Structure–activity relationship studies of 4-methylcoumarin derivatives as anticancer agents

Context: Cancer is a leading cause of death worldwide and novel chemotherapeutic agents with better efficacy and safety profiles are much needed. Coumarins are natural polyphenolic compounds with important pharmacological activities, which are present in many dietary plants and herbal remedies.

Objectives: The objective of this study is to investigate natural and synthetic coumarin derivatives with considerable anticancer capacity against three human cancer cell lines.

Materials and methods: We synthesized 27 coumarin derivatives (mostly having 4-methyl moiety) and examined their cytotoxic effect on three human cancer cell lines, K562 (chronic myelogenous leukemia), LS180 (colon adenocarcinoma), and MCF-7 (breast adenocarcinoma) by MTT reduction assay. Screened compounds included 7-hydroxy-4-methylcoumarins (7-HMCs), 7-acetoxy-4-methylcoumarins (7-AMCs), and different dihydroxy-4-methylcoumarin (DHMC) and diacetoxy-4-methylcoumarin (DAMC) derivatives. Some compounds with methoxy, amine, and bromine substitutions were also examined.

Results: 7,8-DHMCs bearing alkyl groups at C3 position were the most effective subgroup, and of which, the most potent is compound 11, with an n-decyl chain at C3, which had IC₅₀ values of 42.4, 25.2, and 25.1?µM against K562, LS180, and MCF-7 cells, respectively. The second most active subgroup was 7,8-DAMCs containing ethoxycarbonylmethyl and ethoxycarbonylethyl moieties at C3 position. Compound 27 (6-bromo-4-bromomethyl-7-hydroxycoumarin), the only derivative containing bromine also showed reasonable cytotoxic activities (IC₅₀ range: 32.7–45.8?µM).

Discussion and conclusion: This structure–activity relationship (SAR) study of 4-methylcoumarins shows that further investigation of these derivatives may lead to the discovery of novel anticancer agents.     

Synthesis of novel 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole derivatives as antiproliferative agents: A structure–activity relationship study

A series of novel 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole derivatives 5(a–m) were synthesized with different substituted aromatic/heterocyclic acid chlorides (R-CO-Cl) and characterized by ¹H NMR, LC/MS, FTIR and elemental analyses. All the compounds synthesised were evaluated for their antiproliferative activity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The antiproliferative effects of the synthesised compounds were tested against viable human skin fibroblast cells and carcinoma cells namely HeLa cells, HT-29 cells, MCF-7 cells, HepG-2 cells by adopting positive and negative control. The importance of the aromatic and heterocyclic moiety was confirmed. From the SAR studies, it reveals that, the substitution at N-terminal of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole by the heterocyclic ring plays a dominant role and was responsible for the antiproliferative activity. Among the synthesized compounds 5a, 5d and 5k have showed potent antiproliferative activity on all the carcinoma cells tested.     

Synthesis, antitumor activity of 2-amino-4H-benzo[h]chromene derivatives, and structure–activity relationships of the 3- and 4-positions

Several 2-amino-4H-benzo[h]chromenes (3a–i) and (5a–h) were obtained by reaction of 4-chloro-1-naphthol (1) with α-cyanocinnamonitrile (2a–i) or ethyl α-cyanocinnamate derivatives (4a–h), respectively. Structures of these compounds were established on the basis of spectral data. The antitumor activity of the synthesized compounds was investigated in comparison with Vinblastine, Colchicine, and Doxorubicin well-known anticancer drugs, using MTT colorimetric assay. Among them, the compounds 5e, 3c, 5f, b, d, 3d, 5c, a were the most active against MCF-7, 5a against HCT-116 and 5a, 3e, a against HepG-2 as compared with the standard drug Vinblastine, while the compounds 5e, 3c, 5f, b, d, 3d, 5c, a, h, 3i, g, a, e were the most active against MCF-7, 5a, c, e, f, b, 3e, c, g, b, 5d, h, 3d, i, 5g against HCT-116, 5a, 3e, a, 5e, 3c, 5d, c, f, 3b, 5g, 3g, 5h against HepG-2 as compared with the standard drug Colchicine. The structure–activity relationships of the 3- and 4-positions were discussed.     

Synthesis and structure–activity relationship of acylthiourea derivatives as inhibitors of microsomal epoxide hydrolase

Microsomal epoxide hydrolase (mEH) is a liver enzyme involved in hepatic and extrahepatic metabolism of xenobiotics, namely, the hydrolysis of epoxides and arene oxides to the corresponding diols. In some cases, the action of mEH activates xenobiotics, such as 7,12-dimethylbenz[a]anthracene, potentiating their ability to induce mammary, ovarian, skin, and other types of cancer according to Rajapaksa et al. (Toxicol. Sci 96:327–334, 2006). Similarly, mEH polymorphisms have been linked to several types of cancer as stated by Benhamou et al. (Cancer Res. 58:5291–5293, 1998), and also to emphysema according to Smith and Harrison (Lancet 350:630–633, 1997). mEH inhibitors would provide insight into the multiple roles of this enzyme and potentially have clinical relevance for preventing disease in high-risk individuals. In this article, we describe the design and synthesis of acylthiourea analogs as inhibitors of mEH.     

Synthesis and structure–activity relationship of nuciferine derivatives as potential acetylcholinesterase inhibitors

Acetylcholinesterase inhibitors (AChEIs) are currently the best available pharmacotherapy for Alzheimer patients, but because of bioavailability issues, there is still great interest in discovering better AChEIs. The aporphine alkaloid is an important class of natural products, which shows diverse biological activity, such as acetylcholinesterase inhibitory activity. To find new lead AChEIs compounds, eight aporphine alkaloids were synthesized by O-dealkylation, N-dealkylation, and ring aromatization reactions using nuciferine as raw material. The anti-acetylcholinesterase activity of synthesized compounds was measured using modified Ellman’s method. The results showed that some synthesized compounds exhibited higher affinity to AChE than the parent compound nuciferine. Among these compounds, 1,2-dihydroxyaporphine (2) and dehydronuciferine (5) were the most active compounds (IC₅₀ = 28 and 25 μg/mL, respectively). Preliminary analysis of structure–activity relationships suggested that aromatization of the C ring, the presence of the alkoxyl group at C1 and the hydroxy group at C2 position as well as the alkyl substituent at the N atom were favorable to the acetylcholinesterase inhibition. Molecular docking was also applied to predict the binding modes of compounds 1, 2, and 9 into the huperzine A binding site of AChE.     

Quantitative structure–activity relationship studies of diarylpyrimidine derivatives as anti-HIV drugs using new three-dimensional structure descriptors

A novel three-dimensional holographic vector of atomic interaction field (3D-HoVAIF) was used to describe the chemical structures of 34 wild-type DAPYs, 33 mutant form L100I, 30 mutant form Y181C and 29 mutant form Y188L as anti-HIV drugs. Here four quantitative structure activity relationship models were built by partial least square regression. The estimation stability and prediction ability of models were strictly analyzed by both internal and external validations. The correlation coefficient (R _cum ² ), leave-one-out cross-validation correlation coefficient (Q _CV ² ) and predicted values versus experimental ones of external samples (Q _ext ² ) were 0.925, 0.769 and 0.949 for 34 diarylpyrimidines; 0.899, 0.788 and 0.889 for 33 mutant form L100I; 0.844, 0.761 and 0.935 for 30 mutant form Y181C; 0.890, 0.757 and 0.912 for 29 mutant form Y188L. These values indicated that the built PLS models had both favorable estimation stability and good prediction capabilities. Furthermore, the satisfactory results showed that 3D-HoVAIF could preferably express the information related to the biological activity of DAPY derivatives.     

Synthesis, antitumor activity, and structure–activity relationship of some 4H-pyrano[3,2-h]quinoline and 7H-pyrimido[4′,5′:6,5]pyrano[3,2-h]quinoline derivatives

Several 4H-pyrano[3,2-h]quinoline (3a–d, 4a, 7a,b, 9a–c, 10a,b, 11a,b, and 13a–c) and 7H-pyrimido[4′,5′:6,5]pyrano[3,2-h]quinoline derivatives (8a–c) were obtained by treatment of 8-hydroxyquinoline (1a) and 8-hydroxy-2-methylquinoline (1b) with α-cyano-p-chloro/bromocinnamonitrile (2a,b) or 4H-pyrano[3,2-h]quinoline derivatives (3a,c,d) with different electrophilic reagents followed by nucleophilic reagents. Structures of these compounds were established on the basis of spectral data. The antitumor activity of the synthesized compounds was investigated in comparison with Vinblastine. Among them, compounds 3c,d, 4a, 8b, 9b,c, 11a,b, and 13a,c inhibited the growth of cancer cells compared to Vinblastine. The structure–activity relationships were discussed.     

Serotonin transporter activity of imidazolidine-2,4-dione and imidazo[2,1-f]purine-2,4-dione derivatives in aspect of their acid–base properties

Affinities of arylpiperazinylalkyl derivatives of imidazo[2,1-f]purine-2,4-dione and imidazolidine-2,4-dione for serotonin transporter and their acid–base properties were evaluated. The dissociation constant (pK _a) of compounds 1–22 were determinated by potentiometric titration and calculated using pKalc 3.1 module of the Pallas system. The data from experimental methods and computational calculations were compared and suitable conclusions were reached.     

Structure–activity relationship studies of indolin-2-one derivatives as vascular endothelial growth factor receptor inhibitors and anticancer agents

Angiogenesis is a requirement for the growth of cancer cells. The family of vascular endothelial growth factor receptors (VEGFRs) is the main target in metastasis. Indolin-2-one is proved to be an essential scaffold of antiangiogenic drugs. Sunitinib is the first oral indolin-2-one derivative marketed as a VEGFR inhibitor in the treatment of renal cell carcinoma and gastrointestinal stromal tumors. Therefore, novel compounds possessing the scaffold of sunitinib were designed and synthesized by different researchers to improve the anticancer activity, bioavailability, and solubility, and to decrease the toxicity of sunitinib. In this comprehensive review, the structure–activity relationship of different indolin-2-one analogs as VEGFR inhibitors is discussed. It has been observed that the indolin-2-one core is necessary for the inhibition of VEGFRs. It was determined that substitutions at C-3 of the oxindole ring play an important role in their antiangiogenic and anticancer activities.     

Synthesis and structure–activity relationships of serotonin derivatives effect on α-glucosidase inhibition

The α-glucosidase inhibitory activities of serotonin derivatives were evaluated. Two serotonin derivatives, N-p-coumaroyl serotonin (2) and N-caffeoyl serotonin (4) exhibited most potent inhibition on α-glucosidase, whereas, cinnamic acid derivatives were less efficient. Furthermore, we analyzed their structural importance for α-glucosidase inhibition. The linkage of cinnamic acid moiety and serotonin moiety and the olefin in cinnamic acid moiety of serotonin derivatives were crucial for α-glucosidase inhibition. This is the first report on structure–activity relationships (SAR) for the α-glucosidase inhibitory activity of serotonin derivatives.     

Synthesis,antibacterial and antifungal activities of naphthoquinone derivatives: a structure–activity relationship study

The synthesis of 1,4-naphthoquinone derivatives is of great interest since these compounds exhibit strong activity as antimalarial, antibacterial, antifungal and anticancer agents. A series of 50 naphthoquinone derivatives was synthesized and evaluated for antibacterial and antifungal activity against Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, Candida krusei, Candida parapsilosis and Cryptococcus neoformans using the broth microdilution method. The Candida species were the most susceptible microorganisms. Halogen derivatives of 1,4-naphthoquinone presented strong activity, e.g., 2-bromo-5-hydroxy-1,4-naphthoquinone, which exhibited inhibition at an MIC of 16 µg/mL in S. aureus, and 2-chloro-5,8-dihydroxy-1,4-naphthoquinone, with an MIC of 2 µg/mL in C. krusei. These compounds showed higher activity against fungi, but the antibacterial activities were very low. The study of structure–activity relationships is very important in the search for new antimicrobial drugs due to the limited therapeutic arsenal.     

Synthesis and studies on antidepressant activity of 2′,4′,6′-trihydroxychalcone derivatives

In this study, we synthesized a series of 2′,4′,6′-trihydroxychalcone derivatives and evaluated their antidepressant activities. The results of the nine compounds showed significantly reduced times during the forced swimming test at a dose of 10?mg/kg, indicative of antidepressant activity. Among the compounds, 2-bromo-2′,4′,6′-trihydroxychalcone (3h) was found to be the most potent, and it was observed that compound 3h at dose of 10, 20, and 40?mg/kg significantly reduced the duration of immobility times in the FST and TST in mice 30?min after treatment.     

Synthesis and biological evaluation of novel 2′,4′,5′-trimethoxyflavonol derivatives as anti-inflammatory and antimicrobial agents

A series of novel 3-hydroxy-2-(2,4,5-trimethoxyphenyl)-4H-chromen-4-one (flavonol) derivatives (2a–u) of biological interest have been prepared via CLAISEN–SCHMIDT condensation followed by ALGAR–FLYNN–OYAMADA reaction and to search for the potent nonsteroidal anti-inflammatory agents from this novel series. All the synthesized compounds have been screened for their in vitro proinflammatory cytokines tumor necrosis factor (TNF-α) and interleukin-6 (IL-6) inhibitory activity along with antimicrobial activity. As many as three compounds viz. 2h, 2l, and 2q from this novel series were found to be potent TNF-α and IL-6 inhibitor (up to 72–81 % TNF-α and 86–92 % IL-6 inhibitory activity) but at 10 μM concentration as compared with the standard dexamethasone (71 % TNF-α and 84 % IL-6 inhibitory activities at 1 μM concentration). While the compounds 2d, 2m, 2n, and 2s were found to be potent antimicrobial agent showing even 2–2.5-fold more potency than that of standard ciprofloxacin and miconazole at the same MIC value of 10 μg/mL.     

Synthesis,structure–activity relationship and antinociceptive activities of some 2-(2′-pyridyl) benzimidazole derivatives

In the present study, a new series of 2-(2′-pyridyl) benzimidazole derivatives 1–11 were resynthesized and evaluated for analgesic activity. The 2-(2′-pyridyl) benzimidazole was quaternized at its nitrogen atom in the ring with various substituted and unsubstituted phenacyl halides. As a result, eleven novel derivatives were synthesized. The structures of these new synthetic derivatives of 2-(2′-pyridyl) benzimidazole were confirmed by using different spectroscopic techniques i.e., UV/Visible, IR, ¹HNMR and Mass spectroscopy. Percentage of carbon, hydrogen and nitrogen was also determined by elemental analysis. All the synthetic compounds showed significant analgesic activity with dose-dependent manner.     

Studies on the synthesis,in vitro antitumor activity of 4H-benzo[h]chromene, 7H-benzo[h]chromene[2,3-d]pyrimidine derivatives and structure–activity relationships of the 2-,3- and 2,3-positions

Some 4H-benzo[h]chromene and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives were prepared as potential cytotoxic agents. The in vitro cytotoxic activity of the synthesized compounds was investigated in comparison with the well-known anticancer standard drugs Vinblastine, Colchicine, and Doxorubicin using MTT colorimetric assay. It was found that compounds 23, 15, 20, and 21 showed the highest anticancer activity against the three tumor cell lines MCF-7, HCT, and HepG-2, compared with Vinblastine and Colchicine, while compound 23 was the most active against HepG-2 as compared with Doxorubicin. We explored the SAR of 4H-benzo[h]chromenes with modification at the 2-,3- positions and 7H-benzo[h]chromeno[2,3-d]pyrimidine at 2,3-positions. The structure–activity relationship (SAR) study revealed that the antitumor activity on 4H-benzo[h]chromene and 7H-benzo[h]chromeno[2,3-d]pyrimidine derivatives were significantly affected by the lipophilicity (hydrophobic or hydrophilic), of the substituent at 2-,3- and 2,3-positions. Structures of these compounds were established on the basis of spectral data, IR, ¹H NMR, ¹³C NMR, ¹³C NMR-DEPT, and MS data.     

Docking and three-dimensional quantitative structure–activity relationship analyses of imidazole and thiazolidine derivatives as Aurora A kinase inhibitors

Aurora A kinase is involved in the inactivation of apoptosis leading to ovarian, breast, colon, and pancreatic cancers. Inhibitors of Aurora A kinase promote aberrant mitosis resulting in arrest at a pseudo G1 state to induce mitotic catastrophe, ultimately leading to apoptosis. In this study, ligand-based and docking-based three-dimensional quantitative structure–activity relationship (3D-QSAR) analyses of imidazole and thiazolidine derivatives as potential Aurora A kinase inhibitors were performed. The results provided highly reliable and predictive 3D-QSAR comparative molecular similarity index analysis (CoMSIA) models with a cross-validated q² value of 0.768, non-cross-validated r² value of 0.983, and predictive coefficient \({\text{r}}_{\text{pred}}^{2}\) value of 0.978. CoMSIA contour maps suggested that the NH and benzyl hydroxy groups in R₉, and the CO group in the thiazolidine ring and pyridine ring were important components for biological activity. The maps also suggest that the introduction of hydroxy groups at C₂ of the imino-phenyl ring, C₅ in the pyridine ring, or the substitution of the imino-phenyl ring for the imino-2-pyridine ring could be applied to enhance biological activity.     

Linear diarylheptanoids as potential anticancer therapeutics: synthesis,biological evaluation,and structure–activity relationship studies

In efforts to develop effective anticancer therapeutics with greater selectivity toward cancerous cell and reduced side-effects, such as emetic effects due to detrimental action of the drug toward the intestinal flora, a series of linear diarylheptanoids (LDHs) were designed and synthesized in 7 steps with good-to-moderate yields. All synthesized compounds were evaluated for their antibacterial, antiproliferative, and topoisomerase-I and -IIα inhibitory activity. Overall, all compounds showed little to no activity against the bacterial strains tested. Most of the synthesized compounds showed good antiproliferative activity against human breast cancer cell lines (T47D); specifically, the IC₅₀ values of compounds 6a, 6d, 7j, and 7e were 0.09, 0.64, 0.67, and 0.99 μM, respectively. Among the tested compounds, 7b inhibited topo-I by 9.3% (camptothecin 68.8%), 7e and 7h inhibited topo-IIα by 38.4 and 47.4% (etoposide 76.9%), respectively, at the concentration of 100 μM. These results suggest that a set of promising anticancer agents can be obtained by reducing inhibitory actions on different microbes to provide enhanced selectivity against cancerous cells.