Design, synthesis and biological evaluation of novel quinazoline-2,4-diones conjugated with different amino acids as potential chitin synthase inhibitors.

A series of (2-(1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl) acetamido) acids) (6 a-m), (7) has been designed to inhibit the action of fungus chitin synthase enzyme (CHS). The synthesis of the designed compounds was carried out in four steps starting from the reaction between 1-methylquinazoline-2,4(1H,3H)-dione and ethyl chloroacetate to yield the ethyl acetate derivative. This ester was hydrolyzed to the corresponding carboxylic acid derivative that was then utilized to couple several amino acids getting the final designed compounds. The synthesized compounds were tested for their inhibition against CHS. Compound 7 showed the highest potency among others with minimum inhibitory concentration (IC50) of 0.166 mmol/L, while polyoxin B (the positive control) had IC50 of 0.17 mmol/L. The synthesized compounds were also evaluated for their in vitro antifungal activity using Aspergillus fumigates, Aspergillus flavus, Crytococcus neoformans and Candida albicans. Unfortunately, the 14 synthesized compounds showed lower in vitro activity compared to the used active controls. However, compound 6m and fluconazole have synergistic effect on Aspergillus flavus; Compounds 7 and fluconazole have synergistic effects on Aspergillus fumigates.

Design, Synthesis and Microbiological Evaluation of Novel Compounds as Potential Staphylococcus aureus Phenylalanine tRNA Synthetase Inhibitors.

AS THE RESISTANCE of Staphylococcus aureus to antibiotics represents a major threat to global health, anti-infectives with novel mechanisms must be developed. Novel compounds were generated as potential phenylalanine tRNA synthetase (PheRS) inhibitors based on the published homology model of S. aureus PheRS to aid the design process using Molecular Operating Environment (MOE) software. PheRS was selected as it is structurally unique enzyme among the aminoacyl-tRNA synthetases (aaRS), it is considerably different from human cytosolic and human mitochondrial aaRS and it is essential and conserved across bacterial species. The designed compounds were synthesized according to different clear schemes. The compounds were confirmed by 1H NMR, 13C NMR, HRMS and/or microanalysis, and they were microbiologically evaluated.

Exploring the binding sites of Staphylococcus aureus phenylalanine tRNA synthetase: A homology model approach.

Increased resistance of MRSA (multidrug resistance Staphylococcus aureus) to anti-infective drugs is a threat to global health necessitating the development of anti-infectives with novel mechanisms of action. Phenylalanine tRNA synthetase (PheRS) is a unique enzyme of the aminoacyl-tRNA synthetases (aaRSs), which are essential enzymes for protein biosynthesis. PheRS is an (αb)2 tetrameric enzyme composed of two alpha subunits (PheS) and two larger beta subunits (PheT). Our potential target in the drug development for the treatment of MRSA infections is the phenylalanine tRNA synthetase alpha subunit that contains the binding site for the natural substrate. There is no crystal structure available for S. aureus PheRS, therefore comparative structure modeling is required to establish a putative 3D structure for the required enzyme enabling development of new inhibitors with greater selectivity. The S. aureus PheRS alpha subunit homology model was constructed using Molecular Operating Environment (MOE) software. Staphylococcus haemolyticus PheRS was the main template while Thermus thermophilus PheRS was utilised to predict the enzyme binding with tRNAphe. The model has been evaluated and compared with the main template through Ramachandran plots, Verify 3D and Protein Statistical Analysis (ProSA). The query protein active site was predicted from its sequence using a conservation analysis tool. Docking suitable ligands using MOE into the constructed model were used to assess the predicted active sites. The docked ligands involved the PheRS natural substrate (phenylalanine), phenylalanyl-adenylate and several described S. aureus PheRS inhibitors.

Synthesis, Anticonvulsant Activity, and SAR Study of Novel 4-Quinazolinone Derivatives.

Series of N-(4-substitutedphenyl)-4-(1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-alkanamides (5a-j) and 4-chloro-N'-((1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-alkaloyl)benzohydrazides (6a-f) were designed based on the previously reported essential structural features for anticonvulsant activity. Several amino acids were incorporated within the synthesized quinazolin-4(3H)-ones to improve their bioavailability and the anticonvulsant activity. Synthesis of the target compounds was accomplished in four steps starting from the reaction between N-methyl isatoic anhydride and the appropriate amino acid. Then, the carboxylic acid group was utilized to synthesize the required final structures. The new quinazolinone derivatives were evaluated for their anticonvulsant activity according to the Anticonvulsant Drug Development (ADD) Program protocol. All the 16 new quinazolinones exhibited good anticonvulsant activity; especially 5f, 5b, and 5c showed superior anticonvulsant activities in comparison to the reference drug, with ED50 values of 28.90, 47.38, and 56.40 mg/kg, respectively.

Targeting methionyl tRNA synthetase: design, synthesis and antibacterial activity against Clostridium difficile of novel 3-biaryl-N-benzylpropan-1-amine derivatives.

The synthesis of a series of benzimidazole-N-benzylpropan-1-amines and adenine-N-benzylpropan-1-amines is described. Subsequent evaluation against two strains of the anaerobic bacterium Clostridium difficile was performed with three amine derivatives displaying MIC values of 16 µg/mL. Molecular docking studies of the described amines determined that the amines interact within two active site pockets of C. difficile methionyl tRNA synthetase with methoxy substituents in the benzyl ring and an adenine biaryl moiety resulting in optimal binding interactions.

Non-carboxylic analogues of arylpropionic acids: synthesis, anti-inflammatory activity and ulcerogenic potential.

Two series of 1,2,4-triazoles and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles derived from three selected arylpropionic acids namely, ibuprofen, flurbiprofen and naproxen, were synthesized and evaluated for anti-inflammatory activity and ulcerogenic potential. All the tested compounds exhibited anti-inflammatory activity comparable to that of hydrocortisone. Compared to ibuprofen, however, all the tested compounds displayed more potent anti-inflammatory activity. Compounds tested for ulcerogenicity showed no or minimal ulcerogenic effect compared to indomethacin.

Hydrazones of 2-aryl-quinoline-4-carboxylic acid hydrazides: synthesis and preliminary evaluation as antimicrobial agents.

A new series of 2-arylquinoline-4-carboxylic acid hydrazide-hydrazones was synthesized using an appropriate synthetic route. All the target compounds were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus as an example for Gram-positive bacteria, Escherichia coli as an example for Gram-negative bacteria, and Candida albicans as a representative of fungi. The minimum inhibitory concentration (MIC) was determined for test compounds as well as for reference standards. Among the compounds tested, compounds having nitro substituents at the arylidene moiety showed the most potent antifungal as well as antibacterial activities against E. coli. Compound 23 displayed an antifungal activity comparable to that of nystatin. However, none of the compounds demonstrated any antibacterial activity against S. aureus. Hydrophobicity of the target compounds correlated weakly with their antibacterial and antifungal activities. The most potent compounds namely, 7, 18, 19, 22, and 23 were assessed for hemolytic toxicity and found to be non-hemolytic up to a concentration of 100mug/mL. In addition, the most potent compound (23) was evaluated for in vitro cytotoxic activity against various cancer cell lines. This compound was found to display no cytotoxic activity but rather it induces the proliferation rate of Hep-G2 cells.