Résumé: Recently, benzothiazole derivatives have garnered significant attention among the research community due to their pharmaceutical and biological significance. Likewise, in this study, novel benzothiazole derivatives were synthesized via a novel green approach and characterized by IR, NMR, and ESI MS spectroscopic methods. The synthesized compounds were evaluated for their urease inhibitory potential. All analogs exhibited varied degrees of urease inhibitory potential with IC50 values ranging between 6.01±0.23 and 21.07±0.77 μM, when compared with thiourea as the standard urease inhibitor (IC50= 11.58±0.34 μM). Among the tested derivatives, compound 3b (6.01±0.23 μM) was identified as the most potent inhibitor of urease. Based on the promising in vitro evaluation, a further in-silico study was carried out in order to understand the structure-activity relationship using DFT calculation. Molecular docking and ADMET prediction were investigated to evaluate the affinity of our synthesized compounds with anti-ureas targets. Then, a molecular dynamic simulation was suggested to confirm the stability of our derivatives in interaction within the active site.

Résumé: Microbial resistance to drugs currently traded in the market is a serious problem in modern medicine. In this field of research, we synthesized a novel N-acylsulfonamides (NAS) derivatives starting from commercially available compounds; morpholine, isocyanate of chlorosulfonyl and alcohols. The in vitro antimicrobial potential of synthesized compounds was screened against 04 Gram-negative bacteria; Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, 02 Gram-positive bacteria: Streptococcus sp, Staphylococcus aureus and 07 yeasts and fungi: Candida albicans, Candida spp, Penicillum spp, Aspegillus sp, Aspergillus flavus, Fusarium sp, and Cladosporium spp. The results of inhibition growth were compared with standard antimicrobial drugs with the goal of exploring their potential antimicrobial activity. In addition, the anti-inflammatory activity of the synthesized compounds was determined in-vitro by protein denaturation method. The obtained bioactivity results were further validated by in silico DFT (Density Functional Theory), ADME (Absorption-Distribution-Métabolisation-Excrétion), molecular docking studies and molecular dynamics simulations.

Résumé: The objective of this study is to evaluate a series of molecules based on cyclosulfamide as potential anticancer agents. Additionally, the study aims to analyze the obtained results through in silico studies; by conducting experiments and utilizing theoretical methods. In this context, we investigated the cytotoxic activity of enastron analogues on three human cell lines PRI (lymphoblastic cell line) derived from B-cell lymphoma. JURKAT (ATCC TIB-152) acute T cell leukaemia and K562 (ATCC CLL-243) is a chronic myelogenous leukaemia. Most of the tested compounds showed good inhibitory activity compared with the reference ligand (chlorambucil). The 5a derivative demonstrated the strongest effect against all cancer cells used. Furthermore, molecular docking simulations of the Eg5–enastron analogue complex revealed that studied molecules have the ability to inhibit the Eg5 enzyme, as evidenced by their calculated docking score. Following the promising results from the molecular docking study, the complex Eg5–4a underwent a 100 ns molecular dynamics simulation using Desmond. During the simulation, the receptor-ligand pairing demonstrated substantial stability after the initial 70 ns. In addition, we used DFT calculations to analyze the electronic and geometric characteristics of the studied compounds. The HOMO and LUMO band gap energies, and the molecular electrostatic potential surface were also deducted for the stable structure of each compound. Also, we studied the prediction of absorption, distribution, metabolism and excretion (ADME) of the compounds.

Résumé: New annulated pyrano[2,3-d]pyrimidine derivatives were synthesized with hydroxyl, methoxy, bromine, nitrile and nitro substituents on its skeleton. The correlated electronic effect of substituents on the magnitude of antibacterial activity was noted. The electron donating substituents (namely; 4–OH, 4–OCH3, 4-Br) and electron withdrawing substituents (4-NO2) on phenyl ring in the pyrano[2,3-d]pyrimidine skeleton exerted different influence on its antimicrobial activity against some Gram-positive and Gram-negative bacteria such as Pseudomonas aureus, E. coli, Staphylococcus aureus, Klebsiella pneumonia and Bacillus cereus. All the pyrano[2,3-d]pyrimidines were characterized by spectroscopic analyses. Antibacterial screening revealed that the presence of heteroaryl, cyano and amino groups on pyrano[2,3-d]pyrimidine skeleton increases its penetrating power on the bacterial cell wall so that the product becomes more biologically active. So the the nature of electron withdrawing or electro-donnor Impact of substituents should be taken in consideration in drug design. Hydrolysis of -CRN to amide restored vital Intramolecular interaction like ortho-nitrophenyl and single bondONOδ-…single bondNHδ+/amide link, offering a crucial template for antibacterial single bondNH, HO-pharmacophore sites, which ultimately elevated innate antimicrobial profiles. POM combinatorial analysis of tangible electronic contributions due to armed annulated pyrano[2,3-d]pyrimidines concluded their broad antimicrobial activity and viable/prominent drug score index through perspective parameters particularly: inter atomic distance/linkers, steric, electronic, polar parameters, and with a different polarising effect of electron donating/withdrawing environments of substituents. Furthermore, an anti-Kinase pharmacophore site (single bondOdouble bondCNHsingle bondCdouble bondO) was evaluated in continuation of the POM investigations. All synthesized products verified fewer side effects than standard streptomycin, but facile implication in selective cancer media (viz. breast or leucemia still needs to be screened).

Résumé: We demonstrate here a rapid and comfortable synthetic sequence to benzothiadiazinone dioxide (six-membered cyclic sulfamide) derivatives, analogues of Monastrol, which is known to be a specific mitotic kinesin Eg5 inhibitor. Fourteen novel compounds (1d–14d) were synthesized through three component Biginelli reaction, by condensation of aromatic aldehyde, sulfamide, and cyclohexane-1,3-dione. A wide range of substrates is compatible in this reaction, producing excellent yields (82–92%) in short time (5–10 min). The reaction is performed under solvent-free, catalysed by H2SO4/CH3COOH (1/9) using microwave irradiation. The structure of the obtained substances was confirmed by 1H, 13C, HMBC, HSQC NMR spectroscopy, IR spectroscopy, and mass spectrometry, as well as elemental analysis. A single crystal of the (4-phenyl-4,6,7,8-tetrahydro-1H benzo[c][1,2,6]thiadiazin-5(3H)-one 2,2-dioxide has been obtained after recrystallization in ethanol/acetone (9/1) and selected for X-ray study.

Résumé: We demonstrate here a rapid and comfortable synthetic sequence to benzothiadiazinone dioxide (six-membered cyclic sulfamide) derivatives, analogues of Monastrol, which is known to be a specific mitotic kinesin Eg5 inhibitor. Fourteen novel compounds (1d–14d) were synthesized through three component Biginelli reaction, by condensation of aromatic aldehyde, sulfamide, and cyclohexane-1,3-dione. A wide range of substrates is compatible in this reaction, producing excellent yields (82–92%) in short time (5–10 min). The reaction is performed under solvent-free, catalysed by H2SO4/CH3COOH (1/9) using microwave irradiation. The structure of the obtained substances was confirmed by 1H, 13C, HMBC, HSQC NMR spectroscopy, IR spectroscopy, and mass spectrometry, as well as elemental analysis. A single crystal of the (4-phenyl-4,6,7,8-tetrahydro-1H benzo[c][1,2,6]thiadiazin-5(3H)-one 2,2-dioxide has been obtained after recrystallization in ethanol/acetone (9/1) and selected for X-ray study.

Résumé: A computational Petra/Osiris/Molinspiration/DFT (POM/DFT) based model has been developed for the identification of physico-chemical parameters governing the bioactivity of series of oxazaphosphinanes derivatives 1a-1f containing potential antifungal O, N-pharmacophore. Molecular docking study was performed in order to evaluate synthesized compounds their possible antifungal properties and their interactions in the binding site. Molecular docking studies revealed that the compounds 1a-1f have the potential to become lead molecules in the drug discovery process. The six compounds 1a–1f analyzed here were previously synthesized by our group.

Résumé: A series of novel α-sulfamidophosphonate derivatives was rationally designed and synthesized following the principle of the superposition of bioactive substructures by the combination of sulfonamide, aldehyde and triethylphosphite. The relative cytotoxicity of these derivatives in comparison to chlorambucil has been reported. The crystal structure of diethyl phenyl (N-phenylsulfamoylamino)methylphosphonate has been determined. This crystal belongs to the C 2/c space group. The P atom has a distorted tetrahedral configuration with the O–P–O angle as the minimum bond angle (105.34) and one of the Odouble bondP–O angles as the maximum angle (116.18). In addition, the results of bioinformatics POM (Petra, Osiris, Molinspiration) analyses and molecular docking show that all compounds exhibited good bioavailability, pharmacokinetic, and no toxicity profiles. Furthermore, drug likeness analysis suggests that the synthesized α-sulfamidophosphonate derivatives might have appropriate oral absorption and brain penetration for therapeutic applications. As the compounds were found to be non-toxic and in a safe range containing an important antiviral O,O-pharmacophore site, they present good candidates for further antiviral study.

Résumé: Background: Human lactate dehydrogenase 5 (hLDH5) represents a promising anticancer target, particularly for the treatment of hypoxic tumors, where it is often hyperexpressed. In fact, by catalyzing the reduction of pyruvate to lactate, hLDH5 allows the survival of tumor cells under hypoxic conditions by means of glycolysis. Despite the efforts dedicated to the identification and development of hLDH5 inhibitors, only few compounds showing promising activity in cancer cell lines have been reported. Objective: In the present study, we developed a virtual screening (VS) protocol aimed at identifying new small molecule inhibitors of hLDH5. Method: The VS strategy consisted in a pharmacophore-driven consensus docking (CD) approach, combining a structure-based pharmacophore screening and CD protocol employing three different docking methods. Results: The VS protocol was applied to filter the Enamine commercial database and allowed the selection of three candidate ligands to be subjected to hLDH5 inhibition assays. One of the selected compounds showed a promising activity, compared to its low molecular weight, with an IC50 of 180.7 ± 16.5 µM. Conclusion: We identified a new small-molecule inhibitor of hLDH5 that can be considered as a new lead for the development of potent hLDH5 inhibitors. Moreover, these results demonstrate the reliability of the VS protocol developed.

Résumé: Inhibitors of human lactate dehydrogenase (hLDH5)—the enzyme responsible for the conversion of pyruvate to lactate coupled with oxidation of NADH to NAD+—are promising therapeutic agents against cancer because this enzyme is generally found to be overexpressed in most invasive cancer cells and is linked to their vitality especially under hypoxic conditions. Consequently, significant efforts have been made for the identification of small-molecule hLDH5 inhibitors displaying high inhibitory potencies. X-ray structure of hLDH5 complexes as well as molecular modeling studies contribute to identify and explain the main binding modes of hLDH5 inhibitors reported in literature. The purpose of this review is to analyze the main three-dimensional interactions between some of the most potent inhibitors and hLDH5, in order to provide useful suggestions for the design of new derivatives.