Novel Benzotriazole-ß-lactam Derivatives as Antimalarial Agents: Design, Synthesis, Biological Evaluation and Molecular Docking Studies.

Many people around the world suffer from malaria, especially in tropical or subtropical regions. While malaria medications have shown success in treating malaria, there is still a problem with resistance to these drugs. Herein, we designed and synthesized some structurally novel benzotriazole-ß-lactams using 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid as a key intermediate. To synthesize the target molecules, the ketene-imine cycloaddition reaction was employed. First, The reaction of 1H-benzo[d][1,2,3]triazole with 2-bromoacetic acid in aqueous sodium hydroxide yielded 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid. Then, the treatment of 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid with tosyl chloride, triethyl amine, and Schiff base provided new ß-lactams in good to moderate yields.The formation of all cycloadducts was confirmed by elemental analysis, FT-IR, NMR and mass spectral data. Moreover, X-ray crystallography was used to determine the relative stereochemistry of 4a compound. The in vitro antimalarial activity test was conducted for each compound against P. falciparum K1. The IC50 values ranged from 5.56 to 25.65 µM. A cytotoxicity profile of the compounds at 200 µM final concentration revealed suitable selectivity of the compounds for malaria treatment. Furthermore, the docking study was carried out for each compound into the P. falciparum dihydrofolate reductase enzyme (PfDHFR) binding site to analyze their possible binding orientation in the active site.

Promising Larvicidal Effects of Nanoliposomes Containing Carvone and Mentha spicata and Tanacetum balsamita Essential Oils Against Anopheles stephensi.

PURPOSE: The use of synthetic pesticides to control the spread of mosquito-borne diseases has caused environmental pollution and insecticide resistance in mosquitoes. Developments of new green insecticides have thus received more attention to overcome these problems. METHODS: Nanoliposomes containing carvone and essential oils were first prepared. The nanoliposome physicochemical characteristics (particle size, morphology, and successful loading) were then evaluated by Dynamic Light Scattering (DLS), Transmission Electron Microscopy (TEM), and the Attenuated Total Reflection-Fourier Transform InfraRed (ATR-FTIR) analyses. Larvicidal effects of carvone, Mentha spicata, and Tanacetum balsamita essential oils were investigated against the main malaria vector, Anopheles stephensi, in non-formulated and nanoformulated states. RESULTS: The larvicidal effects of nanoformulated states were significantly more potent (7.2 folds, 3.5 folds, and 8 folds) than non-formulated states. Nanoliposomes containing M. spicata and T. balsamita essential oils with particle sizes of 175 ± 8 and 184 ± 5 nm showed the best efficacies (LC50 values = 9.74 and 9.36 µg/mL). CONCLUSION: The prepared samples could be used as new green potent larvicides against An stephensi mosquito in further field trials. It is also recommended to investigate their efficacies against other mosquitoes.

Comparative Effects of Elettaria cardamomum Essential Oil and Its Nanoliposomal State on Mortality of Anopheles stephensi Larvae.

Background: Malaria has remained the most dreadful vector-borne disease; hence, vector control is the most affordable and achievable approach to mitigate the disease burden. Due to the emergence of resistance and environmental pollution, herbal larvicides are considered an alternative to chemical types. Also, nanotechnology has been proposed as a promising solution to improve the efficiency of plant larvicides. This study aimed to develop an effective herbal larvicide. Methods: The chemical composition of Elettaria cardamomum essential oil (EO) was first investigated. Nanoliposomes containing the EO were then prepared using the ethanol injection method. After that, the larvicidal efficacy of the EO and its liposomal state were compared against Anopheles stephensi in laboratory conditions. Results: Alpha-terpinyl acetate (77.59%), eucalyptol (4.38%), nerolidol (2.96%), linalool (1.77%), and limonene (1.69%) were the five major compounds of the EO. Nanoliposomes containing the EO with a particle size of 73±5 nm and a zeta potential of -16.3±0.8 mV were prepared. Additionally, the ATR-FTIR analysis verified the successful loading of the EO into nanoliposomes. The larvicidal activity of nanoliposomes exhibited remarkable potency, with an LC50 value of 14.35 (10-18) µg/mL, significantly more potent than the non-formulated EO, which had an LC50 value of 33.47 (28-39) µg/mL against Anopheles stephensi larvae. Conclusion: The nanoliposomes containing E. cardamomum EO showed promising efficacy against An. stephensi larvae. It could thus be considered for further application against other species of mosquitoes.

Synthesis, docking and evaluation of in vitro anti-inflammatory activity of novel morpholine capped ß-lactam derivatives.

This study reports the synthesis and biological investigation of three series of novel monocyclic ß-lactam derivatives bearing a morpholine ring substituent on the nitrogen. The resulting ß-lactam adducts were synthesized via Staudinger's [2 + 2]-ketene-imine cycloaddition reaction. New synthesized products were fully characterized by spectral data and elemental analyses, and then evaluated for anti-inflammatory activity toward human inducible nitric oxide synthase (iNOS) and cytotoxicity toward HepG2 cell line. The compounds 3e, 3h, 3k, 5c, 5f, 6c, 6d and 6f showed higher activity with anti-inflammatory ratio values of 38, 62, 51, 72, 51, 35, 55 and 99, respectively, in comparison to the reference compound dexamethasone having an anti-inflammatory ratio value of 32. Hence, these compounds can be considered as potent iNOS inhibitors. They also exhibited IC50 values of 0.48 ± 0.04 mM, 0.51 ± 0.01 mM, 0.22 ± 0.02 mM, 0.12 ± 0.00 mM, 0.25 ± 0.05 mM, 0.82 ± 0.07 mM, 0.44 ± 0.04 mM and 0.60 ± 0.04 mM, respectively, in comparison with doxorubicin (IC50 < 0.01 mM) against HepG2 cells, biocompatibility and nontoxic behavior. In silico prediction of drug-likeness characteristic indicated that the compounds are compliant with the Lipinski and Veber rules. Molecular docking experiments showed a good correlation between the experimental activity and the calculated binding affinity to human inducible nitric oxide synthase, the enzymatic target for the anti-inflammatory response.

Synthesis of New ß-Lactams Bearing the Biologically Important Morpholine Ring and POM Analyses of Their Antimicrobial and Antimalarial Activities.

Some new ß-lactams bearing biologically important morpholine ring have been synthesized by acylation of amino ß-lactams in the presence of morpholine-4-carbonyl chloride. These novel ß-lactams were prepared under mild reaction conditions without any solvent in short reaction times. Their biological activities have been examined against microbial agents such as Staphylococcus aureus (S. aureus), Escherichia coli (E. coli), Pseudomonas aeruginosa (P. aeruginosa) and fungi such as Candida albicans (C. albicans) and Candida glabrata (C. glabrata). They have been also tested against Plasmodium falciparum K14 resistant strain and showed moderate to good IC50 values.

Asymmetric Organocatalytic Synthesis of Substituted Chiral 1,4-Dihydropyridine Derivatives.

The first cinchona-alkaloid-organocatalyzed enantioselective synthesis of chiral 1,4-dihydropyridine derivatives is described. Bis-cinchona catalyst 3b activates the Michael addition reaction between malononitrile derivatives 2 and enamines 1, affording the appealing and highly substituted 1,4-dihydropyridines 4 with very good results in most cases. This is one of very few examples of the synthesis of chiral 1,4-dihydropyridines by an enantioselective catalytic procedure. The highly substituted final compounds are of interest for their potential biological activity. This efficient protocol opens the door to a new area of research for the asymmetric construction of these skeletons for which enantioselective syntheses are still very limited.

New Organocatalytic Asymmetric Synthesis of Highly Substituted Chiral 2-Oxospiro-[indole-3,4'- (1',4'-dihydropyridine)] Derivatives.

Herein, we report our preliminary results concerning the first promising asymmetric synthesis of highly functionalized 2-oxospiro-[indole-3,4'-(1',4'-dihydropyridine)] via the reaction of an enamine with isatylidene malononitrile derivatives in the presence of a chiral base organocatalyst. The moderate, but promising, enantioselectivity observed (30%-58% ee (enantiomeric excess)) opens the door to a new area of research for the asymmetric construction of these appealing spirooxindole skeletons, whose enantioselective syntheses are still very limited.

1-[3-(Morpholin-4-yl)prop-yl]-3-[(naph-tha-len-2-yl)oxy]-4-(3-nitro-phen-yl)azeti-din-2-one.

In the title compound, C26H27N3O5, the ß-lactam (azetidin-2-one) ring is nearly planar [maximum deviation = 0.011 (3) Å]. The mean plane formed by the four C atoms of the morpholine ring, which adopts a chair conformation, the benzene ring and the naphthalene ring system form dihedral angles of 72.85 (17), 87.46 (15) and 65.96 (11)°, respectively, with the ß-lactam ring. In the crystal, molecules are linked via C-H⋯O hydrogen bonds, forming inversion dimers with R 2 (2)(8).

3-(2,4-Di-chloro-phen-oxy)-1-(4-meth-oxy-benz-yl)-4-(4-nitro-phen-yl)azetidin-2-one.

The ß-lactam ring of the title compound, C23H18Cl2N2O5, is nearly planar [maximum deviation = 0.019 (2) Šfor the N atom] and its mean plane makes dihedral angles of 56.86 (15), 68.83 (15) and 83.75 (15)° with the di-chloro-, nitro- and meth-oxy-substituted benzene rings, respectively. In the crystal, mol-ecules are linked by pairs of C-H⋯O hydrogen bonds, forming inversion dimers with R 2 (2)(10) loops. The dimers are linked by further C-H⋯O hydrogen bonds, forming sheets lying parallel to (001). The mol-ecular packing is further stabilized by C-H⋯π inter-actions.

1-(Morpholin-4-yl)-4-(2-nitro-phen-yl)spiro-[azetidine-3,9'-xanthen]-2-one.

In the title compound, C22H21N3O5, the ß-lactam (azetidin-2-one) ring is nearly planar [maximum deviation = 0.010 (1) Å] and makes dihedral angles of 69.22 (5), 55.32 (5) and 89.42 (4)° with the least-squares planes formed by the four C atoms of the morpholine ring, which adopts a chair conformation, the benzene ring and the xanthene ring system, respectively. In the crystal, C-H⋯O hydrogen-bond contacts connect neighbouring mol-ecules into infinite zigzag chains running parallel to the b axis.

(E)-4-{[(Morpholin-4-yl)imino]-meth-yl}benzo-nitrile.

In the title compound, C12H13N3O, the morpholine ring adopts a chair conformation and its mean plane is inclined to that of the benzene ring by 16.78 (12)°. The N-N=C-C bridge, which has an E conformation, has a torsion angle of 173.80 (19)°. In the crystal, mol-ecules stack along the a axis but there are no significant inter-molecular inter-actions present.

1-[3-(Morpholin-4-yl)prop-yl]-4-(3-nitro-phen-yl)spiro-[azetidine-3,9'-xanthen]-2-one.

The ß-lactam (azetidin-2-one) ring of the title compound, C28H27N3O5, is nearly planar [maximum deviation = 0.010 (1) Å] and makes dihedral angles of 75.77 (5), 52.78 (9) and 88.72 (5)°, respectively, with the benzene ring, the least-squares plane formed by the four C atoms of the morpholine ring, which adopts a chair conformation, and the xanthene ring system. In the crystal, C-H⋯O hydrogen-bond contacts connect neighbouring mol-ecules into infinite zigzag chains running parallel to the b axis.