Synthesis, Structure and Biological Activity of Ephedra Heterocycles

Ephedra compounds are well known due to their biological activity. They have been widely used in asymmetric synthesis during the last decades. Recently, we have prepared reviews about the synthesis of acyclic and heterocyclic ephedra derivative compounds reported in the literature. In this chapter, the synthetic methodology to access acyclic and heterocyclic compounds derived from ephedra alkaloids and its structural analysis are discussed, included those due to the substitution of the hydroxy group by chlorine, sulfur, selenium, or nitrogen atoms. Biological activity analysis of some synthesized compounds was done, and some of them have displayed biological activity

N,N′-Bis(4-amino­benz­yl)oxalamide

In the title compound, C16H18N4O2, the two carbonyl groups are in an anti­periplanar conformation with an O=C—C=O torsion angle of 173.86 (17)°. In the crystal, a pair of inter­molecular N—H⋯O hydrogen bonds, forming an R 2 2(10) ring motif, connect the mol­ecules into an inversion dimer. The dimers are further linked by N—H⋯N and C—H⋯π inter­actions, forming a zigzag chain along the b axis

Isothioureas, Ureas, and Their N-Methyl Amides from 2-Aminobenzothiazole and Chiral Amino Acids

In this investigation, the reaction of 2-dithiomethylcarboimidatebenzothiazole with a series of six chiral amino-acids was studied. The reaction proceeds through the isolable sodium salt of SMe-isothiourea carboxylates as intermediates, whose reaction with methyl iodide in stirring DMF as solvent affords SMe-isothiourea methyl esters. The presence of water in the reaction leads to the corresponding urea carboxylates as isolable intermediates, whose methyl esters were obtained. Finally, the urea N-methyl amide derivatives were isolated when SMe-isothiourea or urea methyl esters were reacted with methylamine in the presence of water. The structures of synthesized compounds were established by 1H and 13C nuclear magnetic resonance and the structures of SMe-isothiourea methyl esters derived from (l)-glycine, (l)-alanine, (l)-phenylglycine, and (l)-leucine, by X-ray diffraction analysis. This methodology allows to functionalize 2-aminobenzothiazole with SMe-isothiourea, urea, and methylamide groups derived from chiral amino acids to get benzothiazole derivatives containing coordination sites and hydrogen bonding groups. Further research on the biological activities of some of these derivatives is ongoing

A Synthetic Method to Access Symmetric and Non-Symmetric 2-(N,N\u27-disubstituted)guanidinebenzothiazoles

Symmetric and non-symmetric 2-(N-H, N-methyl, N-ethylenyl and N-aryl)guanidinebenzothiazoles were synthesized from the reaction of ammonia, methylamine, pyrrolidine and aniline with dimethyl benzo[d]thiazol-2-yl-carbono-dithioimidate (5) as intermediate. The products were characterized by 1H-, 13C-NMR spectroscopy and three of them by X-ray diffraction analysis. HN-phenyl protons formed intramolecular hydrogen bonds that assist the stereochemistry of the second substituent, whereas the HN-alkyl protons were involved in intermolecular hydrogen bonding

Helical Arrangement of 2-(4-hydroxy-3-methoxyphenyl)-Benzothiazole in Crystal Formation and Biological Evaluation on HeLa Cells

Benzothiazoles are a set of molecules with a broad spectrum of biological applications. In particular, 2-(4-hydroxy-3-methoxyphenyl)-benzothiazole is a potential breast cancer cell suppressor whose mechanism of action has been previously reported. In the present work, the title compound was synthesized, crystallized, and its biological activity on HeLa cells was evaluated. Its molecular structure was compared to that obtained by molecular modeling. Theoretical calculations suggest that the syn-rotamer is the most stable form and correlates very well with crystallographic data. The crystal structure adopts a helical arrangement formed through O13—H13∙∙∙N3 intermolecular hydrogen bonding that propagates in the (14 -1 -3) plane. These results suggest that the title compound has the capacity to interleave into DNA and better explain its biological effects related to the increased CHIP expression through AhR recruitment. Finally, the biological experiments indicate that the title compound has the capacity to decrease the viability of HeLa cells with an IC50 = 2.86 μM

Solventless Synthesis of Poly(pyrazolyl)phenyl-methane Ligands and Thermal Transformation of Tris(3,5-dimethylpyrazol-1-yl)phenylmethane

The solventless synthesis of tris(pyrazolyl)phenylmethane ligands of formula C6H5C(PzR2)3 (R = H, Me), starting from PhCCl3 and 3,5-dimethylpyrazole (PzMe2) or pyrazole (Pz) was performed. The sterically crowded C6H5C(PzMe2)3 is thermally transformed into the bis(pyrazolyl)(p-pyrazolyl)phenylmethane ligand PzMe2-C6H4CH(PzMe2)2. In this compound both PzMe2 rings are linked through the N-atom to the methine C-atom. At higher temperatures, the binding mode of PzMe2 changes from N1 to C4. All transformations occurred via quinonoid carbocation intermediates that undergo an aromatic electrophilic substitution on the 4-position of PzMe2. Reaction conditions were established to obtain five tris(pyrazolyl)phenylmethane ligands in moderate to good yields. 1H- and 13C-NMR spectroscopy and X-ray diffraction of single crystals support the proposed structures

Mechanochemical Synthesis and Structure of the Tetrahydrate and Mesoporous Anhydrous Metforminium(2+)-N,N′-1,4-Phenylenedioxalamic Acid (1:2) Salt: The Role of Hydrogen Bonding and n→π * Charge Assisted Interactions

A new organic salt of metformin, an antidiabetic drug, and N,N′-(1,4-phenylene)dioxalamic acid, was mechanochemically synthesized, purified by crystallization from solution and characterized by single X-ray crystallography. The structure revealed a salt-type crystal hydrate composed of one dicationic metformin unit, two monoanionic units of the acid and four water molecules, namely H2Mf(HpOXA)2∙4H2O. X-ray powder, IR, 13C-CPMAS, thermal and BET adsorption–desorption analyses were performed to elucidate the structure of the molecular and supramolecular structure of the anhydrous microcrystalline mesoporous solid H2Mf(HpOXA)2. The results suggest that their structures, conformation and hydrogen bonding schemes are very similar. To the best of our knowledge, the selective formation of the monoanion HpOXA−, as well as its structure in the solid, is herein reported for the first time. Regular O(δ−)∙∙∙C(δ), O(δ−)∙∙∙N+ and bifacial O(δ−)∙∙∙C(δ)∙∙∙O(δ−) of n→π * charge-assisted interactions are herein described in H2MfA organic salts which could be responsible of the interactions of metformin in biologic systems. The results support the participation of n→π * charge-assisted interactions independently, and not just as a short contact imposed by the geometric constraint due to the hydrogen bonding patterns

Crystal structure, DFT calculations and evaluation of 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione as AChE inhibitor

Abstract Dioxoisoindolines have been included as a pharmacophore group in diverse drug-like molecules with a wide range of biological activity. Various reports have shown that phthalimide derivatives are potent inhibitors of AChE, a key enzyme involved in the deterioration of the cholinergic system during the development of Alzheimer’s disease. In the present study, 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione was synthesized, crystallized and evaluated as an AChE inhibitor. The geometric structure of the crystal and the theoretical compound (from molecular modeling) were analyzed and compared, finding a close correlation. The formation of the C6–H6···O19 interaction could be responsible for the non-negligible out of phenyl plane deviation of the C19 methoxy group, the O3 from the carbonyl group lead to C16–H16···O3i intermolecular interactions to furnish C(9) and C(14) infinite chains within the (− 4 0 9) and (− 3 1 1) families of planes. Finally, the biological experiments reveal that the isoindoline-1,3-dione exerts a good competitive inhibition on AChE (Ki = 0.33–0.93 mM; 95% confidence interval) and has very low acute toxicity (LD50 > 1600 mg/kg) compared to the AChE inhibitors currently approved for clinical use

Synthesis and Biological Importance of 2-(thio)ureabenzothiazoles

The (thio)urea and benzothiazole (BT) derivatives have been shown to have a broad spectrum of biological activities. These groups, when bonded, result in the 2-(thio)ureabenzothizoles (TBT and UBT), which could favor the physicochemical and biological properties. UBTs and TBTs are compounds of great importance in medicinal chemistry. For instance, Frentizole is a UBT derivative used for the treatment of rheumatoid arthritis and systemic lupus erythematosus. The UBTs Bentaluron and Bethabenthiazuron are commercial fungicides used as wood preservatives and herbicides in winter corn crops. On these bases, we prepared this bibliography review, which covers chemical aspects of UBTs and TBTs as potential therapeutic agents as well as their studies on the mechanisms of a variety of pharmacological activities. This work covers synthetic methodologies from 1935 to nowadays, highlighting the most recent approaches to afford UBTs and TBTs with a variety of substituents as illustrated in 42 schemes and 13 figures and concluded with 187 references. In addition, this interesting review is designed on chemical reactions of 2-aminobenzothiazoles (2ABTs) with (thio)phosgenes, iso(thio)cyanates, 1,1′-(thio)carbonyldiimidazoles [(T)CDI]s, (thio)carbamoyl chlorides, and carbon disulfide. This topic will provide information of utility for medicinal chemists dedicated to the design and synthesis of this class of compounds to be tested with respect to their biological activities and be proposed as new pharmacophores