Quinazolinones, the Winning Horse in Drug Discovery.

Quinazolines are nitrogen-containing heterocycles that consist of a benzene ring fused with a pyrimidine ring. Quinazolinones, oxidized quinazolines, are promising compounds with a wide range of biological activities. In the pharmaceutical field, quinazolinones are the building blocks of more than 150 naturally occurring alkaloids isolated from different plants, microorganisms, and animals. Scientists give a continuous interest in this moiety due to their stability and relatively easy methods for preparation. Their lipophilicity is another reason for this interest as it helps quinazolinones in penetration through the blood-brain barrier which makes them suitable for targeting different central nervous system diseases. Various modifications to the substitutions around the quinazolinone system changed their biological activity significantly due to changes in their physicochemical properties. Structure-activity relationship (SAR) studies of quinazolinone revealed that positions 2, 6, and 8 of the ring systems are significant for different pharmacological activities. In addition, it has been suggested that the addition of different heterocyclic moieties at position 3 could increase activity. In this review, we will highlight the chemical properties of quinazolinones, including their chemical reactions and different methods for their preparation. Moreover, we will try to modify some of the old SAR studies according to their updated biological activities in the last twelve years.

Quinazolin-4(3H)-one based potential multiple tyrosine kinase inhibitors with excellent cytotoxicity.

A series of quinazolin-4(3H)-one derivatives were synthesised and evaluated for their cytotoxicity against human Caucasian breast adenocarcinoma (MCF-7) and human ovarian carcinoma (A2780) cell lines. Cytotoxicity of the most tested compounds was 2- to 30-fold more than the positive control lapatinib (IC50 of 2j = 3.79 ± 0.96; 3j = 0.20 ± 0.02; and lapatinib = 5.9 ± 0.74) against MCF7 cell lines except two compounds (IC50 of 2 b = 15.72 ± 0.07 and 2e = 14.88 ± 0.99). On the other hand, cytotoxicity was 4 - 87 folds (IC50 of 3a = 3.00 ± 1.20; 3 g = 0.14 ± 0.03) more the positive control lapatinib (IC50 = 12.11 ± 1.03) against A2780 cell lines except compound 2e (IC50 = 16.43 ± 1.80). Among the synthesised quinazolin-4(3H)-one derivatives, potent cytotoxic 2f-j and 3f-j were investigated for molecular mechanism of action. Inhibitory activities of the compounds were tested against multiple tyrosine protein kinases (CDK2, HER2, EGFR and VEGFR2) enzymes. As expected, all the quinazolin-4(3H)-one derivatives were showed comparable inhibitory activity against those kinases tested, especially, compound 2i and 3i showed potent inhibitory activity against CDK2, HER2, EGFR tyrosine kinases. Therefore, molecular docking analysis for quinazolin-4(3H)-one derivatives 2i and 3i were performed, and it was revealed that compounds 2i and 3i act as ATP non-competitive type-II inhibitor against CDK2 kinase enzymes and ATP competitive type-I inhibitor against EGFR kinase enzymes. However, in case of HER2, compounds 2i act as ATP non-competitive type-II inhibitor and 3i act as ATP competitive type-I inhibitor. Docking results of known inhibitors were compared with synthesised compounds and found synthesised 2i and 3i are superior than the known inhibitors in case of interactions. In addition, in silico drug likeness properties of quinazolin-4(3H)-one derivatives showed better predicted ADME values than lapatinib.

Antioxidant and hepatorenal protective effects of bee pollen fractions against propionic acid-induced autistic feature in rats.

In the brain, propionic acid (PA) can cross cell membranes and accumulate within cells, leading to intracellular acidification, which may alter neurotransmitter release (NT), communication between neurons, and behavior. Such elevation in levels of PA constitutes a neurodevelopmental metabolic disorder called propionic acidemia, which could clinically manifest as autism. The purpose of this study was to investigate the protective effects of different fractions of bee pollen (BP) on PA-induced autism in rats, and to evaluate their effects on the expression of liver and renal biomarkers. Groups of rats received treatments of different fractions of BP at a dose of 250 mg/kg of body weight/day for a period of 1 month. Normal control group I and group II were orally administered with phosphate-buffered saline and propionic acid, respectively, for 3 days. BP contains various health-promoting phenolic components. Different fractions of BP administered pre- and post-treatment with PA showed significant reduction in the levels of liver and renal biomarkers (p < .05). Also, a significant enhancement in the levels of glutathione S-transferase (GST), catalase CAT), and ascorbic acid (VIT C) was observed. Supplementation with BP significantly reduced biochemical changes in the liver, kidneys, and brain of rats with PA-induced toxicity. It exhibited protective effects against oxidative damage and reactive oxygen species produced by PA-induced adverse reactions in rats. Taken together, our study shows that BP possesses protective effects in PA-induced liver and kidney damage.

A Series of Isatin-Hydrazones with Cytotoxic Activity and CDK2 Kinase Inhibitory Activity: A Potential Type II ATP Competitive Inhibitor.

Isatin derivatives potentially act on various biological targets. In this article, a series of novel isatin-hydrazones were synthesized in excellent yields. Their cytotoxicity was tested against human breast adenocarcinoma (MCF7) and human ovary adenocarcinoma (A2780) cell lines using MTT assay. Compounds 4j (IC50 = 1.51 ± 0.09 µM) and 4k (IC50 = 3.56 ± 0.31) showed excellent activity against MCF7, whereas compound 4e showed considerable cytotoxicity against both tested cell lines, MCF7 (IC50 = 5.46 ± 0.71 µM) and A2780 (IC50 = 18.96± 2.52 µM), respectively. Structure-activity relationships (SARs) revealed that, halogen substituents at 2,6-position of the C-ring of isatin-hydrazones are the most potent derivatives. In-silico absorption, distribution, metabolism and excretion (ADME) results demonstrated recommended drug likeness properties. Compounds 4j (IC50 = 0.245 µM) and 4k (IC50 = 0.300 µM) exhibited good inhibitory activity against the cell cycle regulator CDK2 protein kinase compared to imatinib (IC50 = 0.131 µM). A molecular docking study of 4j and 4k confirmed both compounds as type II ATP competitive inhibitors that made interactions with ATP binding pocket residues, as well as lacking interactions with active state DFG motif residues.

Glutamate excitotoxicity induced by orally administered propionic acid, a short chain fatty acid can be ameliorated by bee pollen.

BACKGROUND: Rodent models may guide investigations towards identifying either environmental neuro-toxicants or drugs with neuro-therapeutic effects. This work aims to study the therapeutic effects of bee pollen on brain glutamate excitotoxicity and the impaired glutamine-glutamate- gamma amino butyric acid (GABA) circuit induced by propionic acid (PPA), a short chain fatty acid, in rat pups. METHODS: Twenty-four young male Western Albino rats 3-4 weeks of age, and 45-60 g body weight were enrolled in the present study. They were grouped into four equal groups: Group 1, the control received phosphate buffered saline at the same time of PPA adminstration; Group 2, received 750 mg/kg body weight divided into 3 equal daily doses and served as acute neurotoxic dose of PPA; Group 3, received 750 mg/kg body weight divided in 10 equal doses of 75 mg/kg body weight/day, and served as the sub-acute group; and Group 4, the therapeutic group, was treated with bee pollen (50 mg/kg body weight) for 30 days after acute PPA intoxication. GABA, glutamate and glutamine were measured in the brain homogenates of the four groups. RESULTS: The results showed that PPA caused multiple signs of excitotoxicity, as measured by the elevation of glutamate and the glutamate/glutamine ratio and the decrease of GABA, glutamine and the GABA/glutamate ratio. Bee pollen was effective in counteracting the neurotoxic effects of PPA to a certain extent. CONCLUSION: In conclusion, bee pollen demonstrates ameliorating effects on glutamate excitotoxicity and the impaired glutamine-glutamate-GABA circuit as two etiological mechanisms in PPA-induced neurotoxicity.

Therapeutic potency of bee pollen against biochemical autistic features induced through acute and sub-acute neurotoxicity of orally administered propionic acid.

BACKGROUND: It is now well documented that postnatal exposure to certain chemicals has been reported to increase the risk of autism spectrum disorder. Propionic acid (PA), as a metabolic product of gut microbiotaandas a commonly used food additive, has been reported to mediate the effects of autism. Results from animal studies may help to identify environmental neurotoxic agents and drugs that can ameliorate neurotoxicity and may thereby aid in the treatment of autism. The present study investigated the ameliorative effects of natural bee pollen against acute and sub-acute brain intoxication induced by (PA) in rats. METHODS: Twenty-four young male Western Albino ratswere enrolled in the present study. They were classified into four equal groups, eachwith6 rats. The control group received only phosphate buffered saline; the oral buffered PA-treated groups (II and III) received a neurotoxic dose of 750 mg/kg body weight divided in 3 dose of 250 mg/kg body weight/day serving asthe acute group and 750 mg/kg body weight divided in 10 equal dose of 75 mg/kg body weight/day as the sub-acute group. The fourth group received 50 mg bee pollen for 30 days after PA-acute intoxication. RESULTS: The obtained data showed that the PA-treated groups demonstrated multiple signs of brain toxicity, as indicated by a depletion of serotonin (5HT), dopamine and nor-adrenaline, together withan increase in IFN-γ and caspase 3. Bee pollen was effective in ameliorating the neurotoxic effect of PA. All measured parameters demonstrated minimal alteration in comparison with thecontrol animal than did those of acute and sub-acute PA-treated animals. CONCLUSIONS: In conclusion, bee pollen demonstrates anti-inflammatory and anti-apoptotic effects while ameliorating the impaired neurochemistry of PA-intoxicated rats.

Synthesis, anticonvulsant activity and molecular modeling study of some new hydrazinecarbothioamide, benzenesulfonohydrazide, and phenacylacetohydrazide analogues of 4(3H)-quinazolinone.

A new series of quinazoline analogues was designed and synthesized to get the target compounds 18-21, 30-41, 46-53, and 57-76. The Obtained compounds were evaluated for their anticonvulsant activity using PTZ and picrotoxin convulsive models. Compounds 47, 63, 68 and 73 proved to be the most active compounds in this study with a remarkable 100% protection against PTZ induced convulsions. Compounds 47, 63, 68 and 73 proved to be 10, 4, 4, and 5 fold more active, respectively than the used positive control sodium valproate. Structure activity correlation concluded valuable pharmacophoric information which confirmed by molecular modeling studies. Molecular docking study of 68 suggested its agonistic behavior toward GABAA receptor. The studied quinazoline analogues could be considered as useful templates for future development and further derivatization.

Synthesis, in vitro and in vivo evaluation of a delivery system for targeting anticancer drugs to the brain.

A 1, 4-dihydropyridine <--> pyridinium salt type redox system is described as a general and flexible method for site-specific and sustained delivery of drugs to the brain. This concept was used in the present investigation as a model to deliver an alkylating antitumor agent into the brain. A bis-(chloroethyl)amine drug was hooked to 1, 4-dihydropyridine chemical delivery system (CDS) through an amide linkage. Five new-target compounds (23-27) of the 1, 4-dihydropyridine CDS type were synthesized through the reduction of five new pyridinium quaternary intermediates (18-22). The synthesized 1, 4-dihydropyridines were subjected to various chemical and biological investigations to evaluate their ability to cross the blood-brain barrier (BBB), and to be oxidized biologically into their corresponding quaternary compounds. The in vitro oxidation studies showed that 1-benzyl-3-[N-[2-bis(2-chloroethyl)aminoethyl]-carbamoyl]-1, 4-dihydropyridine (23) and 1-(4-nitrobenzyl)-3-[N-[2-bis(2-chloroethyl)aminoethyl ]carbamoyl]-1, 4-dihydropyridine (27) could be oxidized into their corresponding quaternary compounds 18 and 22 respectively, at an adequate rate, which ensure the release of the carried anticancer drug. The in vivo studies showed that compound 23 was able to cross the BBB at detectable concentrations. On the other hand, the in vitro alkylation activity studies revealed that 1-(4-nitrobenzyl)-3-[N-[2-bis(2-chloroethyl)aminoethyl]carbamoyl]pyridinium bromide (22) is an alkylating agent with activity comparable to the known drug chlorambucil.