Synthesis,Biological Activities And OSAR Of Acrvlopimaric Acids Derivatives

Rosin as an important natural resource, is widely available throughout China. Rosin, aswell as its derivatives, has been developed as a starting material for synthesizing variouschemicals and/or intermediates, which are renewable alternatives/substitutes ofpetrochemical-based chemicals. Acrylopimaric acid (APA) is a Diels-Alder adduct of rosin andacrylic acid and has attracted more and more attention because of its unique structure andreactivity. In this paper, amide derivatives, oxime ester derivatives, Shiff bases derivatives,dihydrazone derivatives, diacylthiourea derivatives, thiadiazole derivatives from APA weresynthesized, and their structures were characterized by IR,1H NMR, MS, and elementalanalysis. Meanwhile, their antimicrobial activities and antitumor activities in vitro were alsoinvestigated. In the final, quantitative structure activity relationship (QSAR) of antibacterialactivities of the derivatives from APA were explored. This study was expected to guide thesynthesis of the active compounds.The antibacterial activities of the derivatives of amide, oxime ester, Shiff bases,dihydrazone, diacylthiourea, thiadiazole from APA were estimated by a disc paper method.Staphylococcus aureus (gram-positive bacteria) and Escherichia coli (Gram-negative bacteria)were selected as test species. The result shows the derivatives from APA displayed extensiveanti-bacterial activity against Staphylococcus aureus and Escherichia coli. Among them, oximeester derivatives3c (12.17mm),3d (10.00mm) and3f (10.33mm); Shiff bases derivatives4a(15.70mm),4b(17.00mm)and4c (16.70mm); dihydrazone derivatives5a (10.00mm) and5c(10.00mm); diacylthiourea derivatives6f (10.00mm); thiadiazole derivatives7f (10.66mm)exhibited excellent anti-bacterial activity against Escherichia coli, whereas, the diameter ofinhibition zone of reference Bromogeramine was7.90mm. Further investigation on thestructure antibacterial activity relationship is needed. The antitumor activities in vitro of the derivatives of amide, oxime ester, Shiff bases,dihydrazone, diacylthiourea, thiadiazole from APA were estimated by MTT method. Thehuman non-small cell lung cancer NCI-H460cells, human hepatoma SMMC-7721cells,human breast cancer MCF-7cells under the logarithmic growth phase were selected as testcells. The half inhibitory concentration (IC₅₀) was calculated according to improved Kou'smethod. When the IC₅₀<10μg/mL, the compound has the antitumor activity in vitro. The resultshows the derivatives from APA displayed extensive antitumor activities in vitro againstNCI-H460cells, SMMC-7721cells and MCF-7cells. Among them, the oxime ester derivative3k exhibited good antitumor activities in vitro against NCI-H460cells, SMMC-7721cells andMCF-7cells and their IC₅₀were closed to10μg/mL; the Shiff bases derivatives exhibitedexcellent antitumor activities in vitro against NCI-H460cells, SMMC-7721cells and MCF-7cells and their IC₅₀were closed to or less than10μg/mL, among the Shiff bases derivatives, thecompound4h exhibited good antitumor activities in vitro against NCI-H460cells and MCF-7cells and their IC₅₀were6.75μg/mL and5.58μg/mL respectively; the compound4i alsoexhibited good antitumor activities in vitro against MCF-7cells and its IC₅₀was5.19μg/mL.The promising results obtained from these new derivatives justify their consideration aspotential candidates.The lowest energy conformers of the derivatives of amide, oxime ester, Shiff bases,dihydrazone, diacylthiourea, thiadiazole from APA were optimized at the HF/6-31G (d) levelusing the Gaussian03W package of programs. The quantitative structure activity relationship(QSAR) corresponding to against Staphylococcus aureus and Escherichia coli activities werebuilt using the best multilinear regression in Codessa2.7.15. The statistical modelings revealthat against Escherichia coli activity was affected by the following descriptors: Max net atomiccharge for a N atom, Max net atomic charge, Min net atomic charge for a H atom, Max netatomic charge for a C atom, No. of occupied electronic levels/#of atoms; and againstStaphylococcus aureus activity was affected by the following descriptors: Min net atomiccharge for a N atom, Min net atomic charge for a C atom, Min net atomic charge for a H atom, Tot hybridization comp. of the molecular dipole, Image of the Onsager-Kirkwood solvationenergy. Such results are of great benefit to synthetic efforts to discover better compoundshaving practical uses.