Containing well over 2040 species categorized within around 170 genera, Rutaceae family, many members of which are aromatic plants [10] is well-known for its rich chemical profile that makes it the most chemically versatile plant family [11]. Species of Rutaceae have been used in the industries of gastronomy and perfumery and also in traditional medicine [10]. Regarding biological activities, the species of this family have displayed to possess antimicrobial, anticholinesterase, antidiarrheal, antileishmanial, larvicidal, antiprotozoal, fungicidal, and antioxidant activities [10].

Consisting of around 250 species, Melicope plants are scattered through the tropical regions of southern hemisphere [12]. Like genus Acronychia, the species of genus Melicope have been utilized for their therapeutic and healing properties during centuries [13]. The chemical diversity of Melicope species is owed to the presence of compounds such as flavonoids, benzopyrans, alkaloids, and acetophenones [14]. Prenylated acetophenone compounds, however, are the key compounds that constitute the chemotaxonomic traits of the genus [15]. Li et al. reported the isolation of meliviticine A (1) and meliviticine B (2) from M. viticina (16). The former (1) was identified to be a non-aromatic prenylated isopropylated acetophenone derivative; furthermore, the zero value of the specific optical rotation of 1 hinted to it being a racemic mixture. 2 was also figured to be an isopropylated rearranged prenylated acetophenone [16]. The application of subsequent chiral HPLC resolution led to the isolation of the two pairs of enantiomers (1a and 1b) and (2a and 2b) for 1 and 2, respectively [16]. 1 and 2 were moderately effective against six strains of bacteria and fungi [16]. Adsersen et al. isolated and characterized two novel prenylated acetophenones, namely 2,6-dihydroxy-4-geranyloxyacetophenone (3) and 4-geranyloxy-2,6,b-trihydroxyacetophenone (4) from M. obscura and two acetophenones from M. obtusifolia var. arborea, namely 2,6-dihydroxy-4-geranyloxy-3-prenylacetophenone (5) and 4-geranyloxy-3-prenyl-2,6,b-trihydroxyacetophenone (6) [15]. Xu et al. extracted five acetophenone derivatives, three of which were with inseparable interconverting mixtures of tautomers from M. pteleifolia, specified as melicoptelin A (7), melicoptelin B1 (8a) and B2 (8b), melicoptelin C1 (9a) and C2 (9b), melicoptelin D1 (10a) and D2 (10b), and melicoptelin E (11) [17]. Prenylated acetophenone epimers, melicolone A (12) and melicolone B (13) were isolated from M. pteleifolia, followed by performing further chiral HPLC which yielded the entiomers ( +)- and (-)- of both compounds [18]. Nine more acetophenone derivatives, namely melicolones C-K (14–22) were also isolated from M. pteleifolia and examined for their drug resistance reduction characteristics [19]. 14–17 were identified to be as racemic mixtures and 18–22 were pure optically upon extraction. 18–22 boosted the cytotoxicity of doxorubicin with a reversal fold variating between 6.2 and 13.3 in a mixture with doxorubicin at the concentration of 5 µg/mL [19]. Xu et al. furthered isolated four new stereoisomer acetophenone compounds, evodialones A − D (23–26) from M. pteleifolia whose chiral-phase HPLC resolution resulted in the retrieval of eight enantiomers [20]. Shaari et al. investigated the core components of the extract of M. pteleifolia champ ex benth and identified 2,4,6-trihydroxy-3-geranylacetophenone (tHGA) (27) as the compound responsible for its attributed anti-inflammatory characteristics [21]. Upon the application on PBML 5-LOX human enzyme, 27 exerted an inhibitory activity with the IC50 value of 0.42 µM. It also dose-dependently inhibited the LTC4 production with the IC50 value of 1.8 µM with no inflicted cell toxicity [21]. Nakashima et al. succeeded in isolating four acetophenone derivatives assigned to as di-C-glycosides, pteleifolols A–D (28–31) from M. pteleifolia [22]. Studying on the same plant (M. pteleifolia), Nguyen et al. also isolated six more acetophenone derivatives, including five compounds with spiroketal-hexofuranoside rings, denoted melicospiroketal A-E (32–36) and one di-C-glycosidic phloroacetophenone, elucidated as 5-C-β-D-glucopyranosyl-3-C-(6-O-trans-p-coumaroyl)-β-Dglucopyranoside phloroacetophenone (37). The analysis of the extracted compounds indicated little to zero inhibitory effect against H1N1 influenza virus below the concentration of 400 µM [23]. Parsons et al. introduced three new acetophenone derivatives extracted from the stem bark of M. stipitata, named furostipitol (38), 3β- hydroxydihydropyranostipitol-4⍺-ethyl ether (39), and 3,4-dihydroxydihydropyranostipitol (85–40) [24]. The screening of the extract of M. borbonica resulted in the isolation of xanthoxylin (41) and methylxanthoxylin (42), neither 41, nor 42 possessed anti-inflammatory features against HeLa cells; regarding antifungal activities, however, both compounds proved effective. 41 and 42, inhibited Candida albicans and Penicillium expansum with the MIA (minimum inhibitory amount) of 25 and 15 µg, and > 50 and 20 µg, sequentially [25]. Xanthoxylin (41) has been proven to possess various pharmacological traits and potential applications. It has demonstrated anticancer properties, inhibiting the proliferation of oral squamous carcinoma cells, inducing apoptosis, autophagy, and cell cycle arrest [26]. Furthermore, xanthoxylin has shown promise as an agent targeting doxorubicin-resistant breast cancer cells, reducing their stemness and sensitizing them to doxorubicin [27]. Heterodimer compounds bearing acetophenone derivatives, namely meliquercifolin A (43) and meliquercifolin B (44) were found in the leaves of M. quercifolia [28]. 43 revealed to have strong cytotoxic activity against HeLa cancer cells with the IC50 value of 2.6 µM, while 44 maintained ineffective in this regard. Neither 43 nor 44 exhibited any inhibitory effects against P-388 and MCF-7 cancer cells [28]. Chen et al. reported the extraction of three acetophenone compounds from the fruits of M. semecarpifolia (45–47) [14]. The anti-inflammatory qualities of isolated compounds were evaluated by assessing both the suppressing of fMLP/CB-induced superoxide anion and the release of elastase by human neutrophils. With respect to the first test, 45–47 exerted the IC50 values of 21.37, 23.24, and 30.61 µg/mL, respectively. Regarding the latter evaluation, the IC50 values of 27.35, 26.62, and 28.73 µg/mL were documented in the same order [14]. M. lunu-ankenda afforded three prenylated acetophenone derivatives, listed as 8-Acetyl-3,4-dihydroxy-5,7-dimethoxy-2,2-dimethylchroman (48), Isoevodionol (49), and Isoevodionol methyl ether (50) [29]. Phenylethanones acetophenones (51–52) were also extracted from Euodia lunu-ankenda [30]. Le et al. detected the presence of two newly-discovered acetophenone compounds, namely melibarbinon A (53), and melibarbinon B (54) from M. barbigera. The cytotoxic availability of 54 was assessed against A2780 cell lines, which were suppressed at the IC50 value of 30 µM [31]. Vu et al. isolated three acetophenone derivatives, namely patulinones E − G (55–57) from M. patulinervia. The experiment regarding the inhibitory activity of the isolated compounds against α-glucosidase indicated the IC50 values of 41.68, 6.02, and 67.44 μM, attributed to 55–57, respectively [32]. Simonsen isolated four non-aromatic acetophenone compounds, named coodeanone A (58), coodeanones E-B (59), coodeanones Z-B (60) and coodeanone C (61) from M. coodeana [12]. Coodeanone B could be detected in the configuration of either E or Z; hence, being counted as two acetophenone derivatives [12]. The extract of M. erromangensis revealed to contain six novel acetophenone derivatives (62–67) [33]. Acetophenone compounds, refered to by the trivial names of melicopol (68) and methylmelicopo (69) were isolated from the bark of M. broadbentiana [34]. Isolated Acetophenones (1–69) from the genus Melicope are depicted in Fig. 3.

Acetophenone derivatives reported from Melicope species

The genus Acronychia is comprised of 44 species, distributed mainly along Asia and Australia [35]. The various parts of these plants including roots, leaves, stems, and the fruits have a wide range of medical applications such as mitigating diarrhea, asthma, itchy skin, cough, scales, hemorrhage, fever, etc. [36]. Acronychia species are also utilized for the treatment of fungal infection, spasm, pyrexia, stomachache, and rheumatism [35]. The species of the genus Acronychia have been a rich source of bioactive compounds including flavonoids, quinoline, lignans, steroids, coumarins, triterpenes, acridone alkaloids, and acetophenones [35]. Apart from owning therapeutic characteristics, different part of Acronychia plants have had other usages as their essential oil (EO) is used in cosmetics and their aerial parts are used as food and condiments [35].

The chemical compounds of Acronychia oligophlebia were studied by Chen et al. and seven new acetophenone-derived compounds were identified. These compounds, named acrolione A-G (70–76) were all discerned to be responsible for the antioxidant activities of their host plant as they were elucidated to possess the pertaining effects, using DPPH radical-scavenging capacity and FRAP assays. As regards the anti-inflammatory characteristics, 70, 72, 73, and 74 proved to be effective at the IC50 values of 26.4, 46.0, 79.4, and 57.3 µM against RAW 264.7 cells, respectively [37]. Three prenylated acetophenone derivatives, called acronyculatin (P-R) (77–79), were also extracted from A. oligophlebia by Niu et al. [16]. The cytotoxic activity of 77–79 against MCF-7 cancer cells was tested, which resulted in the inhibitory effect at the IC50 values of 56.8, 40.4, and 69.1 µM, respectively [16]. Yang et al. did conducted another investigation on A. oligophlebia which resulted in the isolation of six new acetophenone derivatives from the leaves of the plant (80–85). The cytotoxic activity of 81–85 were evaluated against MCF-7 cancer cells. 81 and 85 exhibited moderate inhibitory activities with the IC50 values of 33.5 and 25.6 µM, respectively; whereas 82–84 exerted weak effects with the IC50 values of 80.2, 71.1 and 46.3 μM, in the same order [38].

Acrovestone (86) was extracted and structurally elucidated from A. pedunculata by Wu et al. [39]. This compound displayed potent cytotoxic activity by exerting total inhibition at the concentration of 0.5 µg/mL in human KB tissue culture. It also demonstrated strong cytotoxicity against A-549, L-1210, and P-388 cancer cells at the ED50 values of 0.98, 2.95, and 3.28 µg/mL, respectively [39]. The continuation of examination on A. pedunculata led to the extraction of an undescribed arylketone acetophenone (87) [40]. Ito et al. discovered three novel acetophenone compounds, namely acrophenones A-C (88–90), in A. pedunculata, all of which failed to inhibit the growth of five leukemia cell lines (NALM6, Jurkat, HPB-ALL, K562, and PBMNC [41]. In pursuit of exploiting the chemical components of A. pedunculata for cancer prevention application, three more acetophenone derivatives were extracted from A. pedunculata by Ito et al., denoted acrophenones D-F (91–93) [42]. Kouloura et al. isolated three more acetophenone dimers from A. pedunculata and elucidated them as: acropyrone (94), acropyranol A (95), and acropyranol B (96). It is noteworthy that prenylated acetophenone dimers are found exclusively in the genus Acronychia [43]. The continuation of research on A. pedunculata, led to the isolation of five more acetophenone compounds by Su et al. acronyculatins A-E ( 97–101) [44]. 77 was also discovered to be in the chemical profile of A. pedunculata [45]. Upon the application on murine leukemia P-388 cells, 77 displayed an inhibitory effect with the IC50 value of 15.42 µM [45]. Acetophenone compounds, assigned as acroquinolones A-B (102 and 103), belonging to a class of acetophenone-alkaloid hybrids were extracted from A. pedunculata (L.) Miq. These compounds were tested against a group of cancer cell lines and proved to exhibit minor inhibitory effects against A549 and HCT116 and moderate cytotoxicity against HT29 and HeLa with the IC50 values of 21.8 and 14.2 µg/mL, respectively [46]. Nathabumroong et al. isolated an isoprenylated acetophenone, named 5’-prenylacrovestone (104) from A. pedunculata [47]. Seven acetophenone monomers, named acronyculatins I − O (105–111) were detected and extracted from A. trifoliolata by Miyake et al. The isolated compounds were evaluated for their antiproliferative properties against five lines of human cancer cells specified as A549, KB, KB-VIN, MDA-MB 231, and MCF-7. While 105 and 106 caused their corresponding inhibitory effects at the IC50 values of 26.6, 25.6, 19.2, > 40, and 30.8 µM (105), and 19.9, 20.4, 16.2, 22.6, and 19.4 µM (106), respectively, the remainder of isolated compounds exhibited IC50 values excessing 40 µM for the collective cell lines [48]. A. crassipetala was elucidated to host two prenylated acetophenones, namely crassipetalonol A (112) and crassipetalone A (113). The latter (113) had been previously detected in Euodia lunu-ankenda, along with the report of its fungicide activity [30], and Urtica dioica L.. 112 also showed to possess high levels of toxicity and little to none antibacterial traits when tested at the high concentration of 156 µM against ESKAPE pathogenes [49]; Comparatively, 113 elucidated to have strong antibacterial activity as it inhibited Entercoccus faecium and Gram-positive bacteria, S. aureus at the MIC75 values of 2.6 and 20.6 µM, respectively [49]. The derived acetophenone compounds from the genus Acronychia are illustrated in Fig. 4.

Acetophenone derivatives reported from the genus Acronychia

Several actephonones were isolated from other species of Rutaceae (Fig. 5). Goh et al. introduced two phloroacetophenone derivatives, namely melifolione 1a (114) and melifolione 1b (115) from Euodia latifolia [50]. The leaves of Bosistoa euodifoumis afforded the prenylated acetophenone derivative, called franklinone (116) [51]. Chou et al. extracted acetophenone derivatives, identified as 4-(1'-geranyloxy)-2,6-dihydroxy-3-isopentenylacetophenone (117), 2-(1'-geranyloxy)-4,6-dihydroxyacetophenone (118), 4-(1'-geranyloxy)-2,6-dihydroxyacetophenone (119), and 4-(1'-geranyloxy)-P,2,6-trihydroxyacetophenone (120) from E. merrillii [52]. Hartmann and Nienhaus discovered an acetophenone compound, xanthoxylin (41), that was extracted from the bark of Citrus limon, infected two strains of fungi, Hendersonula toruloidea and Phytophthora citrophthora. Having been absent in the healthy barks of Citrus lemon, the lesion-tissue-extracted 41 was found trice the concentration it had when inhibiting the growth of the pertaining fungi in vitro at the ED50 value of 0.8 mM. The concentration of 41, also, peaked in the dead tissue [53]. Four novel prenylated acetophenone compounds were isolated from Bosistoa selwynii identified as selwynone (121), pyranoselwynone (122), furanoselwynone (123), and isofuranoselwynone (124) [54]. Quader et alextracted and characterized acetophenones 41 from Acradenia frankliniae [55].

Acetophenone derivatives reported from other Rutaceae species

Titled the biggest family of flowering plants, Asteraceae is comprised of more than 1600 genera and 25,000 species scattered around the world [56]. Most species, however, are present more densely in the arid and semi-arid regions of subtropical areas [57]. Members of Asteraceae have been long used for their medicinal traits such as antipyretic, hepatoprotective, smooth muscle relaxant, laxatives and their ability to heal flatulence, lumbago, hemorrhoids, etc. Furthermore, the anti-oxidant and anti-inflammatory activities of the members of this family are well-acknowledged [57]. Therefore it can be deduced that the majority of Asteraceae members are categorized as medicinal plants, owing to their rich chemical profile, including flavonoids, mucilage, tannins, glycosides, and carbohydrate [57]. The presence of more phytochemical components, namely lignans, polyphenolic compounds, sterols, phenolic acids, diterpenoids, polyphenols and saponins has also been reported to contribute to their therapeutic effects [58]. Acetophenones discovered in some genera of Asteraceae have proven to contribute to the pertaining properties of the family species. Embarking on the attempt to explore the cytotoxic constituents of Eupatorium fortune, Chang et al. isolated an acetophenone derivative, known as eupatofortunone (125) that was elucidated to contribute to the therapeutic values of the host plant [59]. 2-Hydroxy-4-methylacetophenone (126) [60] was also extracted during the process. Compounds 125 and 126 were assayed as to their ability to suppress the proliferation of MCF-7 and A549 cells. Regarding 125, the inhibition was observed at the IC50 value of 82.15 and 86.63 µM, respectively. In another study, 126 showed no the antiproliferation effect (IC50 values of > 100 µM) for both cell lines [59]. Trang et al. also extracted 126 from the aerial parts of E. stoechadosmum [60]. Mendes do Nascimento et al. obtained two p-hydroxyacetophenone (127) derivatives from Calea uniflora and denoted them 2-senecioyl-4-(methoxyethyl)-phenol (128), and 2-senecioyl-4(pentadecanoyloxyethyl)-phenol (129). p-Hydroxyacetophenone (127) has shown various pharmacological activities and potential applications. It has been found to possess hepatoprotective, antioxidative, and anti-inflammatory properties, making it a potential treatment for alcoholic liver disease. It has also demonstrated antioxidative, antinociceptive, and anti-inflammatory effects, suggesting its therapeutic potential in inflammation-associated diseases [61]. Both 128 and 129 exhibited trypanocidal activities against Trypanosoma cruzi parasite. At the administration doses of 100, 250, and 500 µg/mL, 128 and 129 inflicted lysis on Trypanosoma cruzi at the percentage-wise records at three different concentrations of 27.5 (10 µg/mL), 28.9 (250 µg/mL), 42.0 (500 µg/mL), and 8.8 (10 µg/mL), 24.7 (250 µg/mL), and 70.9 (500 µg/mL), respectively [62]; furthermore, 128 and 129 both displayed antifungal traits against four strains of Candida spp, namely C. albicans, C. krusei, C. parapsilosis, C. glabrata, and four dermatophytes including two strains of Trichophyton rubrum (Tr-5 and Tr-19), and two strains of Trichophyton mentagrophyte (Tm-9 and Tm-17). Both 128 and 129 exerted fungitoxicity against all the strains of dermatophytes with the MIC value of 1000 µg/mL. While both compounds were ineffective against inhibiting C. krusei and C. parapsilosis, both 128 and 129 suppressed C. albicans at the same MIC value of 500 µg/mL, and 128 deterred the proliferation of C. glabrata with the MIC value of 500 µg/mL [62]. The aerial parts of Ophryosporus macrodon yielded eight novel diprenylated p-hydroxyacetophenone derivatives (130–137). 136 and 137 were elucidated to be threo and erythro isomers, respectively [63]. 4'-Hydroxy-3'-(3-methylbutanoyl)acetophenone (138) was isolated from Flourensia cernua by Bohlmann and Grenz [64] and from Polymnia sonchifolia by Takasugi and Masuda [65]. 5-Acetyl-2-(1-hydroxy-lmethylethyl)benzofuran (139) was also isolated in this assay. Thomas-Barberan et al. identified 4-hydroxy3(isopentent-2-yl) acetophenone (140) from Helichrvsum italicum, and revealed its antibacterial activity against gram positive bacteria (Bacillus sp. and Staphylococcus epidermidis) and E. coli gram negative bacteria at the MIC values of > 100 and 25 ug/mL, respectively [66]. 140, also, exhibited antifungal quality by inhibiting 5 strains of fungi (Cladosporium herbarum, Phyrhophthora capsica, Neurospora crassa, Penicillium italicurn, and P. digitalum) at the MIC values of 10, 50, 100, 100, and 50 µg/mL, respectively [66]. Takasugi and Masuda also extracted 140 from Polymnia sonchifolia [65]. The examination of H. italicum with respect to its constituting compounds led to the identification of a new acetophenone derivative, named gnaphaliol 9-O-propanoate (141) [