Design and synthesis of new quinazolinone derivatives: investigation of antimicrobial and biofilm inhibition effects.

New quinazolin-4-ones 9-32 were synthesized in an attempt to overcome the life-threatening antibiotic resistance phenomenon. The antimicrobial screening revealed that compounds 9, 15, 16, 18, 19, 20 and 29 are the most broad spectrum antimicrobial agents in this study with safe profile on human cell lines. Additionally, compounds 19 and 20 inhibited biofilm formation in Pseudomonas aeruginosa, which is regulated by quorum sensing system, at sub-minimum inhibitory concentrations (sub-MICs) with IC50 values 3.55 and 6.86 µM, respectively. By assessing other pseudomonal virulence factors suppression, it was found that compound 20 decreased cell surface hydrophobicity compromising bacterial cells adhesion, while both compounds 19 and 20 curtailed the exopolysaccharide production which constitutes the major component of the matrix binding biofilm components together. Also, at sub-MICs Pseudomonas cells twitching motility was impeded by compounds 19 and 20, a trait which augments the cells pathogenicity and invasion potential. Molecular docking study was performed to further evaluate the binding mode of candidates 19 and 20 as inhibitors of P. aeruginosa quorum sensing transcriptional regulator PqsR. The achieved results demonstrate that both compounds bear promising potential for discovering new anti-biofilm and quorum quenching agents against Pseudomonas aeruginosa without triggering resistance mechanisms as the normal bacterial life cycle is not disturbed.

Synthetic non-toxic anti-biofilm agents as a strategy in combating bacterial resistance.

The tremendous increase in the bacterial resistance to the available antibiotics is a serious problem for the treatment of various infections. Biofilm formation in bacteria significantly contributes to the bacterial survival in host cells, and is considered as an crucial factor, responsible for bacterial resistance. The response of the bacterial cells in the biofilm to antibiotics is completely different from that of the free floating planktonic cells of the same strain. The anti-biofilm agents that could inhibit the biofilm production without affecting the bacterial growth, apply less selective pressure over the bacterial strains than the traditional antibiotics; thus the development of bacterial resistance would be of low incidence. Many attempts have been performed to discover novel agents capable of interfering with the bacterial biofilm life cycle, and several compounds have shown promising activities in suppressing the biofilm production or in dispersing mature existing biofilms. This review describes the different chemical classes that have anti-biofilm effects against different Gram-positive and Gram-negative bacteria without affecting the bacterial growth.

Design and synthesis of novel parabanic acid derivatives as anticonvulsants.

In this work a set of novel derivatives of parabanic acid 9a-d, 12a-d and 13a-d was synthesized and their anticonvulsant potential was evaluated. All the compounds under investigation exhibited anticonvulsant activity in both scPTZ and MES tests. In phase II anticonvulsant study, the trimethoxy phenyl derivative 9a evoked the highest potency among the tested compounds in scPTZ test. It displayed 1.72- and 17.05-folds activity more than the standard drugs phenobarbital and ethosuximide, respectively. In addition, the margin of safety for compound 9a is better than that of the reference antiepileptic drug ethosuximide. Also, compound 9a was devoid of hepatotoxicity indicated by measurements of serum level of ALT, AST, ALP, albumin and total protein. Furthermore, treatment with compound 9a significantly increased the GABA brain level by 2.56-folds compared to the control value. Additionally, molecular docking was performed on the active site of GABA-AT to clarify the interactions of the most potent compound 9a with the enzyme. In MES test, compound 12a exhibited the most potent activity against electric stimuli-induced seizures with the lowest ED50 = 13.7 mg/kg and protective index >36.5. Both candidates 9a and 12a could be a good starting point to develop new molecules as novel antiepileptic drugs.

Design, synthesis and anticancer evaluation of novel 1,3-benzodioxoles and 1,4-benzodioxines.

A new set of 1,3-benzodioxoles and 1,4-benzodioxines was designed and synthesized starting from gallic acid as anticancer agents. The antiproliferative effect of the target compounds was evaluated against a panel of cancer cell lines (HepG2, PC-3, MCF-7 and A549) using MTT assay. The 1,4-benzodioxine derivative 11a manifested broad spectrum effect towards the four tested cancer cell lines (IC50 < 10 µM) with lower toxic effect on normal human cell line BJ1. Cell cycle progression of MCF-7 after treatment with compound 11a was studied where it induced cells accumulation at G2/M phase as well as increasing in the percentage of cells at pre-G1. Compound 11a is found to be a tubulin polymerization inhibitor with IC50 = 6.37 µM. Also, flow cytometeric analysis revealed that compound 11a could induce both early and late stage apoptosis in MCF-7 cell line. Moreover, the ability of this compound to stimulate apoptosis in the latter cell line was further confirmed by: increment of Bax/Bcl-2 ratio, increase the expression of tumor suppressor gene p53, boosting the levels of initiator and executioner caspases as well as raise in the amount of cytochrome C. In addition molecular docking study was accomplished on the colchicine binding site of tubulin (pdb: 1SA0) to illustrate the interactions of the most potent compound 11a to the receptor.

Synthesis, molecular modeling studies and anticonvulsant activity of certain (1-(benzyl (aryl) amino) cyclohexyl) methyl esters.

A series of (1-(benzyl (aryl) amino) cyclohexyl) methyl esters 7a-n were prepared and screened for their anticonvulsant profile. Screening of these esters 7a-n and their starting alcohols 6a and 6b revealed that compound 7k was the most potent one in the scPTZ screening test with an ED50 value of 0.0056mmol/kg being about 10- and 164-fold more potent than phenobarbital (ED50=0.056mmol/kg) and ethosuximide (ED50=0.92mmol/kg) as reference drugs, respectively. Meanwhile, in the MES test, compounds 7b and 7k at doses 0.0821mmol/kg and 0.0334mmol/kg, exerted 66% and 50% protection of the tested mice, respectively, compared with diphenylhydantoin, which exerted 100% protection at dose 0.16mmol/kg. In the neurotoxicity screen test, almost all esters 7a-n did not show any minimal motor impairment at the maximum administrated dose. The anticonvulsant effectiveness of esters 7a-n was higher than their corresponding alcohols 6a and 6b. Compounds 7b and 7k exhibited pronounced anticonvulsant activity devoid of neurotoxicity in minimal motor impairment test and hepatotoxicity in the serum enzyme activity assay. 3D pharmacophore model using Discovery Studio 2.5 programs showed high fit value. The obtained experimental results of sc-PTZ activity of compounds 7a-n was consistent with the molecular modeling study.

Synthesis and Anticonvulsant Activity of Substituted-1,3-diazaspiro[4.5]decan-4-ones.

A series of novel spiroimidazolidinone derivatives 6a-d and 8a-x were synthesized and biologically evaluated for their anticonvulsant activity in the maximal electroshock seizure (MES) assay and the subcutaneous pentylenetetrazole (scPTZ) screening test. Compound 8w was the most active derivative in the scPTZ screening test with an ED50 value by about 5- and 83.6-fold lower than those of phenobarbital and ethosuximide as reference drugs, respectively. Most of the tested compounds exhibited moderate to weak activity in the MES screen test, except for 8a which displayed 100% protection at 0.09 mmol/kg. Moreover, all the test compounds did not show any minimal motor impairment in the neurotoxicity test.