Yu-Chao Liu

Recent Developments in the Synthesis and Applications of Isatins

Isatin (1H-indole-2,3-dione, Figure 1) was first obtained by Erdman and Laurent in 1841 as a product from the oxidation of indigo by nitric and chromic acids.1 Since then, isatin and its derivatives have become important heterocycles. They are found in nature and are present in numerous bioactive compounds, which can act as inhibitors of apoptosis,2,3 anticonvulsants,4 antiviral,5,6 anti-bacterial and antifungal7 agents. For example, 5-(3′methylbuten-2′-yl)isatin and 6-(3′-methylbuten-2′-yl)isatin, which were, respectively, isolated from Chaetomium globosum and Streptomyces albus, have been described as novel antifungal compounds.8–11 Indirubin has been shown to be the active ingredient of Danggui Longhui Wan, a mixture of plants that has been used in traditional Chinese medicine to treat chronic diseases for many years and is also found in Chinese medicinal herbs Isatis indigotica and Strobilanthes cusia.12–15 Methisazone and the β-thiosemicarbazone of isatin (IBT) have also been described as smallpox chemoprophylactic agents (Figure 1).6,12 Besides, the versatility of isatins has also led to extensive studies on the use of isatin and its derivatives in organic synthesis.16–30 This review summarizes the recent progress of the preparative methodologies of isatins and their applications in the syntheses of natural products and biologically important heterocyclic compounds for the period of 2000 to 2013.

Computational Design of Novel Inhibitors to Overcome Weed Resistance Associated with Acetohydroxyacid Synthase (AHAS) P197L Mutant

BACKGOUND Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) is the first common enzyme in the biosynthetic pathway leading to the branched-chain amino acids in plants and a wide range of microorganisms. With the long-term and wide application of AHAS inhibitors, weed resistance is becoming a global problem, which leads to an urgent demand for novel inhibitors to antagonize both wild-type and resistant AHAS. RESULTS Pyrimidinyl salicylic acid derivatives, as one of the main classes of commercial AHAS herbicides, show potential anti-resistant bioactivity to wild-type and P197L mutant. In current work, a series of novel 2-benzoyloxy-6-pyrimidinyl salicylic acid derivatives were designed through fragment-based drug discovery. Fortunately, the newly synthesized compounds showed good inhibitory activity against both wild-type and P197L mutant. Some compounds not only had a lower resistance factor value but also showed excellent inhibitory activity against wild-type AHAS and P197L mutant. Furthermore, greenhouse experiments showed compound 11m displayed almost 100% inhibition against both wild-type and high-resistant Descurainia sophia at a dosage of 150 g a.i. ha-1 . CONCLUSION The present work indicated that the 2-benzoyloxy-6-pyrimidinyl salicylic acid motif was well worth further optimization. Also, compound 11m could be used as a potential anti-resistant AHAS herbicide, which requires further research.

Discovery of New 2-[(4,6-Dimethoxy-1,3,5-triazin-2-yl)oxy]-6-(substituted phenoxy)benzoic Acids as Flexible Inhibitors of Arabidopsis thaliana Acetohydroxyacid Synthase and Its P197L Mutant

In the search for new antiresistance acetohydroxyacid synthase (AHAS, EC 2.2.1.6) inhibitors to combat weed resistance associated with AHAS mutations, a series of 2-[(4,6-dimethoxy-1,3,5-triazin-2-yl)oxy]-6-(substituted phenoxy)benzoic acids 11-38 were designed and synthesized via the strategy of conformational flexibility analysis. Compounds 21, 22, 26, 33, 36, and 38 with high potency against both wild-type AtAHAS and its P197L mutant were identified as promising candidates with low resistance factors (RF, defined as the ratio between the ki values toward P197L mutant and wild-type AHAS) ranging from 0.73 to 6.32. Especially, compound 22 (RF = 0.73) was further identified as the most potent antiresistance AHAS inhibitor because of its significantly reduced resistance level compared with that of tribenuron-methyl (RF = 2650) and bispyribac (RF = 4.57). Furthermore, compounds 26, 33, 36, and 38 also displayed promising herbicidal activities against sensitive and resistant (P197L) Descurainia sophia at the dosage of 75-150 g of active ingredient (ai)/ha. Notably, compounds 33 and 38 still maintained over 60% herbicidal activity toward the resistant weed even at much lower dosages (37.5 g ai/ha). Therefore, the designed scaffold has the great potential to discover new candidate compounds for the control of weed resistance associated with AHAS mutation.

Design, Synthesis, and Herbicidal Activity of Pyrimidine–Biphenyl Hybrids as Novel Acetohydroxyacid Synthase Inhibitors

The issue of weed resistance to acetohydroxyacid synthase (EC 2.2.1.6, AHAS) inhibitors has become one of the largest obstacles for the application of this class of herbicides. In a continuing effort to discover novel AHAS inhibitors to overcome weed resistance, a series of pyrimidine-biphenyl hybrids (4aa-bb and 5aa-ah) were designed and synthesized via a scaffold hopping strategy. Among these derivatives, compounds 4aa ( Ki = 0.09 μM) and 4bb ( Ki = 0.02 μM) displayed higher inhibitory activities against Arabidopsis thaliana AHAS than those of the controls bispyribac ( Ki = 0.54 μM) and flumetsulam ( Ki = 0.38 μM). Remarkably, compounds 4aa, 4bb, 5ah, and 5ag exhibited excellent postemergence herbicidal activity and a broad spectrum of weed control at application rates of 37.5-150 g of active ingredient (ai)/ha. Furthermore, 4aa and 4bb showed higher herbicidal activity against AHAS inhibitor-resistant Descurainia sophia, Ammannia arenaria, and the corresponding sensitive weeds than that of bispyribac at 0.94-0.235 g ai/ha. Therefore, the pyrimidine-biphenyl motif and lead compounds 4aa and 4bb have great potential for the discovery of novel AHAS inhibitors to combat AHAS-inhibiting herbicide-resistant weeds.