| Research and development of novel drugs undoubtedly are a time-consumed and money-consumed systematical project, which is mainly due to the procedure of synthesizing and screening for biologically active compounds being generally quite complicated and very long, and even needing to be repeated many times. In this active field, combinatorial chemistry together with mass screening, as a whole set of new, innovative techniques for organic synthesis, bioactive evaluation and pharmacophore screening, has been fully developed to be a new scientific discipline for recent decades, and accordingly, been availably employed in novel drug innovation by many pharmaceutical chemists and various pharmacy companies. Combining the combinatorial chemistry, in pursuit of diversity, with the rational drug design, in search of direction, it is likely to search and obtain the new and perfect drugs with more high efficiency than before.In this M.Sc. thesis, taking innovation of new drug as the mainline, the realization and application of combinatorial chemistry as a novel synthesis technique and/or strategy were explored preliminarily. Mannich condensation, as an environmentally benign and/or ecologically friendly "green" three-component reaction (3CR), was used to detailedly discuss the application of the multi-component reaction (MCR) and synthetic chemometrics (noted as synthetometrics or synthometrics) in combinatorial chemistry. Based on the good quantitative structure-activity relationship (QSAR) studies fulfilled in our laboratory, two types of structural descriptors, one for the vector of molecular electronegativity distance (VMED) and the other for the vector of atomic electronegativity distance (VAED), were further extended and applied in quantitative structure-reactivity/spectrum relationship (QSRR/QSSR) studies, respectively. The obtained molecular modeling results were all quite satisfactory.The main contents and some results are illustrated in detail as follows:1. Synthesis of Mannich bases. Taking Mannich condensation system as the 3CR templet, a small amount of structurally similar target molecules, considered as a mini-size combinatorial compound library, were synthesized under almost coincident reaction conditions through varying the three substrates and/or reagents, namely aromatic ketones, aromatic aldehydes and aromatic amines. In this way, the combinatorial synthesis might be simulated. The concept of atomic efficiency wasintroduced and integrated with synthetic yield, as a traditional synthesis index, to give a novel quantitatively comprehensive indicator for evaluation of this reaction system from the viewpoint of green chemistry. Meanwhile, the effect of reaction conditions, catalyst and reagent structure on the synthetic reaction were discussed in detail. Around thirty new compounds were synthesized with yields from 20.14 to 91.00%, melting points from 71.6 to 396.8 oC, and atomic efficiency from 94.36% to 96.18%.2. Experiment design and optimization for synthesis of cinnamic acid. An improvement was made on a so-called synthometrics technology for preparation of cinnamic acid by simultaneously using potassium carbonate as the basic catalyst and polyethylene glycol-400 (PEG-400) as the phase transfer catalyst (PTC). The experiment/condition space was systematically researched as to explore the preliminary application of synthometrics. The synthetic yield was obviously increased from relatively low, 40-50%, to fairly high, up to 68.69%, by optimization through comparing the molar ratio of benzaldehyde to acetic anhydride, quantity of potassium carbonate, amount of PEG-400, reaction temperature and time with several experimental design methods such as orthogonal, uniform and central composition designs.3. Quantitative structure-reactivity relationship (QSRR) studies for Mannich reaction. The synthometrics was sequentially investigated through systematically examining the reagent/reaction space. Both two novel structural descriptor vectors, one for VMED and the other for the vec...
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