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Chemical Hybridization Approaches Applied to Natural and Synthetic Compounds for the Discovery of Drugs Active Against Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Elena Petricci, Paolo Governa, Fabrizio Manetti
Very good results in term of both selectivity and activity were obtained when the triazine ring was hybridized with the quinazoline moiety (79 and 80, Figure 20) (Sharma et al. 2013). The preparation was a simple functionalization of a previously prepared quinazoline ring with cyanuric chloride, and a systematic substitution of the Cl atoms with different amines. The same quinazoline nucleus was hybridized with peptides thus obtaining 9 promising compounds. The triazine hybrids were both active as antipromastigotes and antiamastigotes with a low cytotoxicity and a very good SI. The hybrid peptide 81 bearing a ferrocene moiety was not active at all on promastigotes, while it strongly affected amastigote proliferation with a SI > 548. However, these hybrids, that were very promising even in in vivo studies in the golden hamster model, strongly reacted with blood proteins with a static and dynamic quenching of intrinsic fluorescence. Tetrahydroquinazoline-triazine hybrid compounds.
Herbicides
Published in Frank A. Barile, Barile’s Clinical Toxicology, 2019
Table 29.3 summarizes the chemical and toxicological properties of selected miscellaneous herbicides. The triazines, substituted ureas, and nitroaromatic and chloroanilide classes are frequently used as contact, preemergence, and select herbicides. Their low to moderate toxicity to humans and animals makes them suitable for agricultural, industrial, and household utility. Their structural commonalities (highlighted in blue in Figure 29.3), such as the nitrogen moieties, explain their relative effectiveness and selective toxicology (Figure 29.3). Structures of selected triazine, substituted urea, and nitro aromatic herbicides. Their structural similarities, highlighted in blue, such as the triazine, urea, and dinitro moieties (for atrazine, monuron, and dinoseb, respectively), account for the relative effectiveness and selective toxicity of nitrogen-containing molecules.
Agrochemicals: A Brief Overview
Published in Dongyou Liu, Handbook of Foodborne Diseases, 2018
Atrazine is an herbicide of the family of triazines, extensively used for control of broad-leaf weeds and certain grasses (37). Their herbicidal action is due to inhibition of photosynthesis, a process unique to plants (11,37), and all triazines have low acute oral and dermal mammalian toxicity (LD50 = 1–2 g/kg). Animal studies have suggested that atrazine may be carcinogenic, as mammary tumors were reported in female Sprague-Dawley rats (37,38); however, such an effect may involve a primary action on pituitary luteinizing hormone seen only at high doses, and it may thus have a threshold (37). Epidemiological studies of triazine herbicides and cancer have provided inconclusive results (39,40), and atrazine is classified by IARC as a Group 3 carcinogen (not classifiable as to its carcinogenicity to humans).
Discovery of novel enasidenib analogues targeting inhibition of mutant isocitrate dehydrogenase 2 as antileukaemic agents
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Ahmed F. Khalil, Tarek F. El-Moselhy, Eman A. El-Bastawissy, Rasha Abdelhady, Nancy S. Younis, Mervat H. El-Hamamsy
Initially, the anticancer effects of target compounds have been assessed at a single (10 μM) dose. The obtained data have been reported as mean-graph of the percent growth (G%) of the treated cancer cells. Percentage growth inhibition (GI%) is calculated (100 − G%) and pronounced in Table 1. Inspection of in vitro antitumor screening data revealed that our s-triazine derivatives exposed variable anticancer activity ranging from low, moderate, to high potency. Preliminary examination of NCI data showed that compounds in series (I) with morpholine head and their corresponding analogues in series (II) with piperidine moiety demonstrated an overall comparable activity as reported in Figure 5. Target compounds in series (III) with manipulated linkers disclosed lower potency. Superiorly, eight s-triazine derivatives from the three series (6a, 6c, 6d, 7a, 7g, 7i, 7l, and 8b) have shown potent broad-spectrum anticancer activity against most the examined cell lines, whereas most of the remaining triazine derivatives, 20 derivatives, have exerted selective anti-proliferative actions towards certain cancer cell lines (Supplementary). The GI% exerted by the examined s-triazine derivatives 6a, 6c, 6d, 7a, 7g, 7i, 7l, and 8b have been listed in Table 1.
Synthesis and biological activity evaluation of 3-(hetero) arylideneindolin-2-ones as potential c-Src inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Salvatore Princiotto, Loana Musso, Fabrizio Manetti, Valentina Marcellini, Giovanni Maga, Emmanuele Crespan, Cecilia Perini, Nadia Zaffaroni, Giovanni Luca Beretta, Sabrina Dallavalle
A small collection of molecules containing highly diverse chemical scaffolds was initially screened on c-Src to evaluate their inhibiting activity at a 100 μM concentration (Table 1). Triazolo-triazine 13 showed the best inhibition potency (90%). However, its closely related analogue 14 did not affect the enzyme activity. Indolinone and N-hydroxyl indolinone derivatives 7–9 exhibited a significant activity (percent inhibition ranging from 77 to 84%). A modest inhibition profile was highlighted for azaindole 1 and kynurenic derivative 17 (about 58%), followed by thiazolylbenzoquinone 10 (43%) and dihydroquinolin-2-one 12 (40%), whereas all the other entries of the library showed low to no activity towards c-Src. ID50 of both triazolo-triazine 13 and indolinone 8 were in the two-digit micromolar concentration (50 and 12.5 µM, respectively).
Applications of fluorine to the construction of bioisosteric elements for the purposes of novel drug discovery
Published in Expert Opinion on Drug Discovery, 2021
The modular nature of the triazine-core allowed the sequential study of three vectors to assay the effect of molecular changes on potency, selectivity, and the physicochemical properties of the inhibitor (Figure 7). Initially the influence of the trifluoromethyl-substituent at the C-4 position of the aminopyridine of 40 was investigated. Within the bis-morpholine-substituted triazine series, the compound featuring the difluoromethyl substituent (41) was shown to be the most potent inhibitor of mTOR both in vitro and in cells with the cellular data reflecting both inhibition of TORC1 and TORC2. In general the affinity toward mTOR increased as function of R in the order : CH3 (47) ≈ CH(OCH3)2 (46) ≈ OCH3 (45) < CF3 (40) ≈ CH2OH (44) ≈ CH2F (43) ≈ H (42) < CHF2 (41) with the loss of the potency for the ether-linked compounds ascribed to an increase in steric bulk while the drop in selectivity for PI3Ka over mTOR (1.7 fold) for the difluoromethyl derivative is hypothesized to highlight the importance of the dipole moment in its interactions with the protein. The ability of the CHF2 in 41 to act as a lipophilic hydrogen bond donor is also supported in a study of the predicted interactions of the inhibitor with both proteins with the slightly more hydrophobic nature of the mTOR pocket serving to enforce a CHF2 proton-Glu2190 hydrogen bond leading to the observed increased mTOR affinity.