The Construction Of Thiazolone And Pyrazole Based Chemical Space With Scaffold Diversity And The Modification Of Triazole Leads To Improve Metabolic Stability

Chemical space was considered as the main source of chemical modulators for chemical genetics. At the same time, combined with the high-throughout screening, it can effective generate lead compounds for drug discovery. The diversification of ’privileged’ structures using diversity-oriented synthesis (DOS) which is defined as rational DOS or ’privileged’ substructure-based DOS (pDOS) strategy, has proven to be fruitful tools to rapidly discover biologically active lead compounds. However, the increasing importance of phenotypic screening to the discovery of new drugs, as well as the arising of new challenging drug targets, such as protein-protein interaction, impose more requests on the strategy of constructing new chemical space. Thus, there is an urgent need to develop new strategies to meet the demand of lead discovery.In recent years, several new triazoles with broad spectrum and excellent in vitro antifungal activity were discovered in our group. One of the lead compounds named iodiconazole is now in phase III clinical trial as a novel agent for superficial fungal infections. However, these triazoles showed poor pharmacokinetic properties and metabolically instability in further pharmacokinetic evaluation. Therefore, it is highly desirable to replace the metabolically instable group with the privileged heterocycles to improve the pharmacokinetic properties and to develop new triazoles for the treatment of systematical fungal infections. In addition, iodiconazole was developed as racemate. Because the optical isomers of chiral compound exhibit different pharmacodynamic, pharmacokinetic and toxicological properties, it is crucial to prepare the optical isomers of iodiconazole through asymmetric synthesis and evaluate the effects of the chiral center on the antifungal activity. In addition,7-methyl-10-((dibutoxyphosphoryl)oxy)-homocamptothecin represents a promising antitumor agent targeted topisomerase I, so the process development and asymmetric synthesis of this clinic candidate for further drug development are also the focus of this study.Therefore, the present thesis will focus on:1) Facile construction of thiazolone based pDOS library with structurally diversity and complexity via divergent organocatalytic cascade reaction (DOCR) and their biological exploratory studies;2) The development of new strategy to construct drug-like chemical space and its application on constructing pyrazole-based chemical space with scaffold and appendage diversity;3) The optimization of triazole antifungal lead compounds by inserting metabolic stable heterocycles and the asymmetric synthesis of iodiconazole;4) The process development and asymmetric synthesis of7-methyl-10-((dibutoxyphosphoryl)oxy)-homocamptothecin1. Facile construction of thiazolone based pDOS library with structurally diversity and complexity via divergent organocatalytic cascade reaction (DOCR) and their biological exploratory studiesAn important bottleneck in privileged structure based diversity-oriented synthesis (DOS) is the lack of efficient methods to quickly synthesize structurally novel and diverse compounds for biological studies. Here, we present a new approach by merging two powerful synthetic tactics-divergent synthesis and cascade organocatalysis to create a divergent cascade organocatalysis strategy for the facile construction of new’privileged’ substructure-based DOS (pDOS) library. As demonstrated, notably5distinct molecular architectures are produced facilely from readily available simple synthons thiazolidinedione and its analogues and α, β-unsaturated aldehydes in1-3steps with the powerful strategy. The beauty of the chemistry is highlighted by the efficient formation of structurally new and diverse products from structurally close reactants under the similar reaction conditions. Notably, structurally diverse spiro-thiazolidinediones and-rhodanines are produced from organocatalytic enantioselective3-component Michael-Michael-aldol cascade reactions of respective thiazolidinediones and rhodanines with enals. Nevertheless, under the similar reaction conditions, reactions of isorhodanine via a Michael-cyclization cascade lead to structurally different fused thiopyranoid scaffolds. This strategy significantly minimizes time-and cost-consuming synthetic works. Furthermore, these molecules possess high structural complexity, and functional, stereochemical, and skeletal diversity with similarity to natural scaffolds. In the preliminary biological studies of these molecules, compounds4f,8a, and10a exhibit inhibitory activity against the human breast cancer cells, while compounds8a,9a, and9b display strong antifungal activities against Candida albicans and Cryptococcus neoformans. Notably, their structures are different from clinically used triazole antifungal drugs. Therefore, they could serve as good lead compounds for the development of new generation of antifungal agents. 2. The development of new strategy to construct drug-like chemical space and constructing of pyrazole-based chemical space with scaffold and appendage diversityA new strategy for constructing of new chemical space was developed by integrating the advantages of current strategies. It is proposed that a drug-like chemical space should be a combination of diverse side chains in amino acid residues and diverse scaffolds embedded with privileged structure. Lipinski’s rule-of-five can be used as a filter for the physicochemical properties of the libraries. It is expected that the chemical space with this new strategy, combined with high-throughout screening, especially the phenotypic screening, will contributed to the discovery of new lead compounds and new targets. Because the new strategy uses side chains derived from the amino acids, it will be helpful for the discovery of novel protein-protein interaction inhibitors. Under the guidance of this principle,7kinds of different scaffolds with high stereoselectivity were generated in a divergent manner on the basis of a reactive intermediate from pyrazolone and cinnamyl aldehyde.5of them are totally new scaffolds. Furthermore, the pyrazole-based chemical space was constructed by assembling versatile enals and pyrazolone, and eight new molecules with different side chains and skeletons were prepared. In the preliminary antitumor test of16new molecules, compounds13a,13b exhibit potent inhibitory activity against human breast, lung and colon cancer cells. Meanwhile, these compounds, including13a and13b, show bad activity against Candida albicans and Cryptococcus neoformans cells. The further construction of this library and related biological evaluations are ongoing now.3. Design and synthesis of novel triazole antifungal lead compounds with improved metabolic stability and the asymmetric synthesis of iodiconazole.In order to improve the metabolic stability and water solubility of the triazole leads from our laboratory, three classes of novel azoles antifungal agents were designed and synthesized through introducing privileged heterocyclic structure. Thirty-one new triazoles with a1,2,3-triazole or thiazolidinedione side chains were obtained. Among them,7compounds (51,8b,8a,13d,131,13m and13p) exhibited excellent activity against common pathogenic fungi except Aspergillus fumigatus. Further in vivo test showed that compounds51and13d had better in vivo antifungal activity than fluconazole. On the other hand,5azoles with1,2,4-Oxadiazoles and1,3,4-Oxadiazoles side chains were synthesized, which displayed broad spectrum in vitro antifungal activity. One of them, compound19c, displayed comparable in vitro antifungal activity with the lead compound2. Interestingly, the in vivo antifungal potency of compound19c was better than fluconazole and the lead compound. Further pharmacokinetic evaluation of the highly potent compounds is ongoing.In addition, tow optical isomers of iodiconazole were prepared through asymmetric synthesis. The preliminary in vitro antifungal activity test revealed that the S-isomer was more active than the R-isomer, which provided basis for the development of chiral antifungal agents.4. The process development and asymmetric synthesis of7-methyl-10-((dibutoxyphosphoryI)oxy)-homocamptothecin7-methyl-10-((dibutoxyphosphoryl)oxy)-homocamptothecin represent a promising antitumor agent targeted topisomerase I. We have developed a more efficient semi-synthetic process with an overall yield of8%, starting from commercially available10-Hydroxy-homocamptothecin so as to prepare enough amount of this compound for further preclinical evaluation. In addition, its asymmetric synthesis route was explored too and the key intermediate for its total synthesis was prepared with an excellent enantioselectivity by a chiral a-phenylethanamine mediated resolution.