Synthesis, Biological Activity And Structure-activity Relationships Of Novel (-)-β-pinene Derivatives

Turpentine is an important natural essential oil, and its annual output is about 100 000 tons in China. However, utilization of turpentine in our country remains at lower level with less value-added. Development of turpentine derivatives with biological activity is an effective way to increase the level of deep processing and utilization of turpentine. In this paper,(-)-β-pinene, one of the main components of turpentine was used as starting material, and a systematic study of the synthesis, biological activity and structure-activity relationships analysis of novel derivatives of(-)-β-pinene was carried out. This study aims to discover some leading compounds with better biological activity through the biological activity screening of derivatives of(-)-β-pinene, and investigate the relationships between structures and biological activity of the derivatives of(-)-β-pinene. This study is expected to offer some useful preliminary information to further molecular design of new derivatives of(-)-β-pinene.Using(-)-β-pinene as the starting material, a group of sixty-four new derivatives of(-)-β-pinene were designed and synthesized. It includes: twenty-five 3-cyanopyridines of(+)-nopinone(compound 2a-2y), thirteen carboxylic myrtanyl esters(compound 3a-3m), eleven N-aryl-myrtanyl amides(compound 4a-4k), four N-(4-arylthiazol-2-yl)-myrtanyl amides(compound 4l-4o), seven N-aryl-N’-myrtanyl acylthiourea(compound 5a-5g), and four N-(4-arylthiazol-2-yl)-N’-myrtanyl acylthiourea(compound 5h-5k). Their structures were characterized by fourier transform infrared spectroscopy(FT-IR), nuclear magnetic resonance spectroscopy(1H NMR, 13 C NMR) and electrospray ionization mass spectrometry(ESI-MS).Antimicrobial activities of these(-)-β-pinene derivatives against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis and Candida albicans were tested. Results show that the minimal inhibitory concentrations(MICs) against S. aureus and S. epidermidis of most of the 3-cyanopyridines of(+)-nopinone are between 15.6-125 mg/L. 3-cyanopyridines of(+)-nopinone, N-aryl-myrtanyl amides, N-(4-arylthiazol-2-yl)-myrtanyl amides, N-aryl-N’-myrtanyl acylthioureas and N-(4-arylthiazol-2-yl)-N’-myrtanyl acylthioureas exhibit antifungal activity against C. albicans, which MICs are in the range of 0.49-125 mg/L. Compound 5i exerts the strongest antifungal activity against C. albicans. Its MIC is 0.49 mg/L, lower than the MIC of positive control rifampicin. This compound can be a potential candidate for further molecular design of new derivatives with antifungal activity.The in vitro anticancer activities of the(-)-β-pinene derivatives against human lung cancer cell line A549, human gastric cancer cell line MKN45, human breast cancer cell line MCF7 and human colorectal cancer cell line SW1116 were measured. Results show that compound 2t, 4c, 4e, 4h, 5b, 5c and 5e exhibit good anticancer activity. The anticancer activities of compound 2t against A549(IC50= 23.78 μmol/L), compound 5b against MCF7(IC50= 55.24 μmol/L) and compound 4c、4e and 4h against SW1116(IC50= 33.46, 36.40 and 32.85 μmol/L,respectively) are comparable to positive control dasatinib. In addition, compound 2t, 4c, 4e, 4h, 5c and 5e demonstrate promising anticancer activity against MCF7, and their IC50 are 53.87, 39.45, 22.98, 20.82, 54.62 and 46.71 μmol/L, respectively. They are comparable to the IC50 of positive control dasatinib against MCF7. These compounds may be used as leading compound for the molecular design of new(-)-β-pinene derivatives with anticancer activity.Insecticidal activities of the(-)-β-pinene derivatives against Plutella xylostella, Mythimna separate, Aphis craccivora and Semiaphis heraclei were evaluated. Results show that some of the tested compounds exhibit good insecticidal activity. At concentration of 1000 mg/L, compound 2i causes 60.00 % corrected mortality against P. xylostella, compound 2h exhibits 68.24 % corrected mortality against A. craccivora, compound 5f shows 84.00 % corrected mortality against M. separate, and compound 3m, 5a and 5d cause 87.50 %, 87.50 % and 91.67 % corrected mortality against S. heraclei, respectively. More importantly, compound 4c, 4e, 4f, 4h, 4j and 4m result in 100.00 % corrected mortality against S. heraclei, which are comparable to the corrected mortality of positive control chlorantraniliprole.These derivatives with good insecticidal activity could be potential candidates for the molecular design of new(-)-β-pinene derivatives.The effect of different substituent groups of(-)-β-pinene derivatives on their biological activity were analyzed, and the preliminary structure-activity relationships of(-)-β-pinene derivatives were studied. Results show that pyridine ring has an important contribution to the biological activity of 3-cyanopyridines of(+)-nopinone, and introduction of halogen substituents in the structure of derivatives will enhance their antifungal, anticancer, and insecticidal activities. Amide groups in the structure of derivatives attribute antifungal, anticancer and insecticidal activities to N-aryl-myrtanyl amides and N-(4-arylthiazol-2-yl)-myrtanyl amides. Introduction of thiazole ring in the structure of derivatives will improve their antifungal activity against C. albicans and insecticidal activity against S. heraclei. These amide derivatives show stronger antifungal activity against C. albicans by introducing electron-donating groups in the structure of derivatives. Besides, introduction of electron-withdrawing groups or halogen substituents will improve their anticancer and insecticidal activities. Acylthiourea groups endow N-aryl-N’-myrtanyl acylthioureas and N-(4-arylthiazol-2-yl)-N’-myrtanyl acylthioureas with antifungal, anticaner and insecticidal activities. Acylthioureas derivatives exhibit stronger antifungal activity against C. albicans by introducing thiazole ring. Introduction of electron-donating groups or fluorinated substituents in the structure of derivatives will improve their antifungal activity against C. albicans, insecticidal activity against S. heraclei and anticancer activity.The quantitative structure-activity relationships between the structures and antifungal activity of(-)-β-pinene derivatives against C. albicans were studied by heuristic regression method. Results show that more sulphur atoms, smaller value of WNSA-3, larger value of PNSA-2, greater maximum net atomic charge, and increasing minimum electrophilic reactivity index for a C atom could improve the antifungal activity of(-)-β-pinene derivatives against C. albicans. This result provides some useful preliminary information to further molecular design of new(-)-β-pinene derivatives with antifungal activity against C. albicans.