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Iodine for vegetable production and livestock breeding
Published in Tatsuo Kaiho, Iodine Made Simple, 2017
Halogens (fluorine, chlorine, bromine, iodine) have played an important role in the development of agricultural chemicals. In particular, chlorine has been widely used as an component of pesticides such as DDT (dichlorodiphenyltrichloroethane) and BHC (benzene hexachloride) (see the diagram). However, the use of chlorine-based agricultural chemicals have been discontinued in developed countries due to safety concerns. In recent years, the introduction of fluorine has shown to significantly change drug efficiency and properties, and the use of fluorine-based agricultural chemicals containing fluorine atoms and the trifluoromethyl group (CF3) have rapidly increased due to their high level of safety. Overall, 30% of all agricultural chemicals presently used are said to be fluorine-based. On the other hand, because iodine is comparatively costly compared to other halogens and in limited supply, hence there are fewer cases of use in agricultural chemicals.
The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Christina Spry, Anthony G. Coyne
In a follow up study, Behnam et al. (2015) applied a fragment growing strategy to improve activity against the DENV protease, as well as the related West Nile virus (WNV). Initially, a benzyloxyether was added at the para position of the C-terminal phenylglycine moiety of peptide 25 (peptide 28, Figure 5), which improved potency against the DENV-2 protease ninefold (IC50 = 0.367 μM) and WNV protease by 80-fold (IC50 = 0.728 μM). Subsequent addition of a trifluoromethyl group (peptide 29, Figure 5) led to a further fivefold improvement in activity against the DENV-2 protease (IC50 = 0.069 μM) and threefold improvement against the WNV protease (IC50 = 0.224 μM). In parallel, they searched for the optimal N-terminal cap; a range of peptide 28 derivatives in which the benzoyl moiety was replaced with various small chemical groups was tested. Substitution of the benzoyl moiety with a thiazole ring (peptide 30) produced the most potent inhibitor of DENV-2 and WNV protease (IC50 = 0.099 and 0.158 μM, respectively). The most productive N and C terminal modifications were then combined into a single molecule through merging of peptides 29 and 30. The resultant peptide (31) was observed to inhibit DENV-2 and WNV protease with IC50 values of 18 and 50 nM, respectively, corresponding to a 180-fold increase in activity against the DENV-2 protease and a > 1000-fold increase in activity against WNV protease relative to peptide 25. Furthermore, peptide 31 also possesses antiviral activity against both DENV-2 and WNV (EC50 = 20.4 and 23.4 μM, respectively). However, a less potent inhibitor of DENV-2 protease showed the highest antiviral activity (peptide 32, Figure 5, EC50(DENV) = 3.42 μM and EC50(WNV) = 15.6 μM), presumably due to improved permeability.
Trifluoromethyl-substituted 3,5-bis(arylidene)-4-piperidones as potential anti-hepatoma and anti-inflammation agents by inhibiting NF-кB activation
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Wei Cong, Yue Sun, Yi-Fan Sun, Wei-Bin Yan, Yu-Long Zhang, Zhong-Fei Gao, Chun-Hua Wang, Gui-Ge Hou, Jia-Jing Zhang
In our previous study, we found that the anti-tumour and anti-inflammatory activities of BAPs were superior after the introduction of the trifluoromethyl group in the aromatic ring, which may be attributed to the introduction of fluorine atoms to further affect the biological activity. As a strong electron-withdrawing substitution, the trifluoromethyl group can alter the electronic effects of target compounds, and its lipophilicity can effectively improve the membrane permeability of target compounds. Furthermore, they can form multiple hydrogen or halogen bonds with the target protein to improve biological activities35. Therefore, we proposed to introduce more trifluoromethyl substitutions on both sides of BAPs to further optimise the biological activities. Our efforts led to the discovery of trifluoromethyl-substituted BAPs, which might become potential anti-hepatoma and anti-inflammation agents by inhibiting the activation of NF-κB.
Fluorinated scaffolds for antimalarial drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Charu Upadhyay, Monika Chaudhary, Ronaldo N. De Oliveira, Aniko Borbas, Prakasha Kempaiah, Poonam S, Brijesh Rathi
As a part of their ongoing research, Vicente et al. developed a new chemical series of quinoxaline-based derivatives and tested them against various strains of malaria [91]. The screening afforded twenty-one compounds with potent antiplasmodial activity (IC50 < 2 µM) against both CQ-sensitive and CQ-resistant malaria strains. The majority of the candidates possess a fluorine or trifluoromethyl group. In the first series, thirty-eight molecules were synthesized by implementing the substitution (with fluorine, trifluoromethoxy group or trifluoromethyl group) at lead compound 82 to improve the therapeutic properties with reduced toxicity. Analogues 82–88 (Figure 15) containing an electron withdrawing group and 89–91 with a trifluoromethyl group displayed better activity (IC50 value ranges from 0.19 µM to 0.52 µM) against the K1 strain.
Design, synthesis and biological evaluation of novel tetrahydrothieno [2,3-c]pyridine substitued benzoyl thiourea derivatives as PAK1 inhibitors in triple negative breast cancer
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2020
Dahong Yao, Jian Huang, Jinhui Wang, Zhendan He, Jin Zhang
To optimise the lead (2169–1087) based on the inhibitory activity against PAK1, we preferentially incorporated substituted-benzoyl thiourea to serve as the suitable linker, yielding compounds 5a–q. The enzymic inhibitory results revealed that most of these compounds showed significant improvement of PAK1 inhibitory activity compared to the lead (Table 1). Among 5a–e, the methyl substitution showed no contribution to inhibitory activity, and 3-methyl (5d) displayed relative benefit. 5e and 5f with 4-site substitution presented an activity decrease, suggesting that 4-site substitution has a negative effect on affinity, which was further confirmed by 5g, 5j and 5n. Next, some halogen substitution derivatives (5g–l and 5o) were synthesised, but these compounds had no significant improvement in activity. Trifluoromethyl group was incorporated into 3- and 4 site respectively to obtain compounds 5m and 5n. Intriguingly, 5m showed higher inhibitory potency with IC50 value of 2.02 μM.