounds has resulted in a broad spectrum of biological activities. Various studies have highlighted that the potent antidepressant activity of many natural compounds is associated with the presence of the prenyl motif. Thus, some studies have attempted to prepare prenyl fragment derivatives with the aim of enhancing their hydrophobicity and developing promising antidepressant compounds. Prenyl motif-containing compounds exhibit antidepressant action via multiple mechanisms, including selective serotonin/norepinephrine reuptake inhibition, blocking of NMDA receptors, 5-HT6 antagonism, TREK-1 inhibition, MAO-A inhibition, and anti-inflammatory and antioxidant properties. This review presents synthetic derivatives of xanthones, flavonoids, and chalcones bearing prenyl groups. It also covers polyprenylated benzoyl phloroglucinols/acylphloroglucinols, naphthoquinones, volatile oils, tricyclic products, and steroidal saponins containing prenyl motifs. This study aims to further guide and support medicinal chemists in directing the synthesis of more potent compounds possessing prenyl fragments as antidepressants, thus advancing treatment options for depression.

The role of the prenyl motif in coumarins, xanthones, flavonoids, polyprenylated acyl/benzoyl-phloroglucinols, naphthoquinones, volatile oils, resveratrol and steroidal saponin derivatives as antidepressants.graphic file with name d5md00473j-ga.jpg

1. Introduction

Depression, also known as major depressive disorder (MDD), is the most common form of mental illness. It is one of the common social problems worldwide and encompasses a variety of physical, social, and emotional problems.1 It is associated with the loss of pleasure, persistent sadness, and an increased risk factor for suicide.2 It is estimated that 3.8% of the population experiences depression, with approximately 280 million people affected, and over 700 000 people dying by suicide annually.3,4 Depression ranks among the top 10 diseases causing morbidity and mortality, affecting approximately 20% of the global population. It involves neuroprogression with stage-related neurodegeneration, cell death, reduced neurogenesis and neuronal plasticity, and increased autoimmune responses.5

A deficiency in endogenous monoamines such as noradrenaline and serotonin (5-HT) is the main cause of depression.2 The oxidation of monoamines such as dopamine (DA) and norepinephrine (NE) by monoamine oxidase (MAO) results in increased generation of free radicals, which decrease the release of glutamate and DA.6 The monoamine hypothesis plays an important role in the treatment of major depressive disorder. Monoamines such as selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are recommended for initial treatment but have certain disadvantages, viz., onset is delayed, one third of patients do not respond to even up to four antidepressants, and nearly 70% relapse in cases. Other conventional methods to target the nervous system implicated in depression include modulation of the neuroendocrine system such as the gamma aminobutyric acid (GABA), adrenergic, dopaminergic and serotonergic systems. Clinical and experimental evidence has shown that antidepressants influence the immune system by reducing pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β. However, the direct link between cytokine (proinflammatory) levels and antidepressant action remain debatable.7 Ketamine and (S)-ketamine, which are N-methyl-d-aspartate receptor (NMDA) antagonists, have demonstrated effectiveness in treating resistant depression. Other classes such as muscarinic receptor antagonists, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor modulators, psychedelic, metabotropic glutamate receptor antagonists, and γ-aminobutyric acid type A receptor modulators are rapid-acting antidepressants, but many compounds failed to show benefits in phase II and III clinical trials.8

Antidepressants are one of the most frequently prescribed drugs. However, currently available therapies are associated with numerous undesirable side-effects such as insomnia and severe withdrawal syndrome, and their effectiveness is limited to specific population groups.6,9 These drugs are not fully metabolized in the human body and either the free parent molecules or their metabolites are excreted in the environment, resulting in an adverse ecotoxicological impact. Furthermore, the improper disposal of expired and unused antidepressants releases toxic compounds into wastewater, negatively impacting aquatic life.10 Also, long treatment and low response to the therapy lead to the development of resistance to the antidepressant treatment. Thus, it is necessary to develop novel therapeutics to treat the severe types of depression. In this case, the use of natural products and inclusion of abundant natural drug pharmacophores/structural motifs in the modified structure of synthesized compounds are strategies for novel drug discovery and development. Conversely, some natural motifs can be structural alerts or toxicophoric. However, their usefulness outweighs their toxicity. Therefore, the inclusion of natural pharmacophores in synthetic derivatives is important for the development of potent molecules. The prenyl group is an important structural fragment abundantly found in natural compounds, which has different biological activities and potential benefits to human health.11 Prenylation is one way for the covalent addition of hydrophobic moieties to chemical compounds or proteins. The addition of the prenyl group to alkaloids, flavonoids and terpenoids adds functionalities and leads to diverse functions. The demand for new drugs has ushered in a new area for discovery by the prenylation of natural and synthetic products.12 Generally, the consensus is that the prenylation of proteins increases their affinity and binding.13 This review focuses on natural and synthetic drugs that have a prenyl motif and exhibit promising antidepressant activity. Also, the importance of the presence of this natural pharmacophore motif in the development of synthesized derivatives are discussed, together with their structure activity relationship (SAR). This review can further support drug design approaches for the development of more potent antidepressant compounds.

2. Mechanism of antidepressant compounds

The development of novel antidepressants relies on new targets such as glutaminergic systems other than monoaminergic systems. Glutamate is one of the excitatory neurotransmitters in the central nervous system (CNS) and its receptors are divided into two groups, i.e., ionotropic including NMDA, AMPA and kainate receptors, and metabotropic glutamate (mGlu), which can transduce synaptic transmission via second messenger signalling pathways. Metabotropic glutamate is a 7 transmembrane and G-protein coupled receptor (GPCR) and represents a major target for a wide range of neurological and psychiatric disorders.14 NMDA functions as glutamate gated with high calcium ion permeability. It plays a role in learning, memory, and neuroplasticity processes, besides the development of the central nervous system and maintenance of breathing rhythm and locomotion. Consequently, the excessive abnormal expression of NMDA receptors is involved in various neurological disorders such as stroke, hypoxia, head, trauma, anxiety, depression, Huntington's, Alzheimer's, and Parkinson's disease.15 Accordingly, NMDA receptors are therapeutics targets for the treatment of these diseases.16

Ketamine was introduced as anaesthetic agent but later emerged as a treatment for major depressive disorders.17 The mechanism of action of ketamine relies on blocking NMDA receptors on the GABA neurons or the extra synapse of glutaminergic systems, thus indirectly stimulating the AMPA receptors. This increases the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B signalling (TrkB) and further activates mTOR and increases synaptogenesis. The (2R,6R)-hydroxynorketamine metabolite of ketamine does not bind to the NMDA receptors, and thus is devoid of side effects. It increases the release of glutamate from the collateral afferent CA1 projection of Schaffer in the hippocampus and leads to the continuous activation of the AMPA receptors.18 The mechanism of ketamine inhibition is represented in Fig. 1.18 The amino acid sequence in NMDA is very similar to that in the glutamate receptor AMPA. mTOR binds with different proteins and promotes cell maturation, growth, and maintenance. Also, it is involved in synaptic plasticity, spine morphology, and maintenance of the size, shape, and neuron dendritic arrangement. mTOR responds to several types of stress. Decreased phosphorylation of the mTOR in the hippocampus, amygdala, and prefrontal cortex in rodents has been observed with chronic unpredictable stress. The knockdown of mTOR resulted in a depressive-like state in mice. Monoaminergic antidepressants such as fluvoxamine, tranylcypromine, paroxetine, and escitalopram also cause the mTOR phosphorylation and phosphorylation of upregulators such as ERK and AKT in rat stress models. It has also been demonstrated that the decreased phosphorylation of mTOR in the prefrontal cortex, hippocampus and amygdala in the rodents is associated with depression-like behaviour. Clinical studies have also shown that decreased mTOR phosphorylation is associated with major depressive disorder.19

Fig. 1. Excessive glutamate causes neurotoxicity. 1Ketamine-caused AMPA activation promotes adenosine release, which binds to the adenosine receptors present in the presynaptic neuron and blocks the release of glutamate. 2Ketamine post-synaptically inhibits the NMDA receptors and blocks the eukaryotic elongation factor 2 (eEF2)-mediated inhibition of BDNF synthesis. 3Ketamine blocks the NMDA receptors present in the GABAergic neuron, and hence promotes the release of glutamate, which binds to the AMPA receptors, increases the release of Ca2+, and activates the BDNF/TrkB pathway.18.

Fig. 1

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3. Advancement in prenyl-containing antidepressant compounds

3.1. Coumarin derivatives

Prenyl group-containing coumarin derivatives possess several biological activities. Coumarin rings with prenyl groups, i.e., ammoresinol; 1, and ostruthin; 2, exhibit potent antimicrobial action.20,21 The drug imperatorin; 3, showed anti-inflammatory activity against chondrocytes, inhibiting the expression of iNOS and decreasing the production of NO in osteoarthritic chondrocytes.22 Pyranocoumarins containing compounds such as grandivitin: 4, and agasyllin: 5, isolated from the roots of Ferulago campestris from the Apiaceae family, showed antioxidant activity by expressing their effect against human whole blood leukocytes (WB) and isolated cells based on their polymorphonucleate (PMN) chemiluminescence (CL) induced by phorbol myristate acetate (PMA), both PMA-stimulated and resting. Agasyllin; 5 also showed antibacterial activity against both Gram-positive and Gram-negative bacterial strains including S. aureus and S. thypii, E. cloacae and E. aerogenes, respectively, with an MIC value of 32 μg mL−1.21 The antidepressant effects of coumarins are well known. The prenyl group forms the major structural fragment of the coumarin ring system, showing an antidepressant effect.23 Coumarin derivatives as effective MAO inhibitors act as antidepressant and anti-Alzheimer's agents.24 Psoralidin; 6 represents the common coumarin compound isolated from Buguzhi i.e., Psoraleae fructus, having a prenyl group and possessing antidepressant action. Psoralidin; 6 showed antidepressant action by increasing 5-hydroxytryptamine (5-HT), 5-hydroxyindole acetic acid (5-HIAA) and DA, whereas it decreased corticosterone (CORT), corticotrophin releasing factor (CRF) and adrenocorticotrophic hormone (ACTH). The drug auraptenol; 7 showed antidepressant action by regulating the 5-HT1A receptor.25 In a study, the drug osthenol; 8 (prenylated coumarin) obtained from the dried roots of Angelica pubescens selectively inhibited human monoamine oxidase-A; hMAO-A (IC50 value of 0.74 μM) with high selectivity (Si > 81.1). It was found to be more potent than the marketed drug toloxatone (IC50 = 0.93 μM) and inhibit hMAO-A through competitive reversible inhibition. It was also confirmed from molecular docking studies that drug 8 showed greater binding affinity to hMAO-A (−8.5 kcal mol−1) than hMAO-B (−5.6 kcal mol−1). The SAR revealed the interesting fact that the presence of the 8-(3,3-dimethylallyl) group in compound 8 increases its ability to inhibit hMAO-A, whereas the presence of 6-methoxy and lack of a prenyl group in scopoletin decrease its binding affinity with hMAO-A. It was also confirmed by docking studies that compound 8 was more stable within the active sites with 4 alkyl and one π–alkyl interaction compared to scopoletin.26 The drug osthole; 9 is another coumarin derivative exhibiting multiple biological activities such as antitumor, anti-inflammatory, antimicrobial, neuroprotective and cardioprotective.27 The drug geiparvarin; 10 is a coumarin derivative found in the leaves of Australian Willow (Geijera parviflora) and is a monoamine oxidase inhibitor.28 Another coumarin derivative, i.e., demethylsuberosin; 11, isolated from the roots of Cudrania tricuspidata protected neuronal cells against 1-methyl-4-phenylpyridinium-induced cell death in human neuroblastoma SH-SY5Y cells with an EC50 value of 0.17 μM compared to betulinic acid with an EC50 value of 4.29 μM.29 The root of Angelica gigas Nakai (AGN) yielded decursin; 12 and decursinol; 13, which showed potential in cancer treatment.30 Two oxyprenylated coumarins, i.e., auraptene; 14 and lacinartin; 15, exhibited anti-inflammatory activity. Auraptene; 14 isolated from the roots of Citrus aurantium and Aegle marmelos showed diverse biological activities including antioxidant, antibacterial and antifungal activity. It also showed an inhibitory effect against the growth of different cancer cell lines.31 The drug lacinartin; 15 showed an inhibitory effect against MAO non-competitively with an IC50 value of 9.2 μM. Compound 15 having a prenyl group showed 4.5-times greater inhibitory activity against MAO in the brain of a mouse compared to coumarin without a prenyl group.32 The coumarin derivatives with a prenyl motif exhibiting an antidepressant effect are shown in Fig. 2.

Fig. 2. Coumarin derivatives with a prenyl motif as antidepressant agents.

Fig. 2

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3.2. Xanthones derivatives

There are several examples of xanthone derivatives containing prenyl groups showing antidiabetic, insecticidal, anti-HIV/AIDS, anti-inflammatory, antibacterial, anticancer and antioxidant activity.33 Tusevski et al. evaluated the phytochemical composition and enzymes inhibitory activity of the roots, flower and non-flower extract of Hypericum perforatum. Their activity was tested against enzymes involved in depression such as tyrosinase, butyrylcholinesterase (BuCh) and acetylcholinesterase. The xanthone derivatives present in the roots showed strong MAO-A and BuCh inhibition indicating that these compounds are potent antidepressants and have neuroprotective activity. Among the xanthone derivatives, the prenyl group-containing compounds are γ-mangostin; 16 and garcinone C; 17. The activity of butyrylcholinesterase (BChE) inhibition was more potent with the presence of C8 prenyl and C7 hydroxy groups of xanthones34 (Fig. 3).

Fig. 3. Structure of γ-mangostin and garcinone C.

Fig. 3

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3.3. Flavonoid derivatives

Flavonoid derivatives such as chalcones, flavones, flavanones isoflavones with a lipophilic prenyl side chain represent a class of agents with potent antioxidant activity.35 Rozsa et al. isolated three prenylflavanones, namely amoradin; 18, amoradicin; 19 and amoradinin; 20, from Amorpha fruticose (Fig. 5).36 These prenylated flavanones are potent antimicrobial agents.37 The drug morusin; 21, a prenylated flavonoid extracted from the mulberry root and twig bark, showed promising activity against Alzheimer's disease.38 The 5,7-dihydroxy-2-(4-hydroxyphenyl)-6-(3-methylbut-2-en-1-yl)-4H-chromen-4-one (6-prenyl apigenin; 22) chemical isolated from the seeds of Achyranthes aspera showed potent MAO-A inhibitory activity in docking studies. Its docking score of −8.06 and calculated inhibition constant of 1.23 μM suggest its significant binding affinity against MAO-A, and thus it might help in treating depressive state and neurodegeneration. Compound 22 could block both the entrance and bindings cavities of the substrate through hydrophobic interactions.39 The other flavonoid derivative 8-prenylnaringenin; 23, isolated from hops has potent phytoestrogen properties and showed potential to prevent tumour growth and bone resorption.40 One of the flavonoid derivatives icariin; 24, extracted from the Chinese herb Herba epimedii possesses antidepressant activity against an unpredictable chronic mild stress model of depression in mice. The mice on exposure to chronic mild stress showed an increase in inflammatory markers and oxidative-nitrosative stress markers including TNF-α and interleukin-1β, increased inducible NO synthase mRNA expression, and activation of the NF-kB signalling pathway. The antidepressant activity was due to the enhanced anti-inflammatory and antioxidant effects in the brain tissue by inhibiting NF-kB signalling activation and negatively regulating caspase-1, IL-1β axis and nod-like receptor-protein 3 inflammasome (NLRP3).41 The aglycone form icaritin; 25, showed diverse biological activities against bone, liver-, heart-, cancer-, and brain-related diseases. This molecule showed improved survival rate of ischemic-reperfusion in mice due to neuroinflammation by inhibiting NF-κB p65, IL-1β, TNF-α, NO, and DNA-binding activity. It also demonstrated antioxidant activity by reducing secondary reactive oxygen species (ROS), malondialdehyde (MDA) and ROS. It inhibited NLRP3 inflammasome and improved the learning ability in SAMP8 mice.42 In another study, compound 24 isolated from Yinyanghuo (Epimedii folium) showed an antidepressant effect by reducing corticotropin releasing factor (CRF), monoamine neurotransmitter and MAO activity and increasing hippocampus neurogenesis.25 However, its poor bioavailability and limited delivery to the brain limit its application, and thus a nanogel-loaded self-assembled thermosensitive hydrogel system was developed to deliver 24 through non-invasive nose-to-brain delivery and to improve its water solubility. The in vivo distribution of the drug in the behavioural despair test and chronic unpredictable test showed zero-order kinetic release in the first 10 h and rapid brain distribution in 30 min. Two tests, i.e., tail suspension test and force swim test, showed a reduction in the immobility time and significant antidepressant effects at a lower dose. It also repaired the neuronal damage in the hippocampi of a chronic unpredictable mild stress rat model. Furthermore, it reversed abnormal testosterone plasma levels, IL-6 and PGE2.43Fig. 4 shows the structure of flavonoid derivatives having antidepressant action. Neuroprotective drugs have cross benefits in neuropsychiatry disorders such as MDD and neurodegenerative disorders, i.e., Parkinson's diseases (PD), and inflammation plays an important role in both conditions.44 Derivatives of 7-prenyloxy-2,3-dihydroflavanone were synthesized and evaluated for their antidepressant-like activity. Two compounds, 26 and 27, showed the most potent antidepressant activity. Both 26 and 27 increased the concentration of 5-HT and NE in the brain hippocampus, cortex, and hypothalamus. The percentage decrease in the immobility duration for compounds 26 and 27 was 75.78% and 73.33%, respectively, which was comparable to that of the standard fluoxetine (74.67%). The compounds did not change motor activity, suggesting that the decrease in the immobility time was not because of CNS-stimulating effects. The increase in the levels of 5-HIAA was attributed to the shut down in the metabolism of the 5-HT neurotransmitter. The SAR showed that the presence of an electron-withdrawing group such as F, Cl, and Br in the B ring of flavanone significantly decreased the immobility time, whereas the introduction of an electron-donating group such as –CH3 and –OCH3 did not result in antidepressant-like activity.45 The bioactive flavonoids (28–31) isolated from Hypericum perforatum showed neuroprotective and anti-neuroinflammatory actions. Compounds 28–30 showed the anti-neuroinflammatory activity by inhibiting the expression of inducible nitric oxide synthase and reduce nitric oxide release, whereas compounds 28 and 31 showed a neuroprotective effect by triggering the Nrf2/HO-1 pathway. It was found that these prenylated flavonoids enhanced the lipophilicity and penetration through the blood–brain barrier.46Fig. 5 shows the structure of the compounds isolated from Hypericum perforatum having neuroprotective and anti-neuroinflammatory potential.

Fig. 5. Prenylated flavonoids from Hypericum perforatum with neuroprotective and anti-neuroinflammatory potential.

Fig. 5

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Fig. 4. Flavonoid derivatives with antidepressant action.

Fig. 4

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3.4. Chalcone derivatives

The available literature reveals that compounds having prenyl groups display good biological activities. Chalcones containing prenyl groups such as xanthohumol (32) have shown immense beneficial pharmacological properties. Compound 32 demonstrated strong antioxidant effects and exerted a potential effect on autophagy and oxidative stress. It prevented ROS and NO production and inhibited NF-kB and Akt activation in endothelial cells. It also inhibited cyclooxygenase (COX) activity for an anti-inflammatory effect and decreased the excessive generation of inflammatory cytokines. More importantly, it increased the expression of BDNF.47 The natural flavonoid isobavachalcone (33) can penetrate the blood–brain barrier (BBB) and is widely distributed in the brain. Furthermore, isobavachalcone has strong antitumor, anti-inflammatory and neuroprotective activity.48 Xie et al. synthesized a series of 2′-hydroxy-4′-isoprenyloxychalcone derivatives and evaluated their antidepressant effect through a forced swim test (FST) and TST. Among the synthesized compounds, compound 34 showed the most potent antidepressant activity with a reduction in the immobility time by 74.06% in the FST test and 67.59% in TST. This compound further increased head-twitching, an indicator of the stimulation of serotonin 5-HT2A receptors. It was concluded that the antidepressant effects of this compound are related to the serotonergic and noradrenergic systems.49 Guan et al. synthesized another series of 2′-hydroxy-4′,6′-diisoprenyloxychalcone derivatives as antidepressant agents. Among the synthesized derivatives, three compounds, 35–37, showed the most potent antidepressant effects with reduced immobility by 38.3%, 34% and 27.4%, respectively. The compounds containing an electron-donating group such as 4-methoxy and electron-withdrawing group such as 4-bromo and 2,4-dichloro groups showed the most potent antidepressant action. Compounds 36 and 37 also increased the number of head-twitches in the 5-hydroxytryptophan-induced mouse head-twitch test; however, it increased the mouse mortality induced by yohimbine. The result showed that the antidepressant-like effect was because of the involvement of the serotonergic and not the noradrenergic system.50 Compound 38 showed an antidepressant effect in both the FST and TST by decreasing the immobility time and found to be similar to the positive control fluoxetine. It also reduced the ambulation in the open field mouse test and increased 5-HT and norepinephrine in the hippocampus and cortex and reduced the metabolism of 5-HT. It reduced the ratio of 5-HIAA (metabolite of 5-HT) and 5-HT by increasing 5-HT and decreasing 5-HIAA, respectively. The antidepressant effect of this compound was due to the increase in 5-HT and norepinephrine in the hippocampus and cortex in the mouse.51Fig. 6 shows the structures of the chalcone-containing compounds as antidepressant agents.

Fig. 6. Structure of chalcone-containing compounds with prenyl groups as antidepressant agents.

Fig. 6

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3.5. Resveratrol derivatives

Human MAO-A degrades AD, 5-HT, NE and is linked to one of the causes of depression. In 2019, Tang et al. synthesized and evaluated the MAO-A and MAO-B inhibitory activities of isoprenyl resveratrol derivatives. Compounds 39 and 40 exhibited neuroprotective effects and were found to be better MAO-B than MAO-A inhibitors. Thus, these compounds can be considered as potential treatment against Alzheimer's disease (AD). They showed neuroprotective effects against H2O2-induced apoptosis and ROS generation and displayed anti-inflammatory properties. Compounds 39 and 40 inhibited MAO-B with an IC50 value of 3.91 and 0.90 μM. These compounds showed good blood brain barrier (BBB) permeation and could easily cross the BBB, which was attributed to the presence of isoprenyl moieties. Due to the presence of two free prenyl groups in compound 39, it significantly inhibited ROS with good anti-inflammatory action.52Fig. 7 shows the structure of the isoprenyl resveratrol derivatives as MAO-B inhibitors.

Fig. 7. Chemical structure of isoprenyl resveratrol derivatives as MAO-B inhibitors.

Fig. 7

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3.6. Polyprenylated benzoyl phloroglucinol derivatives

Dembitsky et al. identified polyprenylated benzoyl phloroglucinol derivatives, also called sampsoninones, as sampsonione J; 41, sampsonione I; 42, epi-isosampsonione J; 43, sampsonione Q; 44, and hyperisampsin G; 45, which were isolated from Hypericum sampsonii. The other derivatives of hookeriones C; 46, and D; 47, were isolated from Hypericum hookerianum. These plant extracts are known for treating depression and psycho-vegetative disorders.53Fig. 8 represents the polyprenylated benzoyl phloroglucinol derivatives known for treating depression.

Fig. 8. Polyprenylated benzoyl phloroglucinol derivatives and hookeriones with antidepressant activity.

Fig. 8

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3.7. Polyprenylated acylphloroglucinol

Polycyclic polyprenylated acylphloroglucinols (PPAP) are comprised of more than 400 natural compounds with a range of biological activities, i.e., antidepressant, anticancer, anti-obesity and antimicrobials.54Hypericum perforatum (St. John's wort) is a herbal medicine commonly used to treat depression. It belongs to the PPAP family. These natural compounds are classified as type A and B depending on the position of the acyl group in their phloroglucinol ring core. The presence of an acyl group at C1 is classified as type A, whereas an acyl group at the C-3 position as type B. The type exo- or endo- is due to the configuration at the C7 position relative to the C-1/C-5 position. Generally, type A has exo-, whereas type B has an endo-group.55 Hyperforin; 48, is the major active antidepressant chemical constituent of H. perforatum and responsible for its antidepressant activity.56 It is one of the best lipophilic chemicals having anticancer, wound healing, larvicidal, and antidepressant properties.57 Compound 48 is chemically known as (1R,5R,7S,8R)-4-hydroxy-1-isobutyryl-8-methyl-3,5,7-tris(3-methylbut-2-en-1-yl)-8-(4-methylpent-3-en-1-yl)bicyclo[3.3.1]non-3-ene-2,9-dione.58 It is unstable, and on exposure to air, it degrades to furohyperforin and furohyperforin hydroperoxide. Various mechanisms have been proposed for its antidepressant action. It inhibits the uptake of 5-HT by peritoneal cells and acts as a synaptosomal unspecific inhibitor. Also, it non-specifically inhibits the uptake of DA and blocks GABA, AMPA and NMDA. It inhibits the uptake of neurotransmitters by specifically activating the transient receptor potential-canonical (TRPC6). It increases the intracellular content of Na+, leading to the uptake of 5-HT inhibitors. It is involved in the significant inhibition of various ion channels at a nanomolar concentration including Ca2+, and therefore referred to as a calcium antagonist according to the calcium hypothesis. It was also found that compound 48 works like neurotrophin BDNF in hippocampal pyramidal neurons. It enhanced the learning ability and memory in rats induced with AD. It disaggregated amyloid fibrils, prevented Aβ-induced neurotoxicity, and decreased Aβ-deposition.59 It also showed a positive influence on the expression of TrkB in both in vitro and in vivo experiments and was abolished in the presence of the Ca2+ channel blocker SKF-96365. Its expression depends on the activity of serine–threonine protein kinase A and involves inducible transcription factor CREB. The active form of CREB controls the expression of several proteins including TrkB.60 The general mechanism of the antidepressant action of compound 48 is represented in Fig. 9. It is also one of the most potent naturally occurring compounds reported as a cyclooxygenase-1 and 5-lipooxygenase inhibitor devoid of gastric side-effects.61 This compound integrates the inhibition of neurotransmitter uptake by specifically activating TRPC6 (Ca2+ conducting channel of the plasma membrane). Other believed that it inhibits the indirect inhibition of vesicular transmitter uptake based on its protonophoric activity and not by activating TRPC6.62 Its protonophoric activity triggers cytosolic acidification (hyperforin-dependent H+ influx and H+ release from vesicles), which causes the plasma membrane to act as a strong sodium proton exchanger, increasing the intracellular sodium concentration and inhibiting neurotransmitter cotransport with Na+.63 Furthermore, it increases the expression of TrkB. Another hyperforin analogue isolated from H. perforatum is adhyperforin (49), which showed antidepressant-like effects in rats. It reduced their immobility time in the TST and FST, and antagonized the reserpine effect without affecting their locomotor activity. It also inhibited the uptake of 5-HT, DA, and NE by their transporters and showed excellent binding affinities to NE and 5-HT.64 Although compound 48 is poorly soluble in water and unstable, its synthetic derivatives such as aristoforin; 50, tetrahydrohyperforin; 51, and octahydrohyperforin; 52 showed increased stability and solubility and were studied for their potential antidepressant activity. Compound 51 displayed promising neuroprotective activity against AD62 (Fig. 10).

Fig. 9. Mechanism of action of hyperforin as an antidepressant.631It inhibits the uptake of 5-HT and DA and inhibits GABA, AMPA and NMDA. 2It inhibits neurotransmitter uptake by activating TRPC6. 3It works by activating BDNF and hence enhances learning ability and memory in rats. 4It shows increased expression of TrkB with mobilisation of intracellular calcium. 5Its protonophoric activity increases the intracellular concentration of sodium and increases the expression of TrkB.

Fig. 9

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Fig. 10. Polyprenyl acylphloroglucinol derivatives as potential antidepressants.

Fig. 10

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The biological properties of compounds 48 and 49 are correlated with their prenylation. Another derivative, hyperfoliatin (53), isolated from the aerial part of H. perfoliatum was investigated for its antidepressant-like activity in mice by do Rego et al. It was found to reduce the dose-dependent immobility time in FST. It also inhibited the uptake of [3H]-DA, [3H]-5-HT, and [3H]-NE by the monoamine transporter without inhibiting their binding to specific ligands (Fig. 10).65 Mitsopoulou et al. isolated the new hyperibine J (54), a PPAP from H. perforatum which is slightly more polar than hyperforin. The same compound was also isolated from H. triquetrifolium Turra. Its structure is similar to compound 48, but it possesses a methyl substituent in place of the prenyl group at C-1 (ref. 57) (Fig. 10). Lou et al., following bioassay results, isolated new PPAPs from the crude ethyl acetate extract of H. perforatum by UPLC-Q-Orbitrap-MS/MS. Among the 10 identified compounds, compounds 55 and 56 showed a potent neuroprotective effect. Compound 56 demonstrated the most potent neuroprotective effect with the cell viability of 64.1% at a concentration of 5 μM. The presence of a five-membered lactone in the structure of 56 plays a critical role in its neuroprotective activity. The presence of a hydroxy group on the prenyl group decreases its activity66 (Fig. 11). An animal study involving the hippocampus and cerebral cortex of rats showed that the long use of antidepressant drugs causes the expression of BDNF genes, which in turn block their depressive-like behaviour, suggesting that mood stabilizing and antidepressant drugs are neuroprotective in nature.67 In 2018, Zeng et al. isolated two new 6-norpolycyclic polyprenylated acylphloroglucinols, namely hypermonins A (57) and B (58), from the leaves and twigs of Hypericum monogynum. Compound 57 exhibited a protective effect against induced injury in PC12 cells, indicating its neuroprotective and antidepressant activities. The other derivative, 58, was found to be inactive, which could be due to the difference in the orientation of the 5-OH group (presence of β-OH in compound 58)68 (Fig. 11). Zeng et al. also isolated a new PPAP, hypermonin C (59), from the leaves and twigs of Hypericum monogynum. It was tested for its neuroprotective effect against chemical-induced injured SH-SY5Y and PC12 cells. Compound hypermonin C showed excellent neuroprotective activity at a concentration of 10 μg mL−1 against potassium chloride (KCl)-induced SH-SY5Y cell injury. The furohyperforin ring was found to be critical for the neuroprotective activity.69 Andinin A; 60, isolated from the underground plant parts of Hypericum andinum showed antidepressant-like activity in the mouse FST. This molecule is a new dimeric acylphloroglucinol derivative, which displayed antidepressant-like activity in mice at a dose of 3 mg kg−1 and its effects are comparable to that of imipramine (20 mg kg−1). One of the well-known dimeric acylphloroglucinols named uliginosin (61) displayed an antidepressant-like effect by increasing the monoamine concentration in the synaptic cleft without binding to the sites of the monoaminergic system.70 It inhibited the synapse uptake of 5-HT, DA, and NE, and modulated Na+, K+ ATPase activity. It was extracted from the hexane fraction of Hypericum polyanthemum.71 Another dimeric acylphloroglucinol hyperbrasilol B (62) from Hypericum caprifoliatum showed antidepressant-like activity. Compound 62 does not have a nitrogen atom and SAR for monoamine transporter showed that the presence of an amine group is important for its binding and uptake activity. Centuriao et al. suggested that the antidepressant-like activity may be due to its Na+ ion influx modifying properties. The anti-immobility effects of 62 were prevented by veratrine Na+ channel opener. It was observed that the mice treated with 62 for 3 consecutive days showed an increase in hippocampus Na+, K+ ATPase activity.72 Zhou et al. isolated new PPAPs, uralodins, from the plant Hypericum uralum and confirmed their chemical structures via single X-ray diffraction analysis. Most of the compounds showed protective effects against PC12 injured cells, with uralodin A (63) exhibiting >85% cell viability. Also, compound 63 showed antidepressant activity in TST and FST in mice at the administered oral dose of 13 and 26 mg kg−1, respectively.73 A 90% ethanolic extract of the dried aerial parts of Hypericum ascyron yielded 3 new polycyclic polyprenylated derivatives known as ascyronines 64–66. These derivatives were evaluated for their antidepressant activity by inhibiting the reuptake of tritiated serotonin ([3H]-5-HT) and noradrenaline ([3H]-5-NE) in rat brain synaptosomes. It was found that compounds 64 and 65 possess weak antidepressant activity, inhibiting [3H]-5-HT.74 The bicyclic polyprenylated acylphloroglucinols demonstrate potential antidepressant, anticancer, antioxidant, anti-inflammatory and antimicrobial activities. Guttiferone A (67) showed neuroprotective effects and acted as an antioxidant, preventing the production of free radicals and superoxide radicals. It also reduced iron-induced neuronal cell damage and inhibited Fe3+-ascorbate reduction, lipid peroxidation and iron-induced oxidative degradation of 2-deoxyribose.75 New terpenylated acylphloroglucinol crassipins were isolated from the rhizomes and roots of the fern Elaphoglossum crassipes and characterized by spectroscopic data. The absolute configuration of these compounds was confirmed by circular dichroism and electronic circular dichroism. Crassipin A (68) and peracetylated derivative (69) isolated from the diethyl ether extract showed the most potent antidepressant activity when administered orally in the mouse FST at a dose of 15 mg kg−1. Compounds 68 and 69 at a dose of 15 mg kg−1 reduced the immobility time significantly compared to the standard imipramine at a dose of 20 mg kg−1. It was also pointed out that the dimeric ring structure in compounds 68 and 69 differed from hyperforin, having a bicyclononane structure, which may be responsible for the serious drug interactions that restrict the clinical use of H. perforatum.76Fig. 11 presents the structures of polyprenylated acylphloroglucinols as potent neuroprotective and antidepressants. H. perforatum yielded new PPAP hyperidiones, which exhibited neuroprotective effects against corticosterone (CORT)-injured SH-SY5Y cells. Compound 70 showed the most potent antidepressant effect at the dose of 5 mg kg−1 in TST, which is equivalent to the dose of the standard fluoxetine (5 mg kg−1), through the hypothalamic–pituitary–adrenal axis.77 New PPAPs were isolated from a 90% ethanolic extract of H. attenuatum and evaluated for their antidepressant activity by inhibiting the reuptake of tritiated serotonin ([3H]-5-HT) and noradrenaline ([3H]-NE) in rat brain synaptosomes. Among them, compound 71 showed the most potent antidepressant activity, inhibiting [3H]-5-HT.78 Two more prenylated acylphloroglucinols paleacenins, 72 and 73, were isolated from the n-hexane and chloroform extract of the rhizomes of the fern Elaphoglossum paleaceum, respectively. Compound 72 inhibited MAO-A and MAO-B with an IC50 value of 31 μM and 4.7 μM, whereas 73 inhibited MAO-A and MAO-B with an IC50 value of 1.3 and 4.4 μM, respectively. Compound 72 was more selective towards MAO-B (MAO-B/MAO-A = 0.1), whereas 73 was more selective towards MAO-A (MAO-B/MAO-A = 3.5). It is evident that compound 73 having less polar groups because of its additional prenyl group exhibited higher inhibition.79Fig. 12 shows the structure of polyprenylated acylphloroglucinols as antidepressants.

Fig. 11. Structure of polyprenylated acylphloroglucinol derivatives with potent neuroprotective and antidepressant activities.

Fig. 11

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Fig. 12. Polyprenylated acylphloroglucinol derivatives as potent antidepressants.

Fig. 12

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3.8. Naphthoquinone derivatives

Red naphthoquinone pigments such as shikonin (74) and its enantiomer isomer alkannin (73), found in the radix cork (Lithospermi radix) layer of Lithospermum erythrorhizon Sieb. have medicinal importance such as anti-bacterial, anti-inflammatory, and anti-tumour. They are listed in the Japanese and Chinese Pharmacopoeia as anti-inflammatory and antipyretic for the treatment of eczema and measles.80Lithospermum erythrorhizon is also used in traditional Chinese medicine (TCM) to cure various diseases. Its phytoconstituents showed anticancer, anti-inflammatory, cardiovascular and brain protective activities by regulating various pathways such as NF-kB, TGF-β, PI3K/Akt/MAPKs, Akt/mTOR, reactive oxygen stress, NLRP3-inflammasome and Bax/Bcl-2 pathways.81 The phytochemical shikonin (74) could reduce the levels of IL-1β, IL-6 and TNF-α in the hippocampus, showing antidepressant and anxiolytic-like effects. It is also reduced neuroinflammation in the hippocampus.82 The ethanol plant extract of Arnebia nobilis possesses anticancer activity. It contains alkannin (75), alkannin β,β-dimethylacrylate (76) and alkannin acetate (77), which were found to exhibit anticancer action.83 The compound alkannin is used in the preparation of antidepressant medicines. It inhibits the increase in the levels of PC12 cell inflammation caused by the induction of corticosterone and decreases the inflammatory reaction.84Fig. 13 represents the naphthoquinone derivatives with a prenyl group as antidepressants.

Fig. 13. Naphthoquinone derivatives with a prenyl group as antidepressants.

Fig. 13

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3.9. Volatile oils

In 2023, Lei et al. recovered the water-soluble fraction of the essential oil from the hydrolate of Paeonia × suffruticosa cultivars. The various oxygenated derivatives detected by GC–MS (gas chromatography–mass spectrometry) and GC-FID (gas chromatography-flame ionization detection) showed that some of the compounds possess good in silico antidepressant effects against the target sodium-dependent serotonin transporter (SERT), 5-hydroxytryptamine receptor 1A (5-HT1A), and MAO-A. Among them, the best docking results were obtained with the compounds containing prenyl groups such as geraniol (78), nerol (79), citronellol (80) and geranic acid (81). These compounds were observed to be bound to the active sites of SERT, and thus may be effective in increasing the 5-HT levels in the CNS.85 The essential oil from Citrus sinensis Osbeck has the potential to reverse the depression behaviours in mice and increase the release of monoamine neurotransmitter in the brain of mice. Among them, β-mene (82), α-pinene (83), (+) limonene (84), and linalool (85) having a prenyl group showed the most potent antidepressant action.25 The phytochemical investigation of volatile oil of Yueju revealed the presence of monoterpenes and sesquiterpenes and small amounts of aromatic and aliphatic acids. This volatile oil contains compounds having prenyl groups such as 83 and 4-carvomenthenol (86). The antidepressant effect of the oil was assessed in chronic unpredictable mild stress (CUMS) mice. The CUMS mouse model showed a decrease in cerebral blood supply, which was reversed by treatment with the volatile oil of Yueju. It was also found that a decrease in blood flow causes the accumulation of Glu outside the synapse, over activates NMDA and Ca2+ influx, and then triggers neuronal apoptosis. The conversion of Glu is regulated by GLT-1 (sodium-glucose co-transporter 1) and its low expression causes depression. The volatile oil of Yueju had the most significant effect on the decreasing content of Glu and upregulated the expression ERK1/2 and AKT and increased the expression of GLT-1.86 The Ferula genus contains monoterpene hydrocarbons, oxygenated monoterpenoids, and sesquiterpenes such as 83, 84, myrcene (87), α-terpineol (88), α-terpinyl acetate (89) and neryl acetate (90) having prenyl groups, which showed several biological activities with no unpleasant side-effects.87Fig. 14 presents the volatile oil derivatives with prenyl groups as antidepressants.

Fig. 14. Compounds having prenyl groups in volatile oil as antidepressants.

Fig. 14

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3.10. Tricyclic products

Beta acids of Humulus lupulus (hops) exhibit antidepressant-like and sedative effects. One of the transformation beta acid products in the process of brewing beer forms tricyclic products. These tricyclic products have close similarity in structure to hyperforin and act via the activation of the TRPC6 cation channel, causing Ca2+ influx. The structures of lupulones (91) and 3 compounds, namely nortricyclolupones (92), dehydrotricyclolupones (93), and tricyclolupones (94), were elucidated via 1D/2D NMR, UHPLC-DAD, and ESI−–MS–MS. The beta acids and the transformation product increased Ca2+ influx across the plasma membrane in PC12 cells similar to hyperforin.88Fig. 15 presents the structure of lupulons and their tricyclic transformation products.

Fig. 15. Structure of lupulones and its tricyclic transformation products.

Fig. 15

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3.11. Steroidal saponin glycosides

The plant-derived compounds in natural foods and medicines have antidepressant activity with low side-effects. The antidepressant effects of the active ingredient of renshen (Ginseng radix) as ginsenoside Rg1 (95) improves the synaptic structure in the prefrontal cortex. It showed antidepressant activity by regulating the expression of the glucocorticoids and BDNF levels. It also upregulated the Cx43 expression in the prefrontal cortex of an animal depression model. The other constituent ginsenoside Rb1 (96) regulates the BDNF/TrkB and AKT pathways, which suppress inflammation and modulate the hypothalamic pituitary adrenal axis. In TST and FST unpredictable mild stress models, the increased immobility time was reduced by compound 95.25 In one of the studies, compound 95 selectively decreased Ly6Chi monocyte recruitment in an inflamed mouse brain, acting as a potential antidepressant. Also, it weakened the release of CCL2 to recruit peripheral monocytes.89 Two saponins, namely cyprotusides A (97) and B (98) found in Cyperi rhizome, known as xiangfu, showed significant antidepressant effects25 (Fig. 16). Other studies showed the antidepressant effect of 95 by enriching the gut microbial indole-3-acetic acid (IAA) in mice via oxytocin signaling. The antidepressant effects of 95 were checked by the gut microbial structure of 16S rRNA sequencing and functional strains by in vitro bacterial culture. The results showed that compound 95 improved unpredictable mild stress, anxiety-like behaviour, and social avoidance and increased hypothalamus oxytocin secretion and restored neuronal proliferation in mice. It also increased the concentration of IAA in the serum and brain because of the enrichment of the gut microbe Lactobacillus murinus. It was confirmed that IAA mimicked the antidepressant action of 95 and the oxytocin receptor antagonist abolished the antidepressant effect of 95 and IAA.90

Fig. 16. Steroidal saponin glycosides as potent antidepressant agents.

Fig. 16

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The aglycone 20(S)-protopanaxadiol; 99, present in ginsenoside Rb3 (100) showed an antidepressant effect. It has 1 xylose and 3 glucose moieties, similar to glycone. Compound 100 gets deglycosylated into its active form in the intestine by the aid of intestinal bacteria. Four deglycosylated derivatives [Rg3 (101), Rh2 (102), compound K (103) and 99] and compound 100 were evaluated for their antidepressant activity using FST, TST and by measuring the mouse brain neurotransmitter (5-HT, NA, and DA) levels. Among them, 101 was found to be the most potent, which produced an antidepressant effect at a lower dose with a quick onset of action, whereas 103 showed similar antidepressant activity to that of 100. The three compounds 100, 101 and 103 increased the levels of NA and only 101 could reverse the swim stress-induced increase levels of adrenocorticotropic hormone (ACTH) and corticosterone. Compounds 99 and 102 did not show any effect91 (Fig. 16).

3.12. Miscellaneous

The hydroalcoholic extract of the bark of Rapanea ferruginea and its major compounds myrsinoic acid A (104) and B (105) were evaluated for their antidepressant-like effect. This evaluation was based on the known anti-inflammatory effects of these compounds, considering that major depressive disorder has been associated with elevated levels of inflammatory mediators. The extract showing an antidepressant-like effect in mice was treated with serotoninergic, dopaminergic and noradrenergic antagonists. It showed an antidepressant-like effect in the TST and increased the time in the splash test. This extract also inhibited the MAO-A activity in the hippocampus and prefrontal cortex of the brain.92 One of the prenyl derivatives, claulenin B (106), obtained from the extract of Clausena lenis Drake also possesses anti-neuroinflammatory potential against LPS-induced NO production in BV-2 microglial cells.93 The plant Crocus sativus (C. sativus) has antidepressant potential, which is attributed to the presence of safranal (107), picrocrocin (108), crocetin (109), crocin (110) in it. These phytochemicals showed antidepressant activity in preclinical animal models of depression including albino mice and rats. The antidepressant effects of C. sativus have been linked to several mechanisms including inhibition of monoamine reuptake, and its action towards the GABAergic receptors and activation of BDNF. Some other studies showed that it increased the levels of VGF, CREB and BDNF in the hippocampus. BDNF helps in the survival of neurons, whereas VGF increases hippocampal synaptic activity and maintains homeostasis regulation.5Fig. 17 shows the chemical structures of the natural compounds containing prenyl groups.

Fig. 17. Chemical structures of naturally occurring compounds containing prenyl groups.

Fig. 17

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Apart from the main mechanism of the antidepressant action such as monoamine reuptake inhibition, NMDA receptor antagonism and GABA-α agonism, anti-inflammatory and antioxidant activities also play an important role in ameliorating the symptoms of depression and demonstrate neuroprotective effects.5 Active-sulfur containing amides were isolated and characterized by Nian et al. from the leaves of Glycosmis pentaphylla. Four of the compounds, 111–114 (Fig. 18), showed the most potent anti-inflammatory activity by showing an inhibitory effect against NO production accelerated by LPS in mouse macrophage RAW 264.7 cells.94 The pyrazoline compounds synthesized by Fioravanti et al. were tested against the human MAO A and B isoforms. The most potent activity was shown with benzyloxy substitution; 115, with pIC50 values of 6.50 and 6.76 against hMAO-A and hMAO-B compared to the standard clorgyline with pIC50 values of 8.35 and 4.21, respectively.95Fig. 19 shows the chemical structure of the most active prenylated pyrazoline as an hMAO-A and MAO-B inhibitor.

Fig. 18. Naturally occurring prenylated sulfur-containing amides from the leaves of Glycosmis pentaphylla showing anti-inflammatory activity.

Fig. 18

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Fig. 19. Prenylated pyrazoline derivative as a human MAO-A and MAO-B inhibitor.

Fig. 19

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4. Conclusion

Synthetic antidepressant drugs are associated with toxicity and resistance. However, the prescribing rate of these drugs are still high based on their therapeutic benefits over the risk and lack of other safer alternatives available. Furthermore, the development of targeted therapy for chronic diseases such as antidepressants are still challenging and insufficient even after continued research in this field. Over the past few decades, medicinal chemists have focused on synthesizing compounds based on natural product pharmacophores or fragments with the aim of obtaining more potent compounds. It has been observed that the prenyl group is present in many bioactive natural products and its incorporation in synthetic derivatives have led to the development of potential drug candidates against depression. The available literature strongly suggests that prenylated compounds exhibit high antidepressant effects, although the comparison of the antidepressant effect of prenylated and non-prenylated compounds still has to be studied. It appears that the prenyl group itself does not impart antidepressant activity given that many other compounds having prenyl groups exhibit various biological activities. Thus, it can be concluded that the presence of prenyl groups together with bioactive nuclei augments the biological activities including antidepressant activity. This review summarised the mechanism and antidepressant activity of the drugs or phytochemicals containing prenyl groups. Some of the important considerations in their design was observed for these compounds to be more potent antidepressants. The attachment of the prenyl group at the 7th or 8th position was observed in the natural coumarin fragments to function as an antidepressant. A prenyl group at the 6th and 8th position on the flavonoid ring and chalcone containing prenyl groups attached through oxygen functionality showed potent antidepressant activity. The acylphloroglucinol/benzoyl phloroglucinol derivatives with polyprenyl structural fragments from different plant extracts showed potential for treating depression. The volatile oils, naphthoquinone, and steroidal saponins with prenyl groups demonstrated promising antidepressant effects. Thus, the inhibition of receptors with reduced toxicity and inclusion of prenyl fragments in newly developed molecules may lead to the development of more potential drug candidates. This review will further support researchers working in this field to develop novel antidepressants utilising the prenyl group.

Author contributions

Conceptualization and writing – original draft preparation [Md Jawaid Akhtar]; methodology and supervision [Khalid Al Balushi]; formal analysis and investigation [Bushara Al Sabahi]; writing-review and editing [Shah Alam Khan]; and data curation [Afrah Al Tamimi].

Conflicts of interest

The authors declare that they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

The authors are thankful to the National University of Science and Technology, Muscat, Sultanate of Oman, for its continuous support and encouragement. One of the authors, Md Jawaid Akhtar is thankful for the BFP/RGP/CBS/23/337 support from the Ministry of Higher Education, Research & Innovation (MOHERI), Muscat Oman.

Biographies

Biography

Mohammad Jawaid Akhtar.

Mohammad Jawaid Akhtar

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He is currently working as an Assistant Professor at the National University of Science and Technology, Muscat Oman. His areas of interest are the synthesis of heterocyclic compounds of medicinal importance and computer-aided drug design. He has a total of 8 years of teaching and research experience, with 70 publications, one book and three book chapters in WoS-indexed journals. Recently, he secured research funding from the Ministry of Higher Education, Oman to design and develop synthetic anticancer agents. He also obtained research funding from the National University to synthesize coumarin derivatives as antioxidant and anti-inflammatory agents. His achievements have been recognized with the ‘NU Best Researcher Award’ in 2023–24.

Biography

Khalid Al Balushi.

Khalid Al Balushi

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Prof. Khalid Al Balushi has been the Dean of College of Pharmacy at the National University of Science and Technology since 2020 and is a Professor of Pharmacology. He worked as a faculty at the College of Medicine and Health Sciences in Sultan Qaboos University, Oman, for 20 years. He received his PhD in Therapeutics from the University of Nottingham, UK, Division of Therapeutics and Molecular Medicine in 2008. His main research interests include pharmacogenomics of diseases in the Omani population and drug prescribing patterns in Oman. Prof. Al Balushi has 39 Scopus-indexed publications with an H-index of 16.

Biography

Bushara Al Sabahi.

Bushara Al Sabahi

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She is currently working as a Lecturer in the National University of Science and Technology, Muscat, Oman. Her area of interest is the extraction of natural products and study of their antioxidant activity. She is also involved in the synthesis of organic compounds and their medicinal uses. She has 3 years of experience in teaching and 18 years of experience as a Lab Instructor and research experience with 5 publications. She recently secured funding from the Ministry of Higher Education, Oman, for the design, synthesis and pharmaceutical analysis of anti-cancer agents.

Biography

Shah Alam Khan.

Shah Alam Khan

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Dr. Shah Alam Khan is currently working as a Professor of Pharmaceutical Medicinal Chemistry at the College of Pharmacy, National University of Science and Technology, Muscat, Oman. He earned his Ph.D. from Jamia Hamdard University, New Delhi, India in 2003 for studying the chemistry and role of Silybum marianum (Milk thistle), silymarin and its synthetic analogues in the hepatoprotection. Dr. Khan is a recipient of the Junior Research Fellowship (JRF-UGC, GATE qualified) and Senior Research fellowship (SRF, CSIR) from the Government of India for pursuing master’s and doctorate degrees. With over 20 years of teaching and research experience, Dr. Khan's research interests include the synthesis and biological evaluation of natural products and synthetic heterocyclic compounds. He has published 190+ full length scientific articles in Scopus/WoS/ISI indexed national and international journals. In addition, he has edited one book on drug repurposing, published by Nova Publishers Inc, USA, and contributed over 19 book chapters in publications by renowned publishers such as Elsevier, CRC Press, Springer Nature, Nova, and Wiley. He is serving as an editorial board member of several international journals and has reviewed scientific papers for over 50 journals in the field of pharmaceutical sciences. Dr. Khan has supervised 40+ undergraduate and post graduate research projects, many of which have won awards in poster/oral presentation category at the international conferences. He has successfully completed eight funded research projects and a few more are ongoing. He has been invited as a guest speaker at numerous national and international conferences. His achievements have been recognized with the ‘NU Best Researcher Award’ in 2020–21, the ‘NU Best Academic Excellence Award in 2021–22’ and Best Professor in Pharmacy in July 2023. He is a life member of professional bodies including the IPA, ATINER, IPGA and APTI.

Biography

Afrah Al Tamimi.

Afrah Al Tamimi

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She is an Applied Chemistry Bachelor's graduate from Sultan Qaboos University. She worked as a Research Assistant for 4 years in Sultan Qaboos University on different projects. Currently she is working as a Research Assistant at the National University of Science and Technology under Dr. Mohammad Jawaid Akhtar for a TRC funded project.

Data availability

No primary research results, software or code have been included, and no new data were generated or analysed as part of this review.

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