Efrén Venancio Garcia Báez

A new family of monothiooxalamide derived from 2-aminobenzothiazole was synthesized with the purpose of investigating its anticancer activity. The design of the compounds was focused on targeting the HDAC6 enzyme, a target for antineoplastic drugs. The in silico affinity of compounds to HDAC6 was performed and confirmed by docking simulation. The structures of monothiooxalamide–benzothiazole hybrids were characterized by 1D and 2D NMR experiments, as well as through mass spectrometry and IR spectroscopy. In addition, the antiproliferative activity of compounds was assessed in human breast cancer cell lines (MCF-7 and MDA-MB231) and non-malignant cells (MCF-10A and NIH/3T3). The most active compound was N-(benzo[d]thiazol-2-yl)-2-((4-methoxybenzyl)amino)-2-thioxoacetamide (1c), which inhibited breast cancer cell growth and invasiveness in vitro and induced late apoptosis in the MCF-7 cell line. The molecular structure of 1c was solved by single-crystal X-ray diffraction. The supramolecular arrangement of benzothiazole and 4-methoxy-benzylamine moieties, present in the crystal structure of 1c, was consistent with the interactions on the docked DD2-HDAC6 catalytic site.

A series of three 1,3-phenylene bis-oxamides 3a–c, structurally related to the GPR35 receptor-agonist drug lodoxamide, has been synthesized by reacting the 1,3-phenylene bis-oxalamates 2a and 2b with amines. The obtained compounds were characterized by ¹H and ¹³C NMR, and IR spectroscopy, they showed characteristic signals for the aromatic, N―H, and C=O groups. Molecular structure was determined using single-crystal X-ray diffraction. The supramolecular architecture is driven by N―H···O=C, N―H···N, C—H···π, and O=C···O=C interactions depicting a supramolecular helix (3a) and tapes (3b–c). Intermolecular interactions were studied using Hirshfeld surface analysis, where N―H∙∙∙X (X = N, O) hydrogen bonding represents 30.2% to the surface of 3a and 17.8–18.8% to the surface of 3b–c. The most energetic interactions involve the amide N—H∙∙∙O hydrogen bonding, contributing in the −113.9 to −97.0 kJ mol⁻¹ range to the crystal energy, being more dispersive than electrostatic in nature. The molecular docking study was performed to evaluate the binding ability of 3a–c compounds to the GPR35 receptor, showing a favorable binding in a similar way to lodoxamide.

The use of tris(4-aminophenyl)amine (TAPA) as central to the synthesis of both polyimines and polyimides and covalent organic frameworks and inorganic cages, among others, has grown in the last few years. The resulting materials exhibit high performance in their area of application. In this contribution, the crystal structures of two TAPA derivatives, triethyl (nitrilotris(benzene-4,1-diyl))tricarbamate (1) and triethyl 2,2′,2″-((nitrilotris(benzene-4,1-diyl))tris(azanediyl))tris(2-oxoacetate) (2), are described. The molecular and supramolecular structures of both compounds were compared between them and with analogous compounds. The analyses of their vibrational and ¹³C-CPMAS NMR spectroscopies, as well as their thermal stability, were included and corelated with the crystal structure. Hirshfeld surface analysis on the crystal structures of both TAPA derivatives revealed the stabilization of the crystal network via the amide N—H∙∙∙O interactions of dispersive nature in the carbamate, whereas dispersive carbonyl–carbonyl interactions also played a competitive role in the supramolecular arrangement of the oxamate. Interaction energy DFT calculations performed at the B3LYP/6-31G(d,p) level allowed us to estimate the energy contributions and nature of several interactions in terms of the stability of both crystal lattices.

(Thio)ureas ((T)Us) and benzothiazoles (BTs) each have demonstrated to have a great variety of biological activities. When these groups come together, the 2-(thio)ureabenzothizoles [(T)UBTs] are formed, improving the physicochemical as well as the biological properties, making these compounds very interesting in medicinal chemistry. Frentizole, bentaluron and methabenzthiazuron are examples of UBTs used for treatment of rheumatoid arthritis and as wood preservatives and herbicides in winter corn crops, respectively. With this antecedent, we recently reported a bibliographic review about the synthesis of this class of compounds, from the reaction of substituted 2-aminobenzothiazoles (ABTs) with iso(thio)cyanates, (thio)phosgenes, (thio)carbamoyl chlorides, 1,1’-(thio)carbonyldiimidazoles, and carbon disulfide. Herein, we prepared a bibliographic review about those features of design, chemical synthesis, and biological activities relating to (T)UBTs as potential therapeutic agents. This review is about synthetic methodologies generated from 1968 to the present day, highlighting the focus to transform (T)UBTs to compounds containing a range substituents, as illustrated with 37 schemes and 11 figures and concluded with 148 references. In this topic, the scientists dedicated to medicinal chemistry and pharmaceutical industry will find useful information for the design and synthesis of this interesting group of compounds with the aim of repurposing these compounds.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder. Inhibiting acetylcholinesterase (AChE), amyloid beta (Aβ_1-42) aggregation and avoiding the oxidative stress could prevent the progression of AD. Benzothiazole groups have shown neuroprotective activity whereas isothioureas groups act as AChE inhibitors and antioxidants. Therefore, 22 benzothiazole-isothiourea derivatives (3a–v) were evaluated by docking simulations as inhibitors of AChE and Aβ_1-42 aggregation. In silico studies showed that 3f, 3r and 3t had a delta G (ΔG) value better than curcumin and galantamine on Aβ_1-42 and AChE, respectively. The physicochemical and pharmacokinetics predictions showed that only 3t does not violate Lipinski’s rule of five, though it has moderated cytotoxicity activity. Then, 3f, 3r and 3t were synthetized and chemically characterized for their in vitro evaluation including their antioxidant activity and their cytotoxicity in PC12 cells. 3r was able to inhibit AChE, avoid Aβ_1-42 aggregation and exhibit antioxidant activity; nevertheless, it showed cytotoxic against PC12 cells. Compound 3t showed the best anti-Aβ_1-42 aggregation and inhibitory AChE activity and, despite that predictor, showed that it could be cytotoxic; in vitro with PC12 cell was negative. Therefore, 3t could be employed as a scaffold to develop new molecules with multitarget activity for AD and, due to physicochemical and pharmacokinetics predictions, it could be administered in vivo using liposomes due to is not able to cross the BBB.

Benzimidazole is an important heterocyclic fragment, present in many biologically active compounds with a great variety of therapeutic purposes. Most of the benzimidazole activities are explained through the existence of 1,3-tautomeric equilibrium. As the binding affinity of each tautomer to a protein target depends on an established bioactive conformation, the effect of tautomers on the ligand protein binding mechanism is determinant. In this work, we searched and analyzed a series of reported ¹³C-NMR spectra of benzazoles and benzazolidine-2-thiones with the purpose of estimating their tautomeric equilibrium. Herein, several approaches to determine this problem are presented, which makes it a good initial introduction to the non-expert reader. This chemical shift difference and C4/C7 signals of benzimidazolidine-2-thione and 1-methyl-2-thiomethylbenzimidazole as references were used in this work to quantitatively calculate, in solution, the pyrrole–pyridine tautomeric ratio in equilibrium. The analysis will help researchers to correctly assign the chemical shifts of benzimidazoles and to calculate their intracyclic or exocyclic tautomeric ratio as well as mesomeric proportion in benzimidazoles.

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.

Nowadays, organic chemists are interested in the field of heterocyclic chemistry due to its use in the synthesis of a great variety of biologically active compounds. Heterocyclic compounds are widely found in nature and are essential for life. Among these, some natural nitrogen containing heterocyclic compounds have been used as chemotherapeutic agents. Their attachment to sugar molecules either as thioglycosides or as nucleosides analogues plays an important role in vital biological processes as well as in synthetic organic chemistry. Molecules containing benzothiazole (BT) nuclei are of this interesting class of compounds because some of them have been found to have a wide variety of biological activities. In this sense, we selected this topic to review and to then summarize the procedures related to the condensation reactions of o-aminothiophenoles (ATPs) as well as their disulfides with carboxylic acids, esters, orthoesters, acyl chlorides, amides, and nitriles. The condensation reactions with carbon dioxide (CO₂) are included. Conventional methods with the use of acid and metal catalysts as well as recent green techniques, such as microwave irradiation, the use of ionic liquids, and ultrasound (US) chemistry, which have proven to have many advantages, were found in the review.

Diabetes mellitus (DM) is a serious chronic degenerative disease characterized by high levels of glucose in the blood. It is associated with an absolute or relative deficiency in the production and/or action of insulin. Some of the complications associated with DM are heart disease, retinopathy, kidney disease, and neuropathy; therefore, new natural alternatives are being sought to control the disease. In this work, we evaluate the antidiabetic effect of Spondias purpurea seed methanol extract (CSM) in vitro and in a glucose-induced diabetic zebrafish model. CSM is capable of lowering blood glucose and cholesterol levels, as well as forming advanced glycation end-products, while not presenting toxic effects at the concentrations evaluated. These data show that CSM has a promising antidiabetic effect and may be useful in reducing some of the pathologies associated with diabetes mellitus.

Myeloperoxidase (MPO) is an enzyme present in human neutrophils, whose main role is to provide defenses against invading pathogens. However, highly reactive oxygen species (ROS), such as HOCl, are generated from MPO activity, leading to chronic diseases. Herein, we report the microwave-assisted synthesis of a new series of stable (E)-(2-hydroxy)-α-aminocinnamic acids, in good yields, which are structurally analogous to the natural products (Z)-2-hydroxycinnamic acids. The radical scavenging activity (RSA), MPO inhibitory activity and cytotoxicity of the reported compounds were evaluated. The hydroxy derivatives showed the most potent RSA, reducing the presence of DPPH and ABTS radicals by 77% at 0.32 mM and 100% at 0.04 mM, respectively. Their mechanism of action was modeled with BDE_OH, IP and ΔE_H-L theoretical calculations at the B3LYP/6 − 31 + G(d,p) level. Compounds showed in vitro inhibitory activity of MPO with IC₅₀ values comparable to indomethacin and 5-ASA, but cytotoxicities below 15% at 100–200 µM. Docking calculations revealed that they reach the amino acid residues present in the distal cavity of the MPO active site, where both the amino and carboxylic acid groups of the α-aminopropenoic acid arm are structural requirements for anchoring. (E)-2-hydroxy-α-aminocinnamic acids have been synthesized for the first time with a reliable method and their antioxidant properties demonstrated.