The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay in Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Noble et al. (2016) screened the Novartis library of 1408 fragments in pools of eight against RdRp using X-ray crystallography. DENV-3 RdRp crystals were soaked with a total of 176 fragment pools, with each fragment tested at a concentration of 625 μM. This led to the identification of a single fragment hit (compound 35) that was subsequently shown by SPR to bind DENV-3 and DENV-4 RdRp with KD values of 210 and 610 μM, respectively (LE = 0.28 and 0.24, respectively). The structure of DENV-3 RdRp, like that of other polymerases, resembles a right hand with subdomains that mimic the fingers, palm and thumb. The fragment hit was observed to bind in a novel allosteric pocket of apo DENV-3 RdRp, between the thumb and palm subdomains and the priming loop that regulates binding of the RNA template and polymerization. Importantly, binding at this site was also shown to translate into an inhibitory effect on enzyme activity, with an IC50 value of 730 μM determined against DENV-4 RdRp in a de novo initiation/elongation assay. Replacement of the terminal phenyl moiety of fragment 35 with a thiophene produced a fragment (36, Figure 6b) with two-to-seven-fold improved affinity and the same binding mode. Guided by X-ray crystallography, this thiophene fragment was subsequently elaborated using a fragment growing strategy (Yokokawa et al. 2016).
Abies Spectabilis (D. Don) G. Don (Syn. A. Webbiana Lindl.) Family: Coniferae
L.D. Kapoor in Handbook of Ayurvedic Medicinal Plants, 2017
Chemical constituents — It contains a large amount of resin and an alkaloidal principal ecliptine. The presence of reducing sugar in the whole plant and sterols in seeds has been observed. Wedelolactone (mp 325 to 330°C) was obtained from leaves and stem.353 The herb also showed the presence of desmethyl wedelolactone and sulfur-containing peptides. The presence of two thiophene derivatives and a polyacetylenic compound has also been reported. Later a new polythienyle compound (α-terthienylmethanol), besides β-amyrin and stigmasterol, was isolated.354 Leaves and twigs of the plant are reported to contain an unnamed alkaloid.10
Monographs of Topical Drugs that Have Caused Contact Allergy/Allergic Contact Dermatitis
Anton C. de Groot in Monographs in Contact Allergy, 2021
Ichthammol is a complex product obtained by the sulfonation and ammoniation of shale oil, the distillation product of bituminous schists. It consists of 10% sulfur, 5–7% ammonium sulfate, hydrocarbons, nitrogenous bases, acids and derivatives of thiophene. The allergen is said to be present in the water- and cyclohexane-soluble fraction (7).
Synthesis of novel, DNA binding heterocyclic dehydroabietylamine derivatives as potential antiproliferative and apoptosis-inducing agents
Published in Drug Delivery, 2020
Fengyi Zhao, Xu Sun, Wen Lu, Li Xu, Jiuzhou Shi, Shilong Yang, Mengyi Zhou, Fan Su, Feng Lin, Fuliang Cao
Both of the thiophene Schiff-bases L3 and thiophene amides L4owned novel structural features with two aromatic rings (thiophene ring and benzene ring) and two aliphatic rings from dehydroabietylamine. For L3, its faint yellow block-shaped single crystal was found to be a monoclinic crystal in a chiral space group P21 with a Flack parameter of 0.009(8). The thiophene ring with C5, N1, and C6 was coplanar (Figure 1(a)). The molecules are stably connected by slightly weak C1 − H1⋅⋅⋅S1# hydrogen bond to assemble an infinite one-dimensional chain structure along b axis (Figure 1(b)). The distance of H1⋅⋅⋅S1 (2.8019(18) Å) and C1⋅⋅⋅S1 (3.6459(64) Å) is corresponding to Shi’s report (H16⋅⋅⋅S2 2.95 Å and C16⋅⋅⋅S2 3.61 Å), which is slightly shorter than the sum of van der Waals radii, proving that a weak interaction existed between H1⋅⋅⋅S1 (Shi & Wen, 1998). The length of the new imine double bond C5 − N1 (1.2520(7) Å) is in accordance with the report from Lu (C10 − N2 1.2913(3) Å) (Lu et al., 2016) and our previous result of C7 − N1 1.2690(4) Å (Zhao et al., 2018). For L4, its colorless block-shaped single crystal was obtained as orthorhombic crystal system in a chiral space group P21 with a Flack parameter of 0.08(5). The molecules are connected by N1 − H1⋅⋅⋅O1# hydrogen bond to assemble an infinite one-dimensional chain structure along b axis (Figure 2(b)). The hydrogen-bond parameters of L3 and L4 are shown in Table 1. Selected bond lengths and angles of L3 and L4are shown in Table 2. The crystallographic data are shown in Table S1 in Supplementary Material.
Design, synthesis and antitumor activity of 5-trifluoromethylpyrimidine derivatives as EGFR inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Yaqing Zuo, Rongrong Li, Yan Zhang, Guochen Bao, Yi Le, Longjia Yan
Thiophene derivatives exist broad activities in the field of pharmaceutical researches especially in anti-microbial, anti-tumour, anti-oxidation, and anti-inflammatory activity15–17. As shown in Figure 1, Olmutinib, a kind of thienopyrimidine compound was an important EGFR inhibitor in market to treat nonsmall-cell lung cancer (NSCLC)18. Moreover, OSI-930 in Figure 1 was a good anticancer reagent as kinase inhibitor in clinical trials for multiple tumors19. In addition, more and more thiophene derivatives were successfully developed as antitumor reagents20–23.
Oxidative metabolism of razuprotafib (AKB-9778), a sulfamic acid phosphatase inhibitor, in human microsomes and recombinant human CYP2C8 enzyme
Published in Xenobiotica, 2021
Patrick Camilleri, Brandi Soldo, Akshay Buch, John Janusz
To discern the metabolic pathway leading to metabolite MS633 (m/z– 633), in vitro incubations of razuprotafib with human liver microsomes and recombinant CYP2C8 were conducted, and the results assessed for selected ions by LC-MS/MS. The analysis showed that several singly oxidised metabolites are formed, and their MS fragmentation patterns can distinguish metabolites oxidised on the phenylalanine-derived benzene ring from those oxidised on the thiophene ring. Three mono-oxidised metabolites, C5, C8 and C11 show a loss of methanol and sulphur trioxide, common losses for almost all metabolites generated from razuprotafib, and all show losses of fragments that contain mono-oxidation in the phenylalanine derived part of razuprotafib. In contrast, mono-oxygenated metabolites, C4 and C10, show losses of a non-oxidised phenylalanine-derived fragment. One of these metabolites is probably the thiolactone based on the observation that enzymatic oxidations of 5-membered heteroaromatic rings, including thiophenes, commonly occurs adjacent to the heteroatom (Dalvie et al. 2002; Gramec et al. 2014) whereas the second metabolite is probably the sulfoxide, observed in the metabolic oxidation of other thiophene-containing compounds (Gramec et al. 2014). The shorter chromatographic retention time of C4 (14.15 minutes) compared to C10 (16.10 minutes) indicates that the former metabolite is more hydrophilic. To further distinguish between the two types of the mono-oxidised thiophene structures of C4 and C10, the LogP (octanol/water partition coefficient) values of two model compounds, 2-methyl-2H-thiophen-5-one and 2-methylthiophene 1-oxide, were calculated, and were found as 1.32 and −0.11, respectively. From the sizeable difference in the hydrophobicity of the two model thiophene derivatives, it is concluded that C4 and C10 are likely to be the sulfoxide and the thiolactone derivatives of razuprotafib, respectively.
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