The development of multi-resistant strains of plasmodium parasite has become a global problem, therefore, the discovery of new antimalarial agents is the only available solution. In order to improve and propose new compounds with antimalarial activity, the three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking studies were carried on aurone analogues acting as Qo site inhibitors in cytochrome b. The 3D-QSAR model was established in this study based on the Comparative Molecular Field Analysis (CoMFA) and the Comparative Molecular Similarity Indices Analysis (CoMSIA). The good predictability was obtained using the CoMFA model (Q² = 0.5; R² = 0.97; R pred 2 = 0.72) and the best CoMSIA model (Q² = 0.526; R² = 0.915; R pred 2 = ​ 0.765). The predictive capacity of the developed model was evaluated through external validation using a test set compound and an applicability domain technique. In this study, the Steric, electrostatic and hydrogen bond acceptor fields played a key role in antimalarial activity. The results of the molecular docking revealed theoretically the importance of the residues his183 and his82 in the active site of the heme b_L, this result was validated by a new assessment method. Based on the previous results, we designed several new potent Cytochrome b inhibitors and their inhibitory activities were predicted by the best model. Furthermore, these new inhibitors were analyzed for their ADMET properties and drug likeness. These results would be of great help in leading optimization for new drug discovery that can solve the problem of multiple drug resistance.

Malaria persists as the most infectious vector-borne disease in the world. The inhibition of the mitochondrial respiratory chain enzyme cytochrome bc1 has become the major focus as a molecular target in malarial parasites. Azaaurone derivatives have the potential to inhibit the mitochondrial respiratory chain of Plasmodium falciparum. Thus, with the aim of improving and proposing new molecules designed for antimalarial activity, we carried out a theoretical study of two-dimensional, three-dimensional-quantitative structure–activity relationships (QSAR) and docking analysis of a series of 53 azaaurones acting as inhibitors of the Qo site in cytochrome b. The generated 2D-QSAR model showed a good correlation coefficient of 0.871 and a very good prediction coefficient of the test set of 0.914. The predictive ability of the 2D-QSAR models was assessed using the Y-randomization test: internal (leave-one-out cross-validation) and external (test set with 11 compounds) validation. The 3D-QSAR model was generated using comparative molecular similarity indices analysis (CoMSIA). The best CoMSIA model with Q² = 0.739, R² = 0.844 and R_pred ² = 0.932 was evaluated using the Y-randomization test. The proposed models gave significant statistical quality. The results of molecular docking revealed that azaaurones specifically interact with the residues His183 and His82; this result was validated with a new validation criterion. Moreover, this is the first theoretical study showing the action of a molecule on the active site of heme b_L. A good consistency between theoretical, 2D- and 3D-SQAR and molecular docking studies provided directions for the design of new drug candidates.

Cedrus atlantica (Endl.) Manetti ex Carriere is an endemic tree possessing valuable health benefits which has been widely used since time immemorial in international traditional pharmacopoeia. The aim of this exploratory investigation is to determine the volatile compounds of C. atlantica essential oils (CAEOs) and to examine their in vitro antimicrobial, antioxidant, anti-inflammatory, and dermatoprotective properties. In silico simulations, including molecular docking and pharmacokinetics absorption, distribution, metabolism, excretion, and toxicity (ADMET), and drug-likeness prediction were used to reveal the processes underlying in vitro biological properties. Gas chromatography–mass spectrophotometry (GC-MS) was used for the chemical screening of CAEO. The antioxidant activity of CAEO was investigated using four in vitro complementary techniques, including ABTS and DPPH radicals scavenging activity, ferric reductive power, and inhibition of lipid peroxidation (β-carotene test). Lipoxygenase (5-LOX) inhibition and tyrosinase inhibitory assays were used for testing the anti-inflammatory and dermatoprotective properties. GC-MS analysis indicated that the main components of CAEO are β-himachalene (28.99%), α-himachalene (14.43%), and longifolene (12.2%). An in vitro antimicrobial activity of CAEO was examined against eleven strains of Gram-positive bacteria (three strains), Gram-negative bacteria (four strains), and fungi (four strains). The results demonstrated high antibacterial and antifungal activity against ten of them (>15 mm zone of inhibition) using the disc-diffusion assay. The microdilution test showed that the lowest values of MIC and MBC were recorded with the Gram-positive bacteria in particular, which ranged from 0.0625 to 0.25 % v/v for MIC and from 0.5 to 0.125 % v/v for MBC. The MIC and MFC of the fungal strains ranged from 0.5 to 4.0% (MIC) and 0.5 to 8.0% v/v (MFC). According to the MBC/MIC and MFC/MIC ratios, CAEO has bactericidal and fungicidal activity. The results of the in vitro antioxidant assays revealed that CAEO possesses remarkable antioxidant activity. The inhibitory effects on 5-LOX and tyrosinase enzymes was also significant (p < 0.05). ADMET investigation suggests that the main compounds of CAEO possess favorable pharmacokinetic properties. These findings provide scientific validation of the traditional uses of this plant and suggest its potential application as natural drugs.

This work describes the synthesis, characterization, and in vitro and in silico evaluation of the biological activity of new functionalized isoxazole derivatives. The structures of all new compounds were analyzed by IR and NMR spectroscopy. The structures of 4c and 4f were further confirmed by single crystal X-ray and their compositions unambiguously determined by mass spectrometry (MS). The antibacterial effect of the isoxazoles was assessed in vitro against Escherichia coli, Bacillus subtilis, and Staphylococcusaureus bacterial strains. Isoxazole 4a showed significant activity against E. coli and B. subtilis compared to the reference antibiotic drugs while 4d and 4f also exhibited some antibacterial effects. The molecular docking results indicate that the synthesized compounds exhibit strong interactions with the target proteins. Specifically, 4a displayed a better affinity for E. coli, S. aureus, and B. subtilis in comparison to the reference drugs. The molecular dynamics simulations performed on 4a strongly support the stability of the ligand–receptor complex when interacting with the active sites of proteins from E. coli, S. aureus, and B. subtilis. Lastly, the results of the Absorption, Distribution, Metabolism, Excretion and Toxicity Analysis (ADME-Tox) reveal that the molecules have promising pharmacokinetic properties, suggesting favorable druglike properties and potential therapeutic agents.

Resistance to folate antagonists is caused by mutations in the dihydrofolate reductase (DHFR) genes. These mutations affect the amino acids at positions 51, 59, 108 and 164 of DHFR, which appear to play a major role in malaria treatment failure. Therefore, the design of new drugs able to overcome the problem of antifolate drug resistance should receive urgent attention. In this study, a three-dimensional quantitative structure-activity relationship (3 D-QSAR) and molecular docking studies have been performed on antimalarial quinazoline derivatives. The CoMFA (Q² = 0.63, R² = 0.83 and $R_{\mathit{pred}}^2$ = 0.70) and the CoMSIA (Q² = 0.584, R² = 0.816, and $R_{\mathit{pred}}^2$= 0.73) models show a good prediction of antimalarial activity. The reliability and robustness of the proposed models have been tested using several validation methods, which showed that the steric, electrostatic, hydrophobic and H-bond acceptor fields of the CoMSIA model play a key role in the prediction of antimalarial activity. Molecular docking studies reveal important interactions between two isomeric compounds (meta and para) and the DHFR receptor in its wild and mutant forms. The obtained outcomes of molecular docking studies have been validated using a new method based on visual inspection. The DFT study of the two isomeric compounds confirms clearly the trends of 3 D-QSAR and molecular docking for the design of new compounds. Moreover, the consistency between theoretical, 3 D-QSAR and molecular docking analysis provides guidance for the design of new drug candidates, which have been tested using ADMET properties and drug likeness analysis. Communicated by Ramaswamy H. Sarma