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Gustavo Pretelín-Castillo,1 Mayra Silva Miranda,2,3 Clara Espitia,2,3 Rosa María Chávez-Santos,1 Abel Suárez-Castro,4 Luis Chacón-García,4 Rodrigo Aguayo-Ortiz,5 Roberto Martinez1 1Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Cd. México, 04510, México; 2Catedrática CONACYT adscrita al Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Cd. México, 04510, México; 3Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Departamento de Inmunología, Ciudad Universitaria, Cd. México, 04510, México; 4Instituto de Investigaciones Químico-Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Edificio B-1, Ciudad Universitaria, Morelia Michoacán, 58030, México; 5Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Cd. México, 04510, MéxicoCorrespondence: Roberto MartinezInstituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Cd. México, 04510, MéxicoTel +52 55 56224441Fax +52 55 56162217Email robmar@unam.mxBackground: Tuberculosis is an infectious disease caused by the bacillus Mycobacterium tuberculosis. Compounds including a sulfur-containing scaffold have been shown to be key scaffolds in various antituberculosis agents. Interestingly, the 3-hydroxy-3-phenyl-prop-2-enedithioic acids 11a-j have, to the best of our knowledge, not been previously described as antituberculosis agents.Purpose: In the present study, we investigated the role of substituents attached to the phenyl ring of a 3-hydroxy-3-phenyl-prop-2-enedithioic acid scaffold (compounds 11a–j) in inhibiting the growth of M. tuberculosis strain H37Rv.Methods: (Z)-3-hydroxy-3-(4-R-phenyl)-prop-2-enedithioic acids 11b–j, with R groups including various electron-donating or electron-withdrawing groups, were designed by structurally modifying the lead compound 11a. The syntheses of 11a–j involved each one-step procedure starting from the corresponding substituted acetophenone. Compounds 11a–j were tested against M. tuberculosis strain H37Rv to evaluate their bacterial growth inhibitory activities. ADMET profiles were predicted by employing three different methods. In addition, molecular docking studies were carried out, based on the molecular similarities of the synthesized compounds with ethionamide ( 5), on the active site of the M. tuberculosis H37Rv (3R)-hydroxyacyl-ACP (HadAB) dehydratase heterodimer.Results: The antituberculosis activities of compounds 11a–j could be explained in terms of the presence of electron-donating or electron-withdrawing substituents on the aromatic ring of the substituted 3-hydroxy-3-phenyl)-prop-2-enedithioic acid core. The activity and selectivity index (SI) value of (Z)-3-hydroxy-3-(4-nitrophenyl)-prop-2-enedithioic acid 11e suggested that this compound could be used for the design of novel antituberculosis agents. Most of the synthesized molecules showed an acceptable ADME profile and a low probability of being toxic. Docking studies of 11d and 11e showed them forming hydrogen bonds with the ACys61 residue of the HadAB enzyme.Conclusion: Our results suggested that the antituberculosis compound 11e could be used for the design of novel antituberculosis agents.Keywords: synthesis, 3-hydroxy-3-(4-R-phenyl)-prop-2-enedithioic acids, antituberculosis agents, docking, theoretical ADME

A synthetic strategy for obtaining a new series of 1,5-disubstituted tetrazole-benzofuran hybrid systems via a one-pot five-component reaction is described. This process involves a Ugi-azide multicomponent reaction coupled to an intramolecular cyclization catalyzed by Pd/Cu, resulting in low to moderate yields from 21 to 67%. This protocol allowed the synthesis of highly substituted benzofurans at the 2-position through an operationally simple process under mild reaction conditions and with high bond forming efficiency due to the formation of six new bonds (two C-C, two C-N, one N-N, and one C-O). Besides, to evaluate the antifungal activity of 1,5-disubstituted tetrazole-benzofurans 9a-n, in vitro studies against Mucor lusitanicus were performed, finding that compound 9b exhibits bioactivity comparable to the commercial antifungal drug Amphotericin B. These results suggest potential for use in controlling mucormycosis infections in animal models, highlighting the importance of these findings given the limited antifungal drug options and high mortality rates associated with this infection.

A molecular switch based on the metastable radical anion derived from a substituted heteroaryl quinone is described. Pyrrolyl quinone thiocyanate (PQ 9) showed an interaction with the fluoride anion that was visible to the naked eye and quantified by UV/vis and 1H and 13 C NMR. The metastable quinoid species formed by the interaction with F - ("ON" state) showed a molecular switching effect autocontrolled by the presence of ascorbate ("OFF" state) and back to the "ON" state by an autooxidation process, measured by visible and UV/vis spectroscopy. Due to its out-of-equilibrium properties and the exchange of matter and energy, a dissipative structural behaviour is proposed. Considering its similarity to the mechanism of coenzyme Q in oxidative phosphophorylation, PQ 9 was evaluated on Saccharomyces cerevisiae mitochondrial function for inhibition of complexes II, III and IV, reactive oxygen species (ROS) production, catalase activity and lipid peroxidation. The results showed that PQ 9 inhibited complex III activity as well as the activity of all electron transport chain (ETC) complexes. In addition, PQ 9 reduced ROS production and catalase activity in yeast. The results suggest that PQ 9 may have potential applications as a new microbicidal compound by inducing ETC dysfunction., (© 2024 Wiley-VCH GmbH.)

Background: A family of 4H-benzo[d][1,3]oxazines were obtained from a group of N-(2-alkynyl)aryl benzamides precursors via gold(I) catalysed chemoselective 6-exo-dig C-O cyclization., Method: The precursors and oxazines obtained were studied in breast cancer cell lines MCF-7, CAMA-1, HCC1954 and SKBR-3 with differential biological activity showing various degrees of inhibition with a notable effect for those that had an aryl substituted at C-2 of the molecules. 4H-benzo[d][1,3]oxazines showed an IC50 rating from 0.30 to 157.4 µM in MCF-7, 0.16 to 139 in CAMA-1, 0.09 to 93.08 in SKBR-3, and 0.51 to 157.2 in HCC1954 cells., Results: We observed that etoposide is similar to benzoxazines while taxol effect is more potent. Four cell lines responded to benzoxazines while SKBR-3 cell line responded to precursors and benzoxazines. Compounds 16, 24, 25 and 26 have the potent effect in cell proliferation inhibition in the 4 cell lines tested and correlated with oxidant activity suggesting a possible mechanism by ROS generation., Conclusion: These compounds represent possible drug candidates for the treatment of breast cancer. However, further trials are needed to elucidate its full effect on cellular and molecular features of cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The anticarcinogenic potential of a series of 1,5-disubstituted tetrazole-1,2,3-triazole hybrids (T-THs) was evaluated in the breast cancer (BC)-derived cell lines MCF-7 (ER+, PR+, and HER2-), CAMA-1 (ER+, PR+/-, and HER2-), SKBR-3 (ER+, PR+, and HER2+), and HCC1954 (ER+, PR+, and HER2+). The T-THs 7f , 7l , and 7g inhibited the proliferation of MCF-7 and CAMA-1, HCC1954, and SKBR-3 cells, respectively. The compounds with stronger effect in terms of migration and invasion inhibition were 7o , 7b , 7n , and 7k for the CAMA-1, MCF-7, HCC1954, and SKBR-3 cells respectively. Interestingly, these T-THs were the compounds with a fluorine present in their structures. To discover a possible target protein, a molecular docking analysis was performed for p53, p38, p58, and JNK1. The T-THs presented a higher affinity for p53, followed by JNK1, p58, and lastly p38. The best-predicted affinity for p53 showed interactions between the T-THs and both the DNA fragment and the protein. These results provide an opportunity for these compounds to be studied as potential drug candidates for breast cancer treatment.

The protein tyrosine kinase (PTK) produced by the BCR-ABL1 gene has generated significant interest in the development of inhibitors since the presence of punctual mutations causes resistance to currently approved drugs, mainly the T315I mutation has been the most difficult to address. In this work, derivatives of 1,6-dihydroazaazulenes are studied as possible inhibitors of this PTK in its wild form and the mutant T315I . The recognition of the ligands was explored through molecular docking, and the stability of the complexes and their evolution over time was studied using molecular dynamics (MD) simulations. Our results show that complexes are energetically stable and reside on the ATP binding site in all cases during the MD experiments. Interestingly, a few of our proposed ligands presented greater affinity for T315I , finding more favorable binding free energies (ΔG) than the reference drug axitinib. Furthermore, they may act as inhibitors for both isoforms. Our findings are promising because mutation of T315I does not prevent ligand recognition, as detailed in this work, which is very important to conduct further experimental research.Communicated by Ramaswamy H. Sarma.

Zygomycetes are ubiquitous saprophytes in natural environments which transform organic matter. Some zygomycetes of gender Mucor have attracted interest in health sector. Due to its ability as opportunistic microorganisms infecting immuno-compromised people and to the few available pharmacological treatments, the mucormycosis is receiving worldwide attention. Concerning to the pharmacological treatments, some triazole-based compounds such as fluconazole are extensively used. Nevertheless, we focused in the quinolines since they are broadly used models for the design and development of new synthetic antifungal agents. In this study, the fungistatic activity on M. circinelloides of various 2-aryl-4-aryloxyquinoline-based compounds was discovered, and in some cases, it resulted better than reference compound fluconazole. These quinoline derivatives were synthesized via the C sp 2 -O bond formation using diaryliodonium(III) salts chemistry. A QSAR study was carried out to quantitatively correlate the chemical structure of the tested compounds with their biological activity. Also, a docking study to identify a plausible action target of our more active quinolines was carried out. The results highlighted an increased activity with the fluorine- and nitro-containing derivatives. In light of the few mucormycosis pharmacological treatments, herein we present some non-described molecules with excellent in vitro activities and potential use in the mucormycosis treatment., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The first gold(I)-catalyzed cycloisomerization procedure applied to the synthesis of substituted 4 H -benzo[ d ][1,3]oxazines has been developed starting from N -(2-alkynyl)aryl benzamides. The chemoselective oxygen cyclization via the 6- exo -dig pathway yielded the observed heterocycles in modest to good chemical yields under very mild reaction conditions. The obtained oxazines were assayed on the breast cancer (BC)-derived cell lines MCF-7 and HCC1954 with differential biological activity. The newly synthesized 4 H -benzo[ d ][1,3]oxazine compounds showed several degrees of cell proliferation inhibition with a remarkable effect for those compounds having a substituted aryl at C-2 of the molecules. The 4 H -benzo[ d ][1,3]oxazines showed an IC 50 ranking from 3.1 to 95 μM in MCF-7 and HCC1954 cells. These compounds represent potential drug candidates for BC treatment. However, additional assays are needed to elucidate their complete effect over the cellular and molecular hallmarks of cancer., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

A high-order multicomponent reaction involving a six-component reaction to obtain the novel linked 1,5-disubstituted tetrazole-1,2,3-triazole hybrids in low to moderate yield is described. This one-pot reaction is carried out under a cascade process consisting of three sequential reactions: Ugi-azide, bimolecular nucleophilic substitution (S N 2), and copper-catalyzed alkyne-azide reaction (CuAAC), with high atom and step-economy due the formation of six new bonds (one C-C, four C-N, and one N-N). Thus, the protocol developed offers operational simplicity, mild reaction conditions, and structural diversity. Finally, to evaluate the antitumoral potential of the synthetized molecules, a proliferation study was performed in the breast cancer (BC) derived cell line MCF-7. The hybrid compounds showed several degrees of cell proliferation inhibition with a remarkable effect in those compounds with cyclohexane and halogens in their structures. These compounds represent potential drug candidates for breast cancer treatment. However, additionally assays are needed to elucidate their complete effect over the cellular hallmarks of cancer.

Perezone is a naturally occurring hydroxyquinone that has been deeply studied from different chemical aspects, such as therapeutics, electrochemistry, physical-chemical properties, or synthetic approaches that turn it an attractive template for new semisynthetic derivatives with a wide range of purposes. Herein, we describe a facile synthetic pathway to obtain new perezone derivatives by the addition of a pyrrole moiety that can be used for ion recognition. Compounds 2-4 showed the capability to interact with several anions and M 2+ cations as separate events that result in colorimetric changes. Moreover, the compounds can behave as heteroditopic receptors. Besides, a previous interaction between fluoride ions and perezone derivatives triggered a successful recognition of M 2+ ions, remarking Ni 2+ as the most interesting phenomenon. These results project the compounds as potential colorimetric receptors for nickel ions in complex solutions., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Deep eutectic solvents (DESs) have been considered "the organic reaction medium of the century" because they can be used as solvents and active catalysts in chemical reactions. However, experimental and theoretical studies are still needed to provide information on the structures of DESs, the kinetics and thermodynamics properties, the interactions between the DESs and the substrates, the effect of water on the DES supramolecular network and its physicochemical properties, and so forth. This information is very useful to understand the essence of the processes that take place in the catalysis of chemical reactions and, therefore, to help in the design of a DES for a specific reaction and sample. This article shows a systematic study of the impact of DES choline chloride/ p -toluenesulfonic acid and DES choline chloride/ p -toluenesulfonic acid-water in the aza-Michael addition of arylamines to maleimide to obtain aminopyrrolidine-2,5-dione derivatives. The derivatives are obtained under very mild reaction conditions with good yield. The global reaction is exothermic, spontaneous, permitted by enthalpy, and prohibited for entropy. The calculated potential energy surface shows a reaction mechanism of six steps controlled by enthalpy (except the last step that is controlled by entropy). The water incorporated in the supramolecular DES complex stabilizes the transition states and favors the enthalpy-driven binding. A set of H/D exchange NMR experiments validates the transition state existing in the fourth stage of the mechanism.

A docking study of a set of several 1,5-disubstituted tetrazoles compounds has been performed to predict the poses of some potential inhibitors of the Abelson tyrosine-protein kinase and the mutated Abelson tyrosine-protein kinase T315I. The study was conducted through Lamarckian genetic algorithms in Autodock4 package. Bayesian calculations were performed; specificity and sensitivity values as well as positive predicted values, and negative predicted values were calculated using a set of 99 known experimentally active ligands and 385 decoys for the Abelson tyrosine-protein kinase from the Directory of Useful Decoys database. Root mean square deviation values were calculated though the X-ray crystallographic data of the bioactive pose of imatinib as reference, and the pose obtained with the above methods. The obtained results show the importance of the protein interactions with the halogens present in some of these 1,5-disubstituted tetrazoles ligands, as well as the presence of some hydrophobic fragments, obtained via the pharmacophoric model, concluding that the eight novels 1,5-disubstituted tetrazoles compounds herein identified, could be effective inhibitors of Abelson tyrosine-protein kinase, using a docking calculations., Competing Interests: Conflict of interestThe authors declare no conflict of interest., (© Springer-Verlag GmbH Germany, part of Springer Nature 2020.)

An efficient transition-metal-based heterogeneous catalyst free procedure for obtaining the oxidative amidation of benzaldehyde using quinones as oxidizing agents in low molar proportions is described here. Pyrrolylquinones (PQ) proved to be more suitable than DDQ and 2,5-dimethylbenzoquinone to conduct the oxidation process. Although the solvent itself acted as the oxidant with low to moderate yields, PQ/DMSO provided an efficient system for carrying out the reaction under operational simplicity, mild reaction conditions, short reaction times and high yields of the desired product. The scope of the method was evaluated with substituted benzaldehydes and secondary amines. Theoretical foundations are given to explain the participation of quinones as an oxidizing agent in the reaction., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A simple and efficient catalytic system based on a Pd complex of 4-aminoantipyrine, 4-AAP-Pd(II), was found to be highly active for Suzuki-Miyaura cross-coupling of aryl iodides and bromides with phenylboronic acids under mild reaction conditions. Good to excellent product yields from the cross-coupling reaction can be achieved when the reaction is carried out in ethanol, in the open air, using low loading of 4-AAP-Pd(II) as a precatalyst, and in the presence of aqueous K2CO3 as the base. A variety of functional groups are tolerated.

We describe the synthesis of the novel 2-(1,5-dimethyl-4-oxo-hexyl)-3-hydroxy-5-methyl-6-pyrrolyl-1,4-benzoquinone 2 from the natural product perezone 1. The anion-guest properties of the new compound were evaluated in the presence of fluoride, chloride, bromide and iodide tetrabutylammonium salts using 1H NMR titration techniques in deuterated dichloromethane or dimethylformamide. The title compound showed interesting colorimetric behavior in the presence of inorganic salts.

The first direct synthesis of beta-unsubstituted meso-decamethylcalix[5]pyrrole from pyrrole and acetone, with moderate yield, is described. The results showed that a bismuth salt was necessary to obtain calix[5]pyrrole, with the best results obtained using Bi(NO(3))(3).

The discovery of new compounds with antitumoral activity has become one of the most important goals in medicinal chemistry. One interesting group of chemotherapeutic agents used in cancer therapy comprises molecules that interact with DNA. Research in this area has revealed a range of DNA recognizing molecules that act as antitumoral agents, including groove binders, alkylating and intercalator compounds. DNA intercalators (molecules that intercalate between DNA base pairs) have attracted particular attention due to their antitumoral activity. For example, a number of acridine and anthracycline derivatives are excellent DNA intercalators that are now on the market as chemotherapeutic agents. Commercially available acridine and anthracycline derivatives have been widely studied from a variety of viewpoints, such as physicochemical properties, structural requirements, synthesis and biological activity. However, the clinical application of these and other compounds of the same class has encountered problems such as multidrug resistance (MRD), and secondary and/or collateral effects. These shortcomings have motivated the search for new compounds to be used either in place of, or in conjunction with, the existing compounds. Unfortunately, the results of this search have not met expectations. The vast majority of candidate intercalator compounds tested for use as anticancer agents have shown little or no biological activity. Research in this area has not been without benefits, however, for it has produced much information on the synthesis and antitumoral properties of hundreds of compounds, which have been tested on diverse tumoral cell lines. This review considers the structural and biological considerations relevant to the use of DNA intercalators and bis-intercalators as antitumoral agents, with an emphasis on the relationship between structure and activity, produced in last decade.

The synthesis of pyrrolo[2,3-e]indole derivatives with the structural characteristics of DNA bis- and mono-intercalators are described. A dihydro benzoindol analogue was also synthesised to elucidate the major structural requirements for cytotoxic activity. A biological evaluation of the test compounds was carried out in six different tumoral cell lines. The factors that affect the cytotoxic activity appear to be the substituents on the phenyl group, the presence of an amide group capable of strong interactions such as hydrogen bonding and solubility.

The one- and two-step syntheses of N,N'-(dinitrophenyl)alkanediamides and N,N'-(diaminophenyl)alkanediamides from 4-nitroaniline were carried out. These compounds were subjected to cytotoxic evaluation against different tumoural cell lines. A QSAR analysis for the aminated series, introducing a QSAR descriptor (D(CL)) designed herein for groove binders, reveals that the activity in the K562 cell line is related to the charge, polarisability, volume and length of the molecules.