Genus Acanthella—A Wealthy Treasure: Secondary Metabolites, Synthesis, Biosynthesis, and Bioactivities

Marine sponges are multicellular and primitive animals that potentially represent a wealthy source of novel drugs. The genus Acanthella (family Axinellidae) is renowned to produce various metabolites with various structural characteristics and bioactivities, including nitrogen-containing terpenoids, alkaloids, and sterols. The current work provides an up-to-date literature survey and comprehensive insight into the reported metabolites from the members of this genus, as well as their sources, biosynthesis, syntheses, and biological activities whenever available. In the current work, 226 metabolites have been discussed based on published data from the period from 1974 to the beginning of 2023 with 90 references.


Introduction
Natural metabolites from various sources, including microbes, animals, minerals, and plants, have been traditionally utilized for treating various human illnesses [1][2][3][4][5][6]. Recently, the developments in high-throughput screening and spectroscopic and analytical technologies have significantly boosted natural drug discovery, including marine-based drugs [7]. The marine environment is a rich source of a vast group of structurally unparalleled metabolites with diverse pharmacological activities that are reported from different marine organisms such as tunicates, sponges, mollusks, and bryozoans [8]. These metabolites are potential candidates for biotechnological applications and a number of them are in clinical trials; therefore, their impact on the pharmaceutical industry is continually growing [9][10][11]. They have been found to display an array of bioactivities, primarily antimicrobial, immunosuppressive, antifouling, anticancer, anthelmintic, antiprotozoal, neuroprotection, antiviral, and anti-inflammatory [7,8]. Among the marine organisms that have been investigated, sponges (Porifera), which are soft-bodied and sessile organisms, have become the focal point of natural product investigations due to the vast range of structurally unique biometabolites separated from these organisms [12,13].
The Axinellidae family (class Demospongiae, order Bubarida, family Dictyonellidae) [14] members, including Axinella and Acanthella genera, produce structurally varied terpenes in the English language in peer-reviewed journals in the period from 1974 to the beginning of 2023. A total of 85 published articles have been highlighted. The suggests irrelevant and non-reviewed journals' published articles, as well as all non-English written articles, were not included. For the non-English work, the data were extracted from the English abstracts whenever available.

Secondary Metabolites of Genus Acanthella
Different metabolites were separated and characterized from different species of this genus using various spectroscopic and chromatographic techniques. The isolated metabolites are categorized according to their chemical classes into sesquiterpenes, diterpenes, alkaloids, steroid compounds, and others. Additionally, their reported biosynthetic and synthetic studies are also highlighted whenever applicable.

Sesquiterpenes
The reported investigations revealed the purification of various classes of sesquiterpenes that are substituted by isonitrile or isothiocyanate functionalities, including mono-, bi-, and tri-cyclic skeletons with 3-, 5-, 6-, and/or 7-membered rings ( Figure 1 and Table  2). Frequently, formamide derivatives were reported along with both isothiocyanate and/or isonitrile moieties. Isonitrile-containing metabolites have been reported from some species belonging to Penicillium and Axinella genera [30]. Several reports stated their characterization from Acanthella. It was reported that A. cavernosa (Dendy, 1922) can convert cyanide and thiocyanate for isocyanide and isothiocyanate biosynthesis, which could be attributed to the presence of rhodanese or the equivalent enzyme [31]. Therefore, thiocyanate was postulated to be the precursor for the isothiocyanate moiety in terpenes by direct utilization or oxidative desulphurization of cyanide, conversion to isocyanide terpenes, and reinsertion of sulfur [31].  Table 2. Sesquiterpenes from the genus Acanthella (molecular weight and formulae, chemical class, species, and sampling locations).      3.1.1. Aromadendrane-Type Sesquiterpenes In 1987, l-isocyanoaromadendrane (3) was reported as a novel isonitrile sesquiterpene from the fish toxic CH 2 Cl 2 fraction of A. acuta using SiO 2 CC (silica gel column chromatography), assigned by spectral and chemical methods [34].

Spiroaxane-Type Sesquiterpenes
Spiroaxane skeletons containing sesquiterpenes are of rare natural occurrence. Compound 19, a new sesquiterpene isocyanide with a spiroaxane (spiro [5,6] decane) skeleton was obtained from Chinese Acanthella sp., which is a 3-oxo derivative of 17 [41]. Additionally, 23 is a spiroaxane sesquiterpene with a C-6 isocyanate and was purified and characterized by Jumaryatno et al. from A. cavernosa specimens collected from Coral gardens/Gneerings reef/Mooloolaba/Australia and from A. klethra collected from Pelorus Island, Queensland, in addition to 17 [19,37].

Eudesmane-Type Sesquiterpenes
Acanthellin-1 (34) is a bicyclic sesquiterpene with isopropylidene and isonitrile moieties. It was separated as an optically active oil from the ether fraction of the acetone extract of A. acuta collected from the Bay of Naples using SiO 2 CC, and was characterized by NMR and chemical methods, as well as optical rotation [30] (Figure 4). A chromatographic investigation of A. klethra collected from Pelorus Island, Queensland, yielded sesquiterpenoids with isothiocyanate and isonitrile groups, i.e., 42, 44, and 45, that were assigned by spectral and X-ray analyses. Compounds 42, 44, and 45 are of eudesmane-type and are related to 34. Compounds 45 and 44 are different in stereo-configuration at C-7 [19,44]. Additionally, 39 and 43 are in the bicyclic cis-eudesmane class of sesquiterpenes, possessing isocyanate and isothiocyanate functionalities, respectively, and were purified and specified from A. acuta [47], whereas 35 is a stereoisomer of 5 [46]. possessing isocyanate and isothiocyanate functionalities, respectively, and were purified and specified from A. acuta [47], whereas 35 is a stereoisomer of 5 [46]. Axiriabiline A (38) was obtained from the acetone fraction of A. cavernosa collected from Xidao Island (Hainan Province, China) and characterized by NMR spectral data and optical rotation [48]. Burgoyne et al. (1993) purified two new sesquiterpenoid acanthenes B and C (35 and 37) along with 40 and 42-44 from the hexane fraction of unidentified Acantbella species using SiO2 flash CC/HPLC. The compounds were characterized by spectral analyses [46].

Other Sesquiterpenes
New axane sesquiterpenoids, 74 and 75, in addition to 77, were separated from the antifungal hexane fraction of A. cavernosa collected from the Hachijo-Jima Islands using flash CC/sephadex LH-20/HPLC. They were elucidated based on spectral data [23]. Compound 74 is a rare oxygenated tricyclic sesquiterpene cyanide belonging to axane-type sesquiterpenes [23]. Furthermore, 66, 75, 76, and 85 were isolated by SiO2 CC and RP-HPLC and identified by alpha-D, spectral data, and chemical methods from Japanese A. cavernosa [40]. Additionally, the new epimaaliane sesquiterpene 79, along with 78, were specified from the antimicrobial acetone extracts of A. pulcherrima using spectral and optical rotation measurements. Compound 79 is an enantiomer of 78 with an opposite [α]D value and differs at the ring junction [35]. Burgoyne et al. purified epimaaliane-type sesquiterpenes 80 and 81 from the hexane fraction of an unidentified Acantbella species using SiO2 flash CC and HPLC. The compounds were characterized by spectral analyses [46] ( Figure 7).

Other Sesquiterpenes
New axane sesquiterpenoids, 74 and 75, in addition to 77, were separated from the antifungal hexane fraction of A. cavernosa collected from the Hachijo-Jima Islands using flash CC/sephadex LH-20/HPLC. They were elucidated based on spectral data [23]. Compound 74 is a rare oxygenated tricyclic sesquiterpene cyanide belonging to axane-type sesquiterpenes [23]. Furthermore, 66, 75, 76, and 85 were isolated by SiO 2 CC and RP-HPLC and identified by alpha-D, spectral data, and chemical methods from Japanese A. cavernosa [40]. Additionally, the new epimaaliane sesquiterpene 79, along with 78, were specified from the antimicrobial acetone extracts of A. pulcherrima using spectral and optical rotation measurements. Compound 79 is an enantiomer of 78 with an opposite [α] D value and differs at the ring junction [35]. Burgoyne et al. purified epimaaliane-type sesquiterpenes 80 and 81 from the hexane fraction of an unidentified Acantbella species using SiO 2 flash CC and HPLC. The compounds were characterized by spectral analyses [46] (Figure 7).

Diterpenoids
Diterpenoids are among the common metabolites reported from various Acanthella species. These compounds are characterized by the existence of nitrogenous functionalities such as isothiocyanato, isocyano, and/or formamido groups. These diterpenes are classified into two major classes, kalihinanes and biflorane derivatives, according to the 8C side chain ( Figure 8 and Table 3). Kalihinanes have a decalin frame structure with C-Scheme 1. Biosynthesis pathway of 12, 16, 49, 68-73, and 84 [43].

Diterpenoids
Diterpenoids are among the common metabolites reported from various Acanthella species. These compounds are characterized by the existence of nitrogenous functionalities such as isothiocyanato, isocyano, and/or formamido groups. These diterpenes are classified into two major classes, kalihinanes and biflorane derivatives, according to the 8C side chain ( Figure 8 and Table 3). Kalihinanes have a decalin frame structure with C-7-attached dihydropyran, tetrahydropyran, or tetrahydofuran moiety. Additionally, these rings may carry various substituents such as OH, Cl, isothiocyanato, isocyano, and formamido groups or chlorine. They include kalihinenes, kalihinols, and kalihipyranes. Kalihinols are spilt into two main categories, tetrahydrofuran (I) and tetrahydropyran (II) groups, according to the C-7 substitution. Commonly, they have trans-decalin framework with a C-4 or C-5 tertiary alcohol and an isocyanate moiety at C-10 and/or C-5. The first group has a tetrahydrofuran moiety featuring NCS, NC, or Cl at C-15, or the gem-dimethyl is substituted by an isopropenyl moiety, whereas the tetrahydropyran group possesses Cl atom at C-14.

Kalihinenes
The first member of this group is kalihinene (139), which was purified from an A. klethra EtOH extract using SiO2 CC/ Develosil ODS-5 CC/HPLC and assigned by NMR and X-ray analyses [23]. Furthermore, compounds 143 and 144 were reported as novel monounsaturated kalihinane class diterpenes derived from A. Cavernosa toxic CH2Cl2 extracts against Artemia salina and Lebistes reticulatus using VLC/Flash/Rp-18 CC. These two compounds are diastereoisomers of 139 that feature a trans-decalin skeleton instead of the

Biflorane Diterpenes
From the Japanese A. cavernosa, biflora-4,9,15-triene (168) was separated, which is a rare biflorane diterpene related to 66, by replacing the methyl hydrogen of the isopropyl group of 66 with a prenyl group [40]. In 2012, Xu et al. reported 169-172 from CH2Cl2 extracts of South China Sea A. cavernosa, bearing a C-10 formamide group that varied in the decalin moiety (cis or trans) configuration and nature of C-7-linked side chain [63] ( Figure 15). Their structures were assigned by spectral and X-ray analyses. Compounds 169, 170, and 172 are trans-decalin derivatives, with a C-7 isoprenoid unit, a mono-olefinic isoprenoid sidechain, and a trisubstituted epoxide in the side chain, respectively. In con-

Biflorane Diterpenes
From the Japanese A. cavernosa, biflora-4,9,15-triene (168) was separated, which is a rare biflorane diterpene related to 66, by replacing the methyl hydrogen of the isopropyl group of 66 with a prenyl group [40]. In 2012, Xu et al. reported 169-172 from CH 2 Cl 2 extracts of South China Sea A. cavernosa, bearing a C-10 formamide group that varied in the decalin moiety (cis or trans) configuration and nature of C-7-linked side chain [63] ( Figure 15). Their structures were assigned by spectral and X-ray analyses. Compounds 169, 170, and 172 are trans-decalin derivatives, with a C-7 isoprenoid unit, a mono-olefinic isoprenoid sidechain, and a trisubstituted epoxide in the side chain, respectively. In contrast, 171 had a cis-decalin moiety [63]. Investigation of A. cavernosa DCM/MeOH extracts led to the separation of two oxirane analogs with a trans-decalin framework, 173 and 174, featuring a trisubstituted epoxide and a terminal epoxide group in the side chain, respectively. Compound 174 was suggested to be a precursor of the kalihipyran skeleton [45]. Clark et al. proposed that the biosynthesis of pyranyl and furanyl kalihinols involves epoxidation of the bifloradiene precursor's terminal double bond by a nucleophilic attack at either epoxide end by a cyanide ion to form a hydroxyisocyanide. The latter initiates cyclisation to afford a bicyclic system (Scheme 3). Compounds 173 and 174 are alternative epoxidation products. Compound 174 was suggested to be a precursor of the kalihipyran skeleton [45]. Investigation of A. cavernosa DCM/MeOH extracts led to the separation of two oxirane analogs with a trans-decalin framework, 173 and 174, featuring a trisubstituted epoxide and a terminal epoxide group in the side chain, respectively. Compound 174 was suggested to be a precursor of the kalihipyran skeleton [45]. Clark et al. proposed that the biosynthesis of pyranyl and furanyl kalihinols involves epoxidation of the bifloradiene precursor's terminal double bond by a nucleophilic attack at either epoxide end by a cyanide ion to form a hydroxyisocyanide. The latter initiates cyclisation to afford a bicyclic system (Scheme 3). Compounds 173 and 174 are alternative epoxidation products. Compound 174 was suggested to be a precursor of the kalihipyran skeleton [45].

Alkaloids
Several reports have stated the isolation of different classes of alkaloids from this genus. It is noteworthy that bromopyrrole alkaloids are the dominant type reported from the species of this genus (Table 4). Oroidin 177 is the first member of pyrrole 2-aminoimidazole alkaloids. These alkaloids were reported to have significant bioactivities, as well as chemical defense against predator fish.

Alkaloids
Several reports have stated the isolation of different classes of alkaloids from this genus. It is noteworthy that bromopyrrole alkaloids are the dominant type reported from the species of this genus (Table 4). Oroidin 177 is the first member of pyrrole 2aminoimidazole alkaloids. These alkaloids were reported to have significant bioactivities, as well as chemical defense against predator fish.   Compounds 177 and 179 are members of the oroidin family of alkaloids that are considered condensation products of prolines. Compound 179 was proposed to be derived from aminoimidazolinone (I) or amino acid (II) intermediates through 1N-C9 cyclization with subsequent side-chain oxidative breakdown [66] (Scheme 4).   Figure 16) [68]. Compounds 180 and 181 were obtained from A. aurantiaca BuOH extracts using Sephadex LH-20 and crystallization and were characterized by spectral and X-ray analyses [67]. In 2014, Macabeo and Guce reported the bromopyrrole-imidazole alkaloids 182-184 from CH 2 Cl 2 -MeOH extracts of A. carteri from The Philippines [17], while 185 is a pyrrole alkaloid isolated from the n-BuOH fraction of Acanthella sp. using Sephadex LH-20/Rp-18 CC [69].  A series of synthetic reactions including Suzuki-Miyaura coupling and debromination resulted in natural analogs 186 and 187, in addition to new synthetic derivatives (−)-4bromo-5-phenylphakellin and (−)-4,5-diphenylphakellin. It was found that the C-5 Br substitution with phenyl or H led to a loss in activity, revealing that the C-5 Br is important for α2B adrenoceptor agonistic activity (Scheme 5) [70]. A series of synthetic reactions including Suzuki-Miyaura coupling and debromination resulted in natural analogs 186 and 187, in addition to new synthetic derivatives (−)-4-bromo-5-phenylphakellin and (−)-4,5-diphenylphakellin. It was found that the C-5 Br substitution with phenyl or H led to a loss in activity, revealing that the C-5 Br is important for α2B adrenoceptor agonistic activity (Scheme 5) [70].
In 2002, Wiese and his group reported the synthesis of 190 using dihydrooroidin that is converted to 188 (Scheme 6). Then, thermal rearrangement of 188 in the presence of K 2 CO 3 produces 190 [73].

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Furthermore, 190 was purified from A. carteri using Sephadex LH-20/SiO2 CC, giving a bright-orange color with a diazotized benzidine. The compound was characterized by NMR and X-ray analyses, as well as chemical methods. Compound 190 is a 6R/10S brominated alkaloid with a fused C-C pyrrole linkage to the cyclic guanidine core belonging to the 189 series [71].
In 2002, Wiese and his group reported the synthesis of 190 using dihydrooroidin that is converted to 188 (Scheme 6). Then, thermal rearrangement of 188 in the presence of K2CO3 produces 190 [73]. kaloids, including a new analog mirabilin K (192), along with 191 and 193, from A. cavernosa collected in Southwestern Australia using diol flash chromatography/Rp-18/HPLC. The compounds were characterized by spectroscopic analyses and optical rotation measurements. Compound 192 has a 4S*/7S*/9R*/11S*/12R* configuration, which differs from 191 in the C9-CH3 group and with the presence of a N-substituted methine group ( Figure  17) [24]. Furthermore,194 and 195 were obtained by Fan et al. from the acetone extracts of A. cavernosa collected from the South China Sea [50].  Diketopiperazines, including the rare cyclo(L-Phe-L-Thr) and cyclo(L-Tyr-L-Ile) (196-202), along with decarboxylated amino acid 207 and deoxyribonucleotides 203-206, were reported and characterized from Fijian A. cavernosa (Figure 18). Their L-L absolute configuration was assigned based on an NMR and CD comparison with synthetic L-L analogs, as well as optical rotation measurements [72].

Steroid Compounds
In 2008, Qui et al. reported the purification of three new nor-steroids, 208-210, along with the known steroids 211-214 from the petroleum ether fraction of A. cavernosa obtained from Hainan Island, China, using SiO 2 CC/HPLC. The new steroids are related to Aring-contracted steroid analogs featuring carbonyl and ketone groups located at C-3 and C-4; they differ in their C-17 side chains [74] (Table 5 and Figure 19). In addition, 215 was obtained from the acetone extract of the same sponge collected from the South China Sea [50].

Other Metabolites
Compound 216 was separated from A. vulgata acetone extracts using an MgO column and crystallization from petroleum ether. The compound belongs to carotenoids, as it has a polyene chain with terminal aromatic moieties on both ends [75] (Figure 20). Mancini et al. were able to purify and characterize 219, a novel methyl-branched glycerol enol ether, and the related linear analog 218 from A. carteri obtained from Southern Red Sea Hanish Islands by utilizing flash CC/HPLC and spectral and chemical methods [76]. Compound 219 has an additional methyl group at C-2 of the sidechain compared to 218, and both have a 2`S configuration [76]. In 2010, Hammami et al. separated the sesterterpene 217 and cerebrosides 220-222 from Tunisian A. acuta diethyl ether extracts [25], whereas 226 was purified from the Chinese A. cavernosa by Fan et al. [50].

Other Metabolites
Compound 216 was separated from A. vulgata acetone extracts using an MgO column and crystallization from petroleum ether. The compound belongs to carotenoids, as it has a polyene chain with terminal aromatic moieties on both ends [75] (Figure 20). Mancini et al. were able to purify and characterize 219, a novel methyl-branched glycerol enol ether, and the related linear analog 218 from A. carteri obtained from Southern Red Sea Hanish Islands by utilizing flash CC/HPLC and spectral and chemical methods [76]. Compound 219 has an additional methyl group at C-2 of the sidechain compared to 218, and both have a 2'S configuration [76].

Biological Activities of Acanthella species and their Metabolites
Various Acanthella species and their metabolites have been found to display various bioactivities. The reported investigations are highlighted below, and some results are listed in Table 6. Table 6. Biological activity of reported metabolites from the genus Acanthella.

Compound Name
Biological Activity

Biological Activities of Acanthella Species and Their Metabolites
Various Acanthella species and their metabolites have been found to display various bioactivities. The reported investigations are highlighted below, and some results are listed in Table 6.

Antimicrobial and Antifouling Activities
McCaffrey and Endean reported that A. kleutha's toluene/methanol (1:3 v/v) and CH 2 Cl 2 extracts displayed antimicrobial potential comparable with penicillin G and streptomycin versus B. subtilis, K. pneumoniae, and S. aureus [77]. The A. carteri MeOH extract that was collected from Ras Nusrani in the Gulf of Aqaba was significantly effective versus B. subtilis, S. aureus, P. vulgaris, E. coli, C. tropicalis, and C. albicans (inhibition zone 9.0-23.3 mm) [78]. On the other hand, the n-BuOH fractions of A. acuta showed more promising antimicrobial potential versus A. niger, C. albicans, and S. aureus than CH 3 Cl fractions [79]. The MeOH extract of Acanthella elongata caused 100% and 87.5% inhibition of marine fish pathogens Aeromonas hydrophila, Pseudomonas aeruginosa, Vibrio alginolyticus, V. anguillarum, V. fischeri, V. fluvialis, V. pelagius, and V. vulnificus at 30 • C and 20 • C [20]. Additionally, A. cavernosa and A. ramosa from the Bay of Bengal exhibited activity versus the virulent fish pathogens Edwardsiella tarda, A. hydrophila, P. aeruginosa, V. alginolyticus, and P. fluorescens [80]. Rajendran          Additionally, 100 displayed antimicrobial effectiveness versus S. aureus, B. subtilis, and C. albicans [83]. Compound 125 was found to have notable antimicrobial potential against S. aureus, C. albicans, and T. mentagrophytes [18]. Bugni et al. assessed the antibacterial activity  of 88, 100, 104-108, 116, 125, 127, and 139 through in vitro inhibition of B. subtilis PY79 growth, as well as inhibition of bacterial folate biosynthesis using agar diffusion/microbroth dilution and luminescence rescue assays, respectively [21]. The results showed that the pyranyl-type 127 and 125 (MICs of 1.56 µg/mL) revealed a potent antibacterial potential; however, they only weakly inhibited the folate biosynthesis, suggesting an additional mechanism of action for these pyranyl derivatives. On the other hand, the furanyl-type 100, 108, and 139 displayed a more selective folate biosynthesis inhibition than pyranyl-type kalihinols. The existence of a formamido moiety at any position markedly decreased the activity, which could be due to a reduced cellular uptake. Additionally, the C-10 substitution pattern greatly affected the potency, which was evident by loss of activity in 88, which differs in the C-10 isonitrile group orientation from the potent 127 and 125 (which have an exo-methylene and isothiocyanate groups, respectively) [21]. Xu et al. reported that 151 showed antifungal activity against T. rubrum and M. gypseum (MICs of 8.0 and 32.0 µg/mL, respectively), while 150 had activity against C. albicans, C. neoformans, T. rubrum, and M. gypseum (MICs of 4.0-8.0 µg/mL). It was noted that the isonitrile functionalities had a substantial role in antifungal activity [63]. The antifungal effects of 20, 177, 178, 217, and 220-222 against phytopathogenic fungi Fusarium oxysporum f. sp. niveum, F. solani f. sp. cucurbitae, Pythium ultimum, and Alternaria solani were assessed. Compounds 177, 178, and 220-222 had antifungal activities against A. solani, whereas 20 was the most active against F. oxysporom, F. solani, and A. solani (IZDs of 11.5 to 25.0 mm) [25]. None of them exhibited activity towards P. ultimum [25].

Antioxidant Activity
A. carteri hydro-EtOH extracts revealed a DPPH scavenging ability (IC 50 of 56.94 µg/mL) compared to ascorbic acid (IC 50 of 0.67 µg/mL) [85]. Putra et al. stated that n-BuOH fractions of A. cavernosa had the largest phenolic content, followed by EtOAc, aqueous, and n-hexane fractions. These fractions demonstrated antioxidant potential with the % inhibition of DPPH radicals ranging from 16.40 to 40.57%, whereas the n-hexane fraction displayed the most powerful DPPH radical suppression (at a concentration of 171.86 µg/mL) [88].

Nanoparticles
Synthesis of nanoparticles (NPs) with green technology is beneficial over chemical procedures because of their lower environmental impacts [89,90]. The use of biological extracts of living organisms, such as actinomycetes, bacteria, yeast, plants, marine sponges, and fungi, in green synthetic processes indicates their considerable potential for NP synthesis [89]. Some researchers have reported the biosynthesis of NPs using species of the genus Acanthella that are cost-effective and compatible with pharmaceutical and biomedical applications and could be utilized commercially for large-scale production. In 2010, Inbakandan et al. synthesized highly stable AuNPs (gold nanoparticles) using an A. elongata extract by reducing aqueous AuCl 4 − , suggesting that this sponge is a perfect candidate for AuNP synthesis [91]. In another study in 2012, AgNPs were synthesized using the H 2 O-soluble extract of A. elongata. These NPs were characterized by UV, XRD (X-ray diffraction), TEM (transmission electron microscopy), and FTIR (Fourier transform infrared spectroscopy). It was found that amines of the sponge extract were accountable for the bio-reduction of the silver salt to the AgNps [90].

Conclusions
The current work presents extensive documentation of the reported studies on the genus Acanthella with a special focus on their diverse chemical classes of metabolites and their bioactivities. The sponges of this genus were obtained from various marine environments. A total of 226 metabolites from various species of this genus were reported in the period from 1974 to the beginning of 2023. These metabolites illustrated in this work belong mainly to terpene (sesqui-and di-terpenes), alkaloid, and steroid chemical classes ( Figure 21).
Metabolites have been reported from A. cavernosa, A. pulcherrima, A. klethra, A. acuta, A. carteri, A. costata, A. vulgate, and unidentified Acanthella species. A. cavernosa (177 compounds), Acanthella sp. (36 compounds), and A. acuta (17 compounds) are frequently studied members of this genus in terms of the number of isolated compounds and have proven to be rich in terpenes and alkaloids ( Figure 22). Interestingly, kalihinane-type diterpenoids are commonly purified from A. carvenosa, which could be a chemotaxonomic marker for this sponge.
In addition, bioactivity investigations of some species extracts are detailed in the literature. Sesquiterpene-and diterpene-containing nitrogen and alkaloids were the dominant metabolites reported from the species of genus Acanthella. These metabolites were mainly assessed for antifouling, antimicrobial, and cytotoxic activities. Limited studies have reported the larvicidal, antimalarial, cyclooxygenase inhibitory, α2B adrenoceptor agonistic, insecticidal, and anthelmintic capacities of these compounds. It is noteworthy that some kalihinol and kalihinene diterpenes have marked antifouling potentials. Additionally, 88 demonstrated notable antifouling, cytotoxic, antimalarial, COX-2 inhibition, and anthelmintic activities. The diverse structural features and bioactivities demonstrated by some of these metabolites make them attractive biological targets that are worthy of further investigation.
the bio-reduction of the silver salt to the AgNps [90].

Conclusions
The current work presents extensive documentation of the reported st genus Acanthella with a special focus on their diverse chemical classes of me their bioactivities. The sponges of this genus were obtained from various ma ments. A total of 226 metabolites from various species of this genus were re period from 1974 to the beginning of 2023. These metabolites illustrated in t long mainly to terpene (sesqui-and di-terpenes), alkaloid, and steroid che ( Figure 21).   (17 compounds) are frequently studied members of this genus in terms of the number of isolated compounds and have proven to be rich in terpenes and alkaloids ( Figure 22). Interestingly, kalihinane-type diterpenoids are commonly purified from A. carvenosa, which could be a chemotaxonomic marker for this sponge. In addition, bioactivity investigations of some species extracts are detailed in the literature. Sesquiterpene-and diterpene-containing nitrogen and alkaloids were the dominant metabolites reported from the species of genus Acanthella. These metabolites were mainly assessed for antifouling, antimicrobial, and cytotoxic activities. Limited studies have reported the larvicidal, antimalarial, cyclooxygenase inhibitory, α2B adrenoceptor agonistic, insecticidal, and anthelmintic capacities of these compounds. It is noteworthy that some kalihinol and kalihinene diterpenes have marked antifouling potentials. Additionally, 88 demonstrated notable antifouling, cytotoxic, antimalarial, COX-2 inhibition, and anthelmintic activities. The diverse structural features and bioactivities demonstrated by some of these metabolites make them attractive biological targets that are worthy of further investigation.

Conflicts of Interest:
The authors declare no conflict of interest.