Prompted by ethnomedicinal uses of Cordia species in preventing and treating various diseases in traditional medicine [7, 8], various studies have been undertaken to shed light on the biological activity of extracts and isolated compounds.

4.1 Cytotoxicity

Evaluation of the cytotoxic activities of cordiachromes [B (2), C (3)], cordiaquinol C (36), globiferin (45), alliodorin (46), and elaeagin (66), isolated from C. globifera, against KB (human epidermoid carcinoma of the mouth), BC-1 (human breast cancer cells), NCI-H187 (human small cell lung cancer), and Vero cell lines (African green monkey kidney fibroblast cells), were carried out. Compounds 2, 3 and 36 exhibited activity against the cell lines mentioned above with IC50 values ranging from 0.2 μM to 6.9 μM, while globiferin (45) was active only against NCI-H187 cells with an IC50 value of 0.5 ± 0.04 μM [17].

The cytotoxicity of compounds 48 and 49 from C. globosa was evaluated in vitro against human colon adenocarcinoma (HCT-116), ovarian carcinoma (OVCAR-8) and glioblastoma (SF-295) cell lines. None showed antiproliferative effects at maximum concentrations of 20 μM [5].

Cordiaquinones B (21), E (24), L (30), N (32), and O (33) from C. polycephala roots were tested against HCT-8 (colon), HL-60 (leukemia), MDA-MB-435 (melanoma), and SF295 (brain) cancer cell lines [4]. All the compounds were active against all these cancer cell lines with IC50 values ranging from 1.2 to 11.1 μM, but compounds 32 and 33 were most active with IC50 values from 1.2 to 3.4 μM. Compound 21 was most active against HL-60 cells with an IC50 value of 2.2 μM (positive reference Doxorubicin with IC50 value = 0.02–0.8 μM) [4]. The authors suggested that the elevated activity of compounds 32 and 33 may be related to the presence of the α, β-conjugated carbonyl at the end of the tigloyloxy chain [4]. Chemical investigation of C. globifera led to the isolation of globiferane (47), which showed weak cytotoxicity against the following cell lines: HepG2 (human hepatocellular liver carcinoma), MOLT-3 (acute lymphoblastic leukemia), A549 (human lung carcinoma), and HuCCA-1 (human lung cholangiocarcinoma) with IC50 values of 148.6, 3.7, 148.6, and 66.0 μM, respectively, using an MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazoliumbromide) assay [80]. Its derivative (1aS*,1bS*,7aS*,8aS*)-4,5-dimethoxy-1a,7a-dimethyl-1,1a,1b,2,7,7a,8,8a-octahydrocyclopropa[3,4]cyclopenta[1,2,b]naphtalene-3,6-dione (50) isolated from C. globosa roots exhibited significant cytotoxicity activity against colon (HCT-8), leukemia (HL-60, CEM), skin (B-16), and MCF-7 (breast) cancer cell lines, with IC50 values ranging between 1.2 and 5.0 μM [31]. The observed cytotoxicity exhibited by compound (50) may be due to the electron-donating methoxy groups on the aromatic ring. They are considered essential for anticancer activity [97]. According to Liew et al., compounds with a methoxy group substituted at C-2 of a quinone ring inhibit the growth of cancer cells. In addition, two or more methoxy substituents attached to its side showed more significant cytotoxicity [98].

Pessoa et al. evaluated the cytotoxicity of oncocalyxones A (18) and C (59) isolated from C. oncocalyx on human cell lines CEM (leukaemia), SW 1573 (lung tumour) and CCD922 (normal skin fibroblasts). Oncocalyxone A revealed toxicity with IC50 values of 0.76 ± 0.05, 7.0 ± 1.7 and 13.4 ± 0.6 μg/mL on CEM, SW 1573, and CCD922, respectively. Oncocalyxone B (58) also showed cytotoxicity with IC50 values of 1.5 ± 0.3, 7.5 ± 0.7 and 12.4 ± 0.5 μg/mL on CEM, SW 1573, and CCD922, respectively [93]. In addition, the cytotoxicity of oncocalyxone A (18) was evaluated against human normal [PBMC (peripheral blood mononuclear cells)] and tumoral [HL-60 (promyelocytic leukemia), SF-295 (glioblastoma), OVCAR-8 (ovarian carcinoma), and HCT-116 (colon carcinoma)] cell lines. It showed high cytotoxic activity on human leukemic cancer cells and normal leukocytes with IC50 values of 11.2 and 6.8 μM, respectively while exhibiting IC50 values above 16.5 μM against the remaining cell lines [85].

Moreover, Marinho-Filho et al. examined the cytotoxic effect of ( +)-cordiaquinone J (28) isolated from C. leucocephala on tumor cells. In an MTT assay, ( +)-cordiaquinone J (28) demonstrated cytotoxicity activity after 72 h of incubation against HL-60 (leukemia), HCT-8 (colon), SF295 (brain), MDA-MB-435 (melanoma), and normal PBMC (Lymphocytes) with IC50 values of 2.7 μM, 4.9 μM, 6.6 μM, 5.1 μM, and 10.4 μM, respectively compared to doxorubicin as a positive control with IC50 0.03 μM, 0.02 μM, 0.4 μM, 0.8 μM, and 1.7 μM, respectively [90].

The cytotoxicity of compounds 1, 2, 3, 36, 39, 40, 41, and 46 isolated from C. fragrantissima and their synthesized analogues (80, 81, and 82) against COS-7 (African green monkey kidney cells, epithelial-like) and HUH-7 (Human liver cancer cells, epithelial-like) were inactive in an XTT assay compared to MG 132 (carbobenzoxy-l-leucyl-l-leucyl-l-leucinal) used as reference [79].

Previous biological studies reported that the cytotoxic activity of quinones is due to their ability to react as dehydrogenating and oxidizing agents [20]. The cytotoxicity of quinones can also be explained by their capacity to inhibit electron transporters [99], protein adduct formation [100], oxidative phosphorylation [101], and reactive oxygen species (ROS) production [102] as well as through enzyme SH groups and direct DNA damage [39, 90].

4.2 Antifungal and larvicidal activities

Ioset et al. evaluated the antifungal and larvicidal activities of cordiaquinones B (21), E (24), F (25), G (26), and H (27) isolated from C. linnaei using TLC bioautographic and agar–dilution assays [81]. The compounds (21, 24–26) were active against Candida albicans and Dosporium cucumerinum with minimum inhibitory concentrations (MIC) ranging from 0.5 to 6 μM compared to nystatin (0.2–1.0 μM) used as a positive reference. However, compound 27 was inactive on both fungi. Its inability to inhibit the bacterial strains might be due to an epoxide [81]. Regarding their larvicidal potential, all the compounds showed activity against Aedes aegypti with MIC values between 12.5 and 50 μg/mL compared to reference plumbagin (MIC = 6.25 μg/mL), except for compound 27, which was not tested [81].

2-(2Z)-(3-Hydroxy-3,7-dimethylocta-2,6-dienyl)-1,4-benzenediol (52), isolated from the roots and bark of C. alliodora, exhibited weak activity against Cladosporium cucumerinum in bioautography and in agar-dilution assays with an MA (Minimum amount to inhibit growth on the SiO2 gel TLC) value of 5 μg and MIC of 15 μM respectively. This compound was inactive against C. albicans on TLC bioautography, and consequently, it was not tested by agar–dilution assay [27].

Cordiaquinones A (20), J (28), and K (29) showed antifungal activity against C. cucumerinum and C. albicans in bioautographic and agar-dilution assays with similar values (MA = 0.5 μg and MIC = 3 μg/mL) as the reference drug nystatin (MA = 0.1 μg and MIC = 1 μg/mL). These compounds also demonstrated weak larvicidal effects on Aedes aegypti with MIC values of 12.5—25 μg/mL [28].

The antifungal activity of ehretiquinone (35), isolated from C. anisophylla, was evaluated on C. albicans (DSY262 and CAF2-1 strains) using bioautography, agar–dilution assays and mature biofilm [91]. The compound was more active against strain DSY262 with a minimum inhibition quantity (MIQ) ≤ 5 μg compared to CAF2-1 with a MIQ of 25 μg. However, the compound (25) was inactive in the agar–dilution assay and mature biofilm [91].

Dettrakul et al. investigated the antifungal activity of cordiachrome B (2) and C (3), isolated from C. globifera. Both compounds exhibited weak antifungal activity against C. albicans with IC50 values of 7.7 μM and 4.6 μM, respectively, whereas globiferin (45), cordiaquinol C (38), and alliodorin (46) were inactive with IC50 values > 20 μM (positive control amphotericin B, IC50 = 0.08 μM) [17]. The antifungal activity of oncocalyxone A (18) done by Silva et al. showed that it did not inhibit the growth of tested fungi (C. albicans ATCC 10234™, C. neoformans ATCC 48184™, A. fumigatus ATCC 13073™, S. schenckii ATCC 201679™ and T. interdigitale 73896) with MIC values > 151 μg/mL [103].

4.3 Antileishmanial activity

The chemical investigation of C. fragrantissima wood extract led to the isolation of several cordiaquinols (36, 39, 40, and 41), cordiachromes (1, 2, and 3) and alliodorin (46) [73, 79]. The authors also synthesized related compounds, 1,4-p-dibromobenzoylcordiaquinol I (80), acetylcordiaquinol I (81), and acetylcordiaquinol C (82) [79]. All the compounds, including their derivatives, were assayed for antileishmanial assay against promastigote forms of Leishmania major, L. panamensis, and L. guyanensis using an MTT assay [79]. All the compounds were active with IC50 values of 1.4–81.4 μM were found more active on L. panamensis and L. guyanensis than L. major, while compounds 1, 2, 36, 40, 46, and 82 exhibited good activity against L. major with IC50 values of 4.1, 2.5, 4.5, 2.7, 7.0, and 1.4 μM, respectively, compared to Amphotericin B (IC50 less than 0.1 μM) used as a positive control [73, 79].

In related studies, cordiaquinone E (24), isolated from the roots of C. polycephala, was evaluated for its activity against promastigote and axenic-amastigote forms of L. amazonensis in vitro. The compound inhibited the growth of the promastigote form with an IC50 value of 4.5 ± 0.3 μM as well as against the axenic-amastigote form with 2.89 ± 0.11 μM, with selectivity indexes (SI) of 54.84 and 85.4, respectively. The evaluation of cordiaquinone E (24) against intracellular amastigotes was carried out to support the notion of antileishmanial activity. It led to a better result with an EC50 value of 1.92 ± 0.2 μM and an SI of 128.54 using an MTT assay. The growth inhibition assay of compound 24 on RAW 264.7 macrophages led to a CC50 value of 1246.81 ± 14.5 μM. Antileishmanial activity of compound 24 on L. amazonensis was evaluated using Amphotericin B [IC50 0.35 ± 0.05 μM (promastigote form); IC50 0.51 ± 0.02 μM (axenic-amastigote form)] and Meglumine antimoniate [IC50 21,502 ± 481 μM (promastigote form); IC50 1730 ± 33.5 μM (axenic-amastigote form)], as reference drugs respectively [89]. Rodrigues et al. explained the antileishmanial activity of cordiaquinone E. Firstly, by apoptosis, which associates externalization of phosphatidylserine and necrotic cell death, and secondly, by immunomodulation [89].

4.4 Anti-inflammatory activity

Five meroterpenoids (15, 38, 42, 43, and 44) isolated from C. glazioviana were evaluated for their anti-inflammatory activity against RAW 264.7 macrophage murine cells through cellular viability and lipopolysaccharide (LPS) induction. The cytotoxicity of isolated compounds was evaluated by MTT assay [34]. Rel-1,4-dihydroxy-8α,11α,9α,11α-diepoxy-2-methoxy-8aβ-methyl-5,6,7,8,8a,9,10,10a-octahydro-10-antracenone (15), cordiaquinol E (38), 10,11-dihydrofuran-1,4-dihydroxyglobiferin (42), 2-[(1ʹE,6ʹE)-3ʹ,8ʹ-dihydroxy-3ʹ,7ʹ-dimethylocta-1ʹ,6ʹ-dienyl]-benzene-1,4-diol (43), and 6-[(2ʹR)-2ʹ-hydroxy-3ʹ,6ʹ-dihydro-2H-pyran-5ʹ-yl]-2-methoxy-7-methylnaphthalene-1,4-dione (44) induced inflammation against RAW 264.7 macrophage cells by reducing cells viability with IC50 range value 71.66 ± 15.44–609.48 ± 5.05 μM. Lipopolysaccharide production was evaluated by inducing oxide nitric in RAW 264.7 cells. Among these compounds, 10,11-dihydrofuran-1,4-dihydroxyglobiferin (42) exhibited the best inhibition of NO (Nitric Oxide) synthesis with IC50 50.34 ± 9.88 μM, followed by compounds 44 (66.73 ± 10.28 μM) and 43 (105.83 ± 5.09 μM); the rest produced weak inhibition to induced inflammation against RAW 264.7 macrophage compared to dexamethasone (IC50 1.79 ± 0.04 μM) used as a positive control [34].

Ferreira et al. examined the anti-inflammatory activity of the water-soluble fraction of the heartwood methanolic extract of C. oncocallyx. The quinone fraction containing mainly oncocalyxone A (18) was very active in inhibiting paw edema induced by a carrageenan injection, with a 57% and 60% reduction three hours after a dose of 10 and 30 mg/kg body weight, respectively [104].

4.5 Antimicrobial, antibiofilm, antimycobacterial and antioxidant activities

Previous biological evaluation of C. oncocalyx revealed that oncocalyxone A (18) could inhibit the growth of Gram-positive and Gram-negative pathogenic strains, even clinical specimens. It was more sensitive to Staphylococcus species than to Enterococcus, Listeria, Acinetobacter, and Stenotrophomonas species with an MCI range from 9.43 μg/mL to 151 μg/mL, and it showed high sensitivity against S. epidermidis (ATCC 12228™) with MIC 9.43 μM compared to vancomycin (MCI 1 μM) used as reference[103]. It also inhibited the growth of S. aureus MED 55 (MIC 18.87 μM), S. aureus COL and S. epidermidis 70D (MIC 37.75 μM); and E. faecalis ATCC512999™ (MIC 75.5 μM) [103]

It showed inhibition of biofilm production by ⁓70% in methicillin-resistant S. aureus MED 55 strain (resistant clinical specimen) [103]

Khan et al. examined the antimicrobial and antioxidant activities of the GC–MS profile fractions of C. rothii roots. The n-hexane fraction, which contained cordiachrome C (3), exhibited weak antibacterial activity against Gram-positive and Gram-negative bacteria. While the MeOH marc extract containing cordiaquinol C (36) and cordiachromene A (57) showed good antibacterial activity against Staphylococcus epidermidis with a minimum inhibitory concentration (MIC) 250 μg/disk, EtOAc marc extract containing cordiol A (55) was inactive against all the tested bacteria [42].

Regarding the antioxidant activity of these extracts, MeOH and EtOAc marc left extract of C. rothii roots have good activity with EC50 93.75 μM than n-hexane extract, which showed weak activity with EC50 187.5 μM [42].

Previous biological studies examined the antioxidant activity of the methanol extract of the heartwood of C. oncocalyx. The quinone fraction (80% oncocalyxone A (18)) was evaluated in a rat model with CCl4-induced hepatotoxicity and the prolongation of pentobarbital sleeping time in mice by measuring plasma GPT and GOT. Only the quinone fraction inhibited the GPT level significantly (29%) with a 30 mg/kg dose. It also caused a significant reduction (45%) of CCl4-induced prolongation of pentobarbital sleeping time with a dose of 10 mg/kg. It confirmed the hepatoprotective effect involving free radical and lipoperoxidation and correlated with the antioxidant properties of quinones [105]. The latter is possibly due to the presence of oncocalyxone A, the main constituent [106]. Moreover, quinones are renowned for redox cycling ability [107]; this is related to their free radical scavenging activity which promotes their antioxidant activity [108].

In addition, cordiachrome C (3) and globiferin (45) showed significant antimycobacterial activity with MIC 1.5 and 6.2 μg/mL, respectively, while cordiachrome B (2) (12.5 μg/mL), cordiaquinol C (36) (25.0 μg/mL), diacetylcordiaquinol C (82) (25.0 μg/mL), alliodorin (46) (12.5 μg/mL), and elaeagin (66) (12.5 μg/mL) displayed weak activity compared to Rifampicin (0.0047 μg/mL), Isoniazid (0.05 μg/mL), and Kanamycin (2.5 μg/mL) used as standard drugs [17].

4.6 Antimalarial and hemolytic activities

Cordiachrome C (3), cordiaquinol C (36), and diacetylcordiaquinol C (82) were evaluated for antimalarial activity against Plasmodium falciparum using dihydroartemisinin (IC50 0.0012 μg/mL), used as reference. They exhibited significant activity with IC50 0.2 ± 0.1 μg/mL, 0.3 ± 0.0 μg/mL, and 0.4 ± 0.1 μg/mL respectively, more than cordiachrome B (2) (IC50 1.5 ± 0.2 μg/mL), globiferin (45) (IC50 2.1 ± 0.5 μg/mL), alliodorin (46) (IC50 3.1 ± 0.5 μg/mL), and elaeagin (66) (3.6 ± 0.1 μg/mL) [17].

Silva et al. evaluated the hemolytic activity of oncacalyxone A (18) through erythrocyte damage due to hemoglobin release. The compound did not show activity at the tested concentrations ≥ 151 μg/mL [103].

Compounds 21, 24, 30, 32, and 33 from C. polycephala roots were evaluated for hemolytic activity in mice erythrocytes. None was active with EC50 > 500 μmol L−1 [4].

4.7 Neuroinhibitory effect

Matos et al. (2017) examined the neuroinhibitory effect of different compounds (9–18) isolated from C. oncocalyx by mice vas deferens bioassay. Compounds 10, 11 and 14 significantly inhibited the neurogenic contraction by 76%, 69%, and 63%, respectively, whereas compounds 12 and 15 did not considerably affect neurogenic contraction. Compounds 9, 10, 14, 16, 17 and 18 showed a completely reversible neuroinhibitory effect upon adding the pharmacological antagonist Promethazine and a partial reversible effect by yohimbine. Neurogenic contraction induced by compound 11 was irreversible by adding naloxone, famotidine, promethazine or yohimbine antagonists. However, compounds 9, 10, 14, 16, 17 and 18 did not inhibit neurogenic contractions using the ODQ, famotidine or naloxone antagonists. The authors found that reversible action may be related to pre-synaptic terminal and pre-synaptic receptor inhibition due to the co-release of histamine and norepinephrine [32].

Although previous reviews reported different isolation methods and biological activities of Cordia quinones, we noted a lack of information that could help to valorize them. We suggest that future research should focus on the structure–activity relationships and mechanisms of action of the quinones of the genus Cordia. More in vivo biological tests and clinical studies should be performed. Up to now, just one clinical study has been done on Cordia quinones (cordiachrome F for allergenic). To improve the number of quinones isolated from Cordia species, pressurized liquid extraction (PLE) could be used. [109]. Pressurized hot water extraction to optimize the extraction of volatile components [110] and dry extraction to enrich powder fractions with an extensive range of secondary metabolites could also be done. [111, 112].