Meroterpenoids: A Comprehensive Update Insight on Structural Diversity and Biology

Meroterpenoids are secondary metabolites formed due to mixed biosynthetic pathways which are produced in part from a terpenoid co-substrate. These mixed biosynthetically hybrid compounds are widely produced by bacteria, algae, plants, and animals. Notably amazing chemical diversity is generated among meroterpenoids via a combination of terpenoid scaffolds with polyketides, alkaloids, phenols, and amino acids. This review deals with the isolation, chemical diversity, and biological effects of 452 new meroterpenoids reported from natural sources from January 2016 to December 2020. Most of the meroterpenoids possess antimicrobial, cytotoxic, antioxidant, anti-inflammatory, antiviral, enzyme inhibitory, and immunosupressive effects.


Introduction
Natural products and their analogs in today's age play a crucial role in the development of novel drugs because of their tremendous structural diversity [1][2][3][4][5]. It has been reported that out of the 877 New Chemical Entities (NCEs) established between 1981 and 2002, ca. 49% arose from natural products, or, synthetic molecules based on natural-product-pharmacophores [6,7]. However, pharmaceutical research into natural secondary metabolites has declined in the last two decades because of the difficulty in isolating compounds with skeletally novel frameworks from natural resources rather than from combinatorial synthetic protocols [7][8][9].
The term "meroterpenoid" was first used by Cornforth [10] in 1986 to describe natural products bearing a mixed terpenoid biogenesis. The prefix "mero-" is derived from the Greek word "merus" which means "fragment, or part, or partial" [11][12][13]. Meroterpenoids are thus a class of natural products derived from hybrid polyketide or non-polyketide and terpenoid biosynthesis. The unusual enzyme reactions responsible for connectivities among their structures, and their unique ring cores create a most interesting chemical diversity among meroterpenoids [11,14,15]. Interestingly, meroterpenoids are mostly reported from fungi and marine organisms while only a limited number of meroterpenoids were obtained from plants [9].
Our review article describes the systematic and complete summary of potentially bioactive meroterpenoids from all natural sources except fungal meroterpenoids during the last five years 2016-2020 (January 2016 to December 2020). In point of fact, an amazing 452 new meroterpenoids were discovered during this period, which were mostly tested for their various biological activities.

Meroterpenoid Classification
The structures of meroterpenoids are exceptionally diverse and complex which is why classifications of these compounds are not easy. Meroterpenoids were often classified in two ways. The first way is to classify these compounds as polyketide-and non-polyketideterpenoids previously described by Geris and Simpson [12]. The second way is to classify these compounds based on a common scaffold, common natural product skeleton, or heterocyclic ring system, viz., phloroglucinol, syncarpic acid, sesquiterpene, phthalide, benzofuran and phenylfuran [11,12]. We followed the second method.

Phloroglucinol-Based Meroterpenoids
Among other anticancer meroterpenoids, diformylphloroglucinol-derived meroterpenoids from Psidium guajava L. were identified by spectroscopic analyses and ECD calculations as psiguajavadials A (1) and B (2), and guajadial (3) (Figure 1) [33]. All these metabolites showed antitumor activity against HCT116, Huh7, DU145, CCRF-CEM, and A549 cells. (Table 1). Compounds 1 and 2 displayed dose-dependent inhibition of Top1 activity [33]. Guajadial (3), inhibited endothelial cell proliferation and migration as well as suppressing tumor growth in human NSCLC (A549 and H1650 cells) and xenograft mouse models. This potential has been reported as being a significant antineoplasmic activity of 3. The Western blotting method to study the underlying mechanisms of VEGF receptor (VEGFR)2-mediated revealed that compound 3 inhibited A549 (IC 50 = 3.58 µM) proliferation via blocking the Ras/MAPK pathway [34]; this activity of 3 is higher than the potential of cisplatin (IC 50 value of 7.51), which was used as a positive control. Diformylphloroglucinol-based meroterpenoids, viz., guajavadials A-C (4-6) ( Figure 2) were obtained from P. guajava and also exhibited cytotoxicity against A-549, HL-60, MCF-7, SMMC-7721, and SW480 cancer cell lines with IC 50 values between 2.28-3.38 µM (Table 1). Compound 6 displayed the highest potential (IC 50 = 3.54 µM) against SMMC-7721 cell lines which is higher than the standard cisplatin (IC 50 = 19.8 µM) [35]. The structures and activity differences revealed that the arrangement of the isoprene units is responsible for the activity potential, and thus the terpenoidal skeleton indeed plays a significant role in the activity level, as can be seen in compounds 5 and 6 [35].
Shang et al. [36] isolated a small range of cytotoxic formylphloroglucinol-derived meroterpenoids; the eucalrobusones A-I (7-15) ( Figure 2) from Eucalyptus robusta. In the MTT assay, compound 7 moderately inhibited the growth of HepG2 (IC 50 : 18.5 µM) and U2OS (IC 50 : 45.0 µM), while metabolite 10 possesses a weaker potential against HepG2 (26.7 µM) ( Table 1). Compound 15 only exhibited moderate inhibition of U2OS cell lines with an IC 50 value of 42.25 µM. Only metabolite 9 proved to be the most potent anticancer agent against the three target cancer cells with IC 50 : of 7.40 to 8.99. Activity of compound 9 has been reported to be comparable to doxorubicin (IC 50 = 5.23, 2.66 and 1.14 µM, respectively). A study on the mechanism of action of compound 9 revealed that it significantly inhibited cell division exerting cell proliferation on MCF-7 in a concentration dependent manner. Eucalrobusones A (7) and B (8) bearing an unusual skeleton having a maaliane sesquiterpene core is linked to a phloroglucinol unit. On the other hand, the chroman ring in eucalrobusone E (11) is attached to a bicyclogermacrane unit at the C-3/C-4 position. Meroterpenoid 12 bearing a phloroglucinol unit is linked to an aromatic dehydromenthane monoterpene group. Eucalrobusones G-I (13)(14)(15) are cubebane-based phloroglucinol-based meroterpenoids linked through a 1-oxaspiro [5.5]undecane unit [36].
Eucalyptus tereticornis is reported to produce formyl phloroglucinol meroterpenoids, since Liu et al. [38] isolated five formyl phloroglucinol-derived meroterpenoids viz., eucalteretials A-E (21)(22)(23)(24)(25). Besides spectroscopic analysis, ECD calculations were used to define the chirality of these compounds. At a concentration of 50 µM, compound 25 exhibited comparable topoisomerase I (Top1) inhibitory activity to that of camptothecin, whereas, only compound 23 displayed growth inhibition of HCT116 cell lines with an IC 50 value of 4.8 µM (Table 1). Among compounds 21-25, both 21 and 22 are rare natural products in which the germacrene core unit and the phloroglucinol core are connected in a different pattern ( Figure 3) [38].
Eucalyptus globulus fruits are also rich in phloroglucinol-derived meroterpenoids, since several have been isolated previously. Indeed, Qin et al. [39] isolated 10 compounds from this source. The spectroscopic data and ECD calculations lead to their absolute structure determination as eucalypglobulusals A-J (26-35) (Figure 4) [39]. Eucalypglobulusal A (26) has an unusual structure bearing a phloroglucinol core coupled to a rearranged sesquiterpene skeleton. Among these compounds, eucalypglobulusal F (31) inhibited the growth of the human acute lymphoblastic cell line (CCRF-CEM) with an IC 50 value of 3.3 µM (Table 1), which is comparable with the positive control VP-16 (IC 50 = 1.1 µM). However, the same compound was not active (IC 50 : > 10 µM) towards HCT116, DU145, Huh7 and A549. Moreover, eucalypglobulusal A (26) inhibited DNA topoisomerase I (Top1) [39]. Phloroglucinol-based meroterpenoids in the form of enantiomers viz., (±)-japonicols A-D (36a,b-39a,b) ( Figure 5) were isolated from Hypericum japonicum. Moreover only compound 37a illustrated good KSHV activity (EC 50 : 8.75 µM; SI: 16.0) while the other compounds exhibited EC 50 values of between 17.6 and 202.9 µM). Biosynthetically, it is suggested that these acylphloroglucinol-derived meroterpenoids are formed by non-enzymatic reactions, since all were isolated from H. japonicum in both enantiomeric forms [40]. New acylphloroglucinol-based meroterpenoid enantiomers viz., (+)-japonicols E-H (40a/b-43a/b ( Figure 6)  were not especially that active towards KSHV. In addition compound 42b illustrated inhibitory effects with IC 50 : 6.7 µM and SI: 7.4 while the enantiomer, viz., compound 42a was not active (IC 50 : 21.3 µM). The authors believe this is illustrative that stereochemistry plays a definite role in enhancing KSHV inhibition. Notably, the activity of 42a is increased and the selectivity of 43a is due to the unique phenyl group at C-7 [41]. Phosphodiesterase-4 (PDE4D-4) inhibitors; psiguajadials A-K (44-54) ( Figure 7) were isolated from P. guajava. All these natural products have been reported to be significant inhibitors of PDE4D-4 with IC 50 values in the range of 1.34-7.26 µM (Table 1) [42]. This activity potential is comparable with the positive control rolipram, a standard PDE4 inhibitor (IC 50 0.62 µM). Since a small difference has been reported in the activity level of all these compounds, it may lead to the conclusion that the diformylphloroglucinol moiety is required for PDE4D2 inhibitory activity. The genus Psidium produced a diverse range of meroterpenoids bearing phloroglucinol-coupled to sesquiterpenoids or monoterpenes. As illustrative of this variety, consider phloroglucinol-coupled to the cubebane sesquiterpenoid core to produce compounds 44 and 45, and compound 46 has globulane as the terpene unit while 49 has caryolane and 50 has caryophyllane, whereas compounds 51-53 have cadinane as the terpene unit [42]. Phytomeroterpenoid eucalrobusones J-P (55-61) and compound 62 ( Figure 8) were isolated from Eucalyptus robusta and evaluated for their antifungal activity against C. albicans and C. glabrata [43]. Structural diversity among the meroterpenoids 55-62 is generated through the wide range of coupling patterns between the sesquiterpenoid and phloroglucinol units. Meroterpene 55 bearing an unusual carbon skeleton, viz., the 1-oxaspiro [5.6]dodecane unit is formed via the aromadendrane core C-14 rather than C-4. On the other hand, metabolite 56 is a guaiane based meroterpene and interestingly, this compound has two oxo bridges between C-10/C-11 and C-3 /C-6 which generates the most unusual polycyclic ring system [43]. Moreover, meroterpenes 57-59 are rare aristolane-based meroterpenoids with only a few examples being reported to date [44]. These metabolites showed different microbial inhibitory potentials (Table 1)   Eucalyptus robusta produces eucarobustols A-I (63-71) (Figure 9), which have been identified as PTP1B inhibitors, since all these isolates displayed significant inhibitory potential (IC 50 = 1.3-5.6 µM, Table 1). In this assay, the standard compound oleanolic acid inhibited the enzyme activity with an IC 50  were even more potent than oleanolic acid. It is speculated from the cases of the two pairs of epimers (63/64 and 69/70) that the relative configuration of H-9 can play a central role in the activity and that this provides useful information for further investigations into a structure-activity relationship [44]. Metabolite 65 displays an unusual coupling moiety of acylphloroglucinol and guaiane through the C-4-C-7 bond. Compound 63 has an acylphloroglucinol coupled sesquiterpene viz., aristolane-type while compounds 67-71 have aromadendrane type sesquiterpene linked to acylphloroglucinol units. Guavadial (72), isolated from Psidium guajava L. has caryophyllene attached to a diformyl phloroglucinol core [45]. Eucalyptusdimers A-C (73-75) were reported from Eucalyptus robusta and were identified via intensive spectroscopic methods. These compounds were shown to bear a fused skeleton between two acylphloroglucinol and two phellandrene cores. Furthermore only compound 73 illustrated anti-AChE effects with an IC 50 : 17.71 µM [46].
Hyperjaponol H (143) (Figure 16), obtained from Hypericum japonicum, was identified with the help of spectroscopic analyses and a comparison of the Cotton effects of an ECD spectrum. Hyperjaponol H (143) is a hybrid of tasmanone and the monoterpene germacrane. An assay on lytic DNA replication of EBV in B95-8 cells indicated that this compound displayed moderate inhibitory effects with an EC 50 value of 25.00 µM [60] ( Table 2). Spectroscopic identification of the secondary metabolites of Rhodomyrtus tomentosa revealed that tomentosenol A (144), 4S-focifolidione (145) and 4R-focifolidione (146) contain a unique free syncarpic acid-derived meroterpenoid skeleton. Compound 144 was also confirmed through biomimetic synthesis and was shown to potentially inhibit the growth of S. aureus with an MIC value of 4.74 µM, which has been reported to be comparable with the standard drug vancomycin (MIC = 1.23 µM). Since the other compounds 113 and 146 have been reported as being inactive, it seems that the pyran ring is responsible for reducing the antibacterial activity. In addition, tomentosenol A (144) moderately inhibited the growth of MCF-7 (IC 50    Liu et al. [62] isolated syncarpic acid-derived meroterpenoids from Myrtus communis. Spectroscopic analysis revealed that myrtucommulones (147-149) ( Figure 17) and (±)-150 having a different skeleton to compound 147 affords a unique octahydrospiro{bicyclo[7.2.0] undecane-2,2 -chromene} tetracyclic ring system. Compounds 147-149 bear a syncarpic acid coupled with the sesquiterpene viz., caryophyllene while compound 150 has humulene as the sesquiterpene core [54]. In an MTT assay, compound 147 inhibited the growth of HepG2 (IC 50 (Table 2). Compounds 149 and 150 were inactive under these conditions [28]. In 2012, Cottiglia et al. [63] reported myrtucommulone K (149a) from M. communis and based on NMR data, the authors confirmed that the structure of 149 is identical to myrtucommulone K (149a).  (Table 2), but all were inactive against HepG2 cells [64]. Triketone-caryophyllene-based meroterpenoids isolated from Rhodomyrtus tomentosa were identified as rhodomyrtials A and B (158 and 159), rhodomentone A (160) and tomentodiones A-D (161-164) ( Figure 18) and all were evaluated for their inhibitory potential on tumor metastasis. Compound 161 has a unique 1-oxaspiro [5,8]tridecane core bearing two units of triketone. Biological evaluation demonstrated that only compound 164 displayed significant metastatic effects towards DLD-1 cells. Since no study has been carried out on the mode of action, it should be mentioned that the stereochemistry at C-7 could play an important role in the activity [65].

Phenazine-and Phyridine-Based Meroterpenoids
Phenazine-derived meroterpenoids, viz., marinocyanins A-F (240-245) ( Figure 26) along with lavanducyanin (246) were produced by the marine Actinomycete strains. Compounds 240-245 are unique secondary metabolites comprising the bromo-phenazinone nucleus supplemented by N-isoprenoid moieties or a cyclolavandulyl ring in their structures [79]. Lavanducyanin (246) was re-isolated from Streptomyces sp. as a testosterone 5α-reductase inhibitor and was named WS-9659A Quite recently Kohatsu et al. [80] reported the total synthesis of lavanducyanin (246). Marinocyanin A (240) has been reported to be a potent antibiotic, since it potentially inhibited (MIC = 0.95 µM) the growth of amphotericin-resistant Candida albicans in vitro, while the other test compounds were reported as only weak inhibitors (Table 3). In addition, marinocyanins A (240) and B (241) illustrated significant in vitro cytotoxic effects towards human colon carcinoma (HCT-116: 240: IC 50 : 0.049 µM; 170: IC 50 : 0.029 µM). SAR studies showed that the cyclic structure of the terpenoidal part (cyclolavandulyl ring) plays a significant role in the antifungal activity, and that the halogen plays no particular role in the activity [79]. The standard drugs used in these assays were vancomycin (MIC = 0.27 µM) for S. aureus and amphotericin B (MIC = 0.084 µM) for C. albicans. Zhang et al. [81] isolated an unusual C21 pyridine bearing meroterpenoid 247 from the sponge Cacospongia sp.

Sesquiterpene-Based Meroterpenoids
The Vietnamian marine sponge Spongia sp. produces a range of meroterpenoids viz., langcoquinone A (248) and B (249) (Figure 27). On the other hand, compounds 248 and 249 were inactive against K. pneumoniae and E. coli, compared to the positive control Kanamycin ((MIC = 6.25 and 12.5 µM, respectively) [82]. In another investigation, Nguyen et al. [83] further isolated sesquiterpene-based meroterpenoids, langconols A-C (250-252) ( Figure 27) and langcoquinone C (253) from the same sponge viz., Spongia sp. Furthermore, compounds 250-252 bear the 4,9-friedodrimane skeleton along with phenolic functionality while langcoquinone C (253) has an hydroxyquinone instead of the phenolic group. Compound 253 exhibited significant inhibitory activity (MIC = 6.25 µM) against B. subtilis and S. aureus, with the same potential as mentioned above for the reference drug ampicillin, whereas, compounds 250 and 253 only inhibited the growth of B. subtilis with MICs of 12.5 and 25.0 µM, respectively. Compound 250 has good potential to be an antibacterial and non-toxic agent and thus offers itself as a strong candidate to be studied for the development of a potentially new antibiotic [83].
The marine sponge Dysidea sp. produces the sesquiterpene-based meroterpenoids dysidphenols A-C (254-256), along with smenospongimine (257), (Figure 28) all of which were characterized by spectroscopic analyses and ECD calculations [84]. Moreover compounds 254-256 all comprise a drimane-type sesquiterpene unit attached to a phenolic entity through either an oxaspiro center or methylene linkage. On the other hand, compound 267 comprises the 4,9-friedodrimane skeleton attached to hydroxybenzoquinone moieties. Compounds 254 and 256 were weakly active against E. coli, B. subtilis and S. aureus. However, the other test compounds 257 was found to be more potent against these three bacterial species with MIC values between 3.1 and 12.5 µg/mL (Table 4).  Compounds 258-265 (Figure 29) have a sesquiterpene moiety attached to either a benzothiazole, phenolic, or benzoquinone core through a C-C bond [85]. An interesting feature of meroterpenoids 258 and 259 is that they comprise a unique thiazole ring which biogenetically, could be derived from cysteine [86].  (Table 4). However, the other metabolites, nakijinol F (268), hyrtiolacton A (269) all isolated from the same marine sponge Hyrtios sp. were inactive. Moreover, none of these compounds were active towards HepG2, RPMI-8226, HeLa, and HL-60 cancer cells. Compounds 267 and 268 have a sesquiterpene coupled to a benzoxazole moiety while in compound 269 the benzoxazole ring is replaced by an α-pyrone and benzoquinone unit respectively [87]. Another sponge, Dysidea villosa also produces some unusual meroterpenoids described as dysivillosins A-D (270-273), which all inhibited the release of β-hexosaminidase with IC 50 ranging from 8.2 to 19.9 µM (Table 4). In addition, compounds 270-273 exert a positive inhibitory effect on LTB-4 and IL-4 and compound 270 potentially inhibited the activation of Syk. It may thus be concluded that this meroterpenoid could potentially be a new chemotherapeutic scaffold targeting Syk-associated allergies [88]. Dysivillosins A-D (270-273) ( Figure 30) are meroterpenes bearing a terpene-polyketide-pyridine system and this type of combination is very rare among meroterpenoids. Moreover, meroterpenoids 270-273 have a 2-pyridone core which could be produced biogenetically from L-lysine through amidation, decarboxylation, and dehydrogenation reactions [89].  (Table 4) [90]. However, the activities of these metabolites are lower than the reference drug taxol, which displayed IC 50 values of 0.001 to 0.07 against these cell lines. In addition, compounds 274-276 have also been reported as inhibitors (IC 50 = 2.6-21 µM) of FGFR3, IGF1R and PDGFRb [90], which is lower than the activity of the positive control satratoxin H (IC 50 = 0.05 µM). Another marine sponge, Dysidea arenaria produces dysiarenone (277) and this compound displayed inhibitory activities towards COX-2 expression with an IC 50 value of 6.4 µM. Compound 277 is a dimeric C-21 meroterpenoid featuring a unique 2-oxaspiro(bicyclo[3.3.1]nonane-9,1 -cyclopentane) carbon skeleton [91]. This compound reduced the production of PGE2 with IC 50 : 6.4 µM and was~10 times more potent than that of the positive control avarol [91].

Chromane/Chromene and Flavone Derived Meroterpenoids
Among other metabolites, the chromene-derived meroterpenoid with an additional furan ring within a prenyl moiety, tuberatolide B (305) (Figure 34), was initially reported from Botryllus tuberatus [99] and later from Sargassum macrocarpum [100]. This diastereomeric meroterpenoid is reported to display anticancer activity since it inhibits lung cancers (H1299 and A549), breast cancers (MDA-MB-453, MDA-MB-231, and MCF7), colon cancers (CT26, HCT116, and SW620), cervical cancer (HeLa), and prostate cancers (DU145 and PC3) [100]. The mechanistic study revealed that compound 305 inhibits the growth of cancer cells by the production ROS in HCT116, A549, and MDA-MB-231, cells. It also increases DNA damage by the formation of γH2AX foci and or the phosphorylation of Chk2 and H2AX, which proteins are generally associated with DNA damage [100]. Chromane/chromene meroterpenoids (CMs), the rubiginosins A-G (306-312) (Figure 34) and anthopogochromenes A (313) and B (314), were reported from Rhododendron rubiginosum [101]. In addition to spectroscopic techniques, their absolute structures were established by making use of the chromane/chromene helicity rule, X-ray crystallography and CD analysis. All these compounds were evaluated for their cytotoxic effects towards A549, HCT116, SK-HEP-1, and HL-60 (Table 4). Compound 310 was the most active against all cell lines with IC 50 values of 10.91, 13.89, 11.71 and 7.40 µM, respectively and then followed compounds 306, 308 and 314. The other tested metabolites are reported to be inactive [101]. Doxorubicin (IC 50 = 0.01-0.2 µM) was used as positive control in this study. Over 20 CMs have been reported from the genus Rhododendron bearing a cannabinoid-like and orcinol core. Moreover, Rhododendron CM was also designated as a cannabicyclol (CBL)-type or cannabichromene (CBC)-type [102]. Interestingly CBC/CBL-type natural products having an orcinoid skeleton are rare in Cannabis and are mostly reported from Rhododendron species [102].    Sargassum siliquastrum produced a small library of the meroterpenoids isopolycerasoidol (315), sargachromanols D (316), E (317), G (318), I (319), S (320), and T (321) ( Figure 35) and all were evaluated for their antioxidant effects. Compound 315 was the most active in DPPH and ABTS antioxidant assays with EC 50 values of 8.23 and 2.33 µM, respectively [103]. Compounds 316-318 were weakly active against the DPPH free radical, but induced significant inhibition (EC 50 : 4.0 to 4.8 µM, Table 4) against the ABTS free radical. On the other hand, compounds 316 and 317 are only weakly active in DPPH and ABTS antioxidant assays with EC 50 values ranging from 15.7 to 57.0 µM. The structure and activity variation of compounds 316-318 suggest that the hydroxyl group at C-13 in the prenyl moiety can be the activity determining factor, since compounds 316 and 317 have the hydroxyl group at C-12, while compounds 318 and 319 have a corresponding keto function. Other literature results show that the chromene nucleus is an important group for antioxidant activities [103]. Another medicinal plant, Rhododendron capitatum produces enantiomeric pairs of meroterpenoids, the (±)-rhodonoids C-G (322-326) ( Figure 36). These compounds existed as racemates and were subsequently purified via chiral HPLC. Moreover, only 322a inhibited HSV-1 with an IC 50 value of 80.6 µM. Compounds 322a and 322b featured the unusual 6/6/6/5 tetracyclic ring core while compounds 323a and 323b bore the rather rare 6/6/5/5 tetracyclic ring system [104]. Another Rhododendron sp., viz., R. nyingchiense interestingly, also produced enantiomeric pairs of the meromonoterpenoids 327a,b-332a,b and all racemic mixtures were separated by chiral-phase HPLC. These compounds possess PTP1B inhibition with IC 50 values ranging from 29 to 61 µM. Compounds 327a,b feature a quite rare 6/6/5 tricyclic ring core [105].
Sargachromenol (333) (Figure 37) was produced by Sargassum serratifolium and inhibited BChE and BACE1 with values for IC 50 : 9.4 and 7.0 µM respectively [106], while the reference compounds used were berberine (IC 50 = 9.4 µM) and quercetin (IC 50 = 5.6 µM) respectively. The alga Cystoseira baccata produced racemic mixtures of two meroterpenoids, tetraprenyltoluquinol (334a,b), and tetraprenyltoluquinone (335a,b). The in vitro anti-leishmanial study demonstrated that compound mixture 334a,b exhibited reasonable effects towards Leishmania infantum with IC 50 : 44.9 µM, whereas compound mixture 335a,b was found to be a weak inhibitor with IC 50 of 94.4 µM. In an SAR study, it was determined that the C-1 ketone decreases the anti-leishmanial effects since the difference between these two compounds viz., 334 and 335 is the keto group [107].  Diplomeroterpenoids A-F (336-341) (Figure 37), were isolated from the roots of Mimosa diplotricha and featured the diterpenoid unit and chromen-4-one framework. Compounds 336-338 and 340 inhibited protein farnesyl transferase (PFTase) with an IC 50 ranging from 5.0 to 8.5 µM [108]. Activity of the reference inhibitor FTase inhibitor II is reported as IC 50 = 0.1 µM. Additionally, diplomeroterpenoid A (336) is also reported to inhibit the growth of HepG2 cancer cells with a GI 50 : 8.6 µM.

Conclusions
In this review, the structures, chemical diversity, and biological properties of 452 new meroterpenoids have been reported. The chemical structures of meroterpenoids are extremely diverse, as may be noted by the various biosynthetic pathways and clearly demonstrated nature's sophisticated synthetic protocols to generate this tremendous chemical diversity via simple and achiral starting units. As comprehensively explored in each section, these types of secondary metabolites possess a tremendous structural diversity resulting from such reactions as condensation, alkylation, oxidation, and reduction. Moreover, meroterpenoids incorporated multiple prenyl moieties or very complex ring cores, which furnish abundant molecular scaffolds for such a wide range of biological activities.