The emergence of drug-resistant underscores the need for innovative therapeutic strategies targeting essential metabolic pathways. We designed, synthesized, and evaluated a series of dual inhibitors targeting two key enzymes of the mycobacterial FAS-II system, HadAB and InhA. Using a diaryl ether scaffold, six thiosemicarbazone derivatives and their aldehyde intermediates were prepared and tested for enzymatic and antimycobacterial activity. Thiosemicarbazone derivatives and aldehyde intermediates both strongly inhibited InhA, and the thiosemicarbazones additionally potentially inhibited HadAB through covalent interaction with the HadA subunit, supporting the dual-target approach. Several compounds showed low micromolar to submicromolar activity against drug-susceptible and clinical strains, including an ethA-deficient mutant. Crystallographic structures of InhA-ligand complexes revealed key binding interactions and clarified inhibition mechanisms. Despite some cytotoxicity concerns, these findings provide a promising basis for developing optimized dual-target inhibitors of the FAS-II pathway.

The emergence of drug-resistant Mycobacterium tuberculosis underscores the need for innovative therapeutic strategies targeting essential metabolic pathways. We designed, synthesized, and evaluated a series of dual inhibitors targeting two key enzymes of the mycobacterial FAS-II system, HadAB and InhA. Using a diaryl ether scaffold, six thiosemicarbazone derivatives and their aldehyde intermediates were prepared and tested for enzymatic and antimycobacterial activity. Thiosemicarbazone derivatives and aldehyde intermediates both strongly inhibited InhA, and the thiosemicarbazones additionally potentially inhibited HadAB through covalent interaction with the HadA subunit, supporting the dual-target approach. Several compounds showed low micromolar to submicromolar activity against drug-susceptible and clinical M. tuberculosis strains, including an ethA-deficient mutant. Crystallographic structures of InhA-ligand complexes revealed key binding interactions and clarified inhibition mechanisms. Despite some cytotoxicity concerns, these findings provide a promising basis for developing optimized dual-target inhibitors of the M. tuberculosis FAS-II pathway.

Considering the importance of organic functionalization of MOFs, we here report a simple, tunable and efficient one-step post-modification procedure for introducing amino and carboxylic groups into the mesoporous metal–organic framework Al- and Cr-MIL-101-NH2 based on its reaction with alkyl bromides. This procedure allows also access to polyfunctionalized MIL-101 decorated with both carboxylic and primary amino groups. Other chemical functions, such as alcohols and alkynes, were also successfully introduced by this method.

N-Nitroso-3-morpholinosydnonimine 3 was prepared by nitrosation of SIN-1 and characterized by 1H-NMR, 13C-NMR and HRMS. Its structure, confirmed by single crystal X-ray diffraction analysis, was found in agreement with its mesoionic and aromatic character. Unlike SIN-1, which releases both nitric oxide and superoxide radical, decomposition of this nitrosylated sydonimine could yield nitric oxide as the only decomposition product, and thus without the formation of toxic peroxynitrite.

N-Nitroso-3-morpholinosydnonimine 3 was prepared by nitrosation of SIN-1 and characterized by 1H-NMR, 13C-NMR, and HRMS. Its structure, confirmed by single crystal X-ray diffraction analysis, was found to be in agreement with its mesoionic and aromatic character. Unlike 3-morpholino-sydnonimine (SIN-1), which releases both nitric oxide and superoxide radical, decomposition of this nitrosylated sydonimine could yield nitric oxide as the only decomposition product, and thus without the formation of toxic peroxynitrite.

Tuberculosis is a serious public health problem worldwide. The search for new antibiotics has become a priority, especially with the emergence of resistant strains. A new family of imidazoquinoline derivatives, structurally analogous to triazolophthalazines, which had previously shown good antituberculosis activity, were designed to inhibit InhA, an essential enzyme for Mycobacterium tuberculosis survival. Over twenty molecules were synthesized and the results showed modest inhibitory efficacy against the protein. Docking experiments were carried out to show how these molecules could interact with the protein’s substrate binding site. Disappointingly, unlike triazolophthlazines, these imidazoquinoline derivatives showed an absence of inhibition on mycobacterial growth.

Selenium compounds have garnered significant attention in the field of medicinal chemistry due to their unique biochemical properties and potential therapeutic applications for different pathologies. In this study, we report the synthesis of a new selenylated bis-pyridone compound using SeO2 as the source of selenium. Detailed 1H and 13C NMR characterizations and mass spectral analysis are given.

A series of 4-hydroxy-6-methyl-3-(1-(4-(aryl/methyl)thiazol-2-yl)-1H-pyrazol-3-yl)-2H-pyran-2-ones 3a–h have been synthesized from aryl/methyl halomethylketones and a key pyrazole intermediate 1 using a convenient one-pot synthesis method. All compounds were characterized by NMR and MS, and the structure of three of them (3a, 3b and 3f) was resolved by X-ray diffraction. These heteroatom-rich thiazole compounds were then evaluated as inhibitors of Mycobacterium tuberculosis InhA, a key enzyme involved in the type II fatty acid biosynthesis pathway of the mycobacterium. Although inhibitory activities were found to be rather weak, molecular docking studies were also been carried out to understand a possible mode of interaction with key residues in the enzyme’s active site.

Selenium compounds have garnered significant attention in the field of medicinal chemistry due to their unique biochemical properties and potential therapeutic applications for different pa-thologies. In this study, we report the synthesis of a new selenylated bis-pyridone compound using SeO2 as the source of selenium. The detailed characterizations 1H and 13C NMR and mass spectral analysis are given.

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) affects 10 million people each year and the emergence of resistant TB augurs for a growing incidence. In the last 60 years, only three new drugs were approved for TB treatment, for which resistances are already emerging. Therefore, there is a crucial need for new chemotherapeutic agents capable of eradicating TB. Enzymes belonging to the type II fatty acid synthase system (FAS-II) are involved in the biosynthesis of mycolic acids, cell envelope components essential for mycobacterial survival. Among them, InhA is the primary target of isoniazid (INH), one of the most effective compounds to treat TB. INH acts as a prodrug requiring activation by the catalase-peroxidase KatG, whose mutations are the major cause for INH resistance. Herein, a new series of direct InhA inhibitors were designed based on a molecular hybridization approach. They exhibit potent inhibitory activities of InhA and, for some of them, good antitubercular activities. Moreover, they display a low toxicity on human cells. A study of the mechanism of action of the most effective molecules shows that they inhibit the biosynthesis of mycolic acids. The X-ray structures of two InhA/NAD+/inhibitor complexes have been obtained showing a binding mode of a part of the molecule in the minor portal, rarely seen in the InhA structures reported so far.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Excited-state intramolecular proton transfer (ESIPT) is a photophysical process that may lead to superior emission properties. For a long time, cinnamoyl pyrone (CP) derivatives have been classified as non-ESIPT molecules. With the exception of those bearing a strong electron-donor substituent, they have been considered to have no interest from a spectroscopic point of view, because they are virtually not fluorescent in solution. Revisiting their photophysical behaviour in solution shows the complexity of the mechanisms involved. It appeared that CPs with no or weak electron-donor substituents indeed undergo ESIPT, but the facile access to a conical intersection subsequently induces non-radiative deactivation, hence the extinction of fluorescence in solution. When substituted by an electron-donating diethylamino group, the molecules deactivate through a radiative intramolecular charge transfer (ICT) state following an ESIPT process. In the solid state, the restricted access to conical intersection (RACI) makes most of the CP derivatives strongly fluorescent. Whatever the electron-donating strength of their substituent, most of these molecules become good emitters in the solid state, with emission ranging from turquoise blue to deep red. Although they need extensive purification, their one-step synthesis and spectacular aggregation-induced emission (AIE) properties make these molecules good candidates for applications in the field of AIE-probes and photoluminescent materials.

The mesoporous metal-organic framework Cr-MIL-101-NH2 (MOF1) has been used to encapsulate, by a simple impregnation method, large amounts of copper sulfate. The resulting loaded material, Cu@MOF1, was successfully employed to slowly release copper(ii) into an appropriate reaction medium in which the reducing agent sodium ascorbate reduces copper(ii) to copper(i), thus allowing the well-known copper(i)-catalyzed alkyne-azide cycloaddition (CuAAC) "click" reaction to proceed in the absence of potentially high local copper(i) concentrations. The use of a MOF-based controlled copper release system such as Cu@MOF1 may be relevant for copper(i)-catalyzed reactions having substrates that could be degraded by potentially high local concentrations of copper(i). The copper chelating ligand TBTA (tris(benzyltriazolylmethyl)amine), a very useful ligand for click chemistry, has been successfully attached to the pores of MOF1. The resulting TBTA-functionalized MOF (MOF3) was compared with its non-functionalized version (MOF1). At copper loadings of ca. 3 mmol g-1, the results revealed that the performances of the two materials are strikingly similar. Upon immersion in methanol/water (95/5) containing sodium ascorbate, both materials slowly released copper encapsulated in their pores and could be recovered and reused efficiently for up to five reaction cycles without reloading with metal ion, while allowing the CuAAC reaction to proceed with excellent conversion rates and yields.

Triclosan and isoniazid are known antitubercular compounds that have proven to be also active against Leishmania parasites. On these grounds, a collection of 37 diverse 1,2,3-triazoles based on the antitubercular molecules triclosan and 5-octyl-2-phenoxyphenol (8PP) were designed in search of novel structures with leishmanicidal activity and prepared using different alkynes and azides. The 37 compounds were assayed against Leishmania donovani, the etiological agent of leishmaniasis, yielding some analogs with activity at micromolar concentrations and against M. tuberculosis H37Rv resulting in scarce active compounds with an MIC of 20 μM. To study the mechanism of action of these catechols, we analyzed the inhibition activity of the library on the M. tuberculosis enoyl-ACP reductase (ENR) InhA, obtaining poor inhibition of the enzyme. The cytotoxicity against Vero cells was also tested, resulting in none of the compounds being cytotoxic at concentrations of up to 20 μM. Derivative 5f could be considered a valuable starting point for future antileishmanial drug development. The validation of a putative leishmanial InhA orthologue as a therapeutic target needs to be further investigated.

A zinc metal-organic framework, namely poly[bis-(N,N-di-ethyl-formamide)(μ4-naphthalene-2,6-di-carboxyl-ato)(μ2-naphthalene-2,6-di-carboxyl-ato)dizinc(II)], [Zn(C12H6O4)(C15H11NO)] n , built from windmill-type secondary building units and forming zigzag shaped two-dimensional stacked layers, has been solvothermally synthesized from naphthalene-2,6-di-carb-oxy-lic acid and zinc(II) acetate as the metal source in N,N-di-ethyl-formamide containing small amounts of formic acid.

This work reports the synthesis and characterization of new benzimidazole-cyclohexanone derivatives 3a-d, 4a-d and 5a-d under different reaction conditions. The intermediates and final compounds were purified and their chemical structures were elucidated using 1 H-NMR, 13 C-NMR and mass spectral data

Two series of heterocyclic compounds derived from 3-acetyl-4-hydroxy-6-methyl-2H-pyran-2-one (DHA) and 2-acetylbutyrolactone have been synthesized and characterized. The compounds were evaluated for their activities against Mycobacterium tuberculosis strain, and as inhibitors of InhA, a key enzyme involved in the type II fatty acid biosynthesis pathway of M. tuberculosis. Among the tested compounds, one DHA derivative, compound 2, showed promising activity against both mycobacteria and InhA. Docking studies were also carried out and give some new structure-activity trends compatible with current structural knowledge.

A direct method has been developed for the synthesis of the dihydropyridine ring system by means of Michael reaction. The reaction of dimedone with 1.0 equiv. of amines in water provides intermediate product, which allowed dihydropyridine derivatives by intramolecular cyclization in various yields. Of particular interest is the use of the water as solvent of reaction and in absence of catalyst. Also these operating conditions protect the environment and economic points of view.

The reaction of 1,2-phenylenediamines (o-PDA) 1 with aromatic aldehyds 2 allows simultaneous formation of two products 3 and 4. In this case, we adopted an operational process which enables us to direct our reaction towards the selective formation of only one product. From these results, we have prepared some news products of benzimidazole structure 5 by reaction of intramolecular heterocyclization of the molecules 3. An oxidation reaction of the nitrated compounds of 5 has allowed us to obtain their dehydrogenated homologues of structure 6.

A zinc-2,6-naphthalenedicarboxylate metal-organic framework, (H2NEt2)[Zn-2(AcO)(NDC)(2)]nDEF (1) (DEF = N,N-diethylformamide, AcO = acetate), was solvothermally synthesized in the presence of small amounts of acetic acid and characterized by single-crystal and powder X-ray diffraction and thermogravimetric analysis. Compound 1 is an anionic 3D paddle-wheel MOF, in which the zinc-naphthalenedicarboxylate sheets are linked together by bridging acetate ions. Compound 1 exhibits large square channels (13x13 angstrom), which contain DEF molecules and, alternatively, charge-balancing diethylammonium cations in situ generated by the hydrolysis of DEF under the solvothermal conditions used. The anionic host framework of 1 is unstable upon removal of guest DEF molecules suggesting that host-guest hydrogen bond interactions are crucial for maintaining the structural integrity of this compound.