Hussein I. El-Subbagh

Synthesis, biological evaluation and molecular modeling study of 2-(1,3,4-thiadiazolyl-thio and 4-methyl-thiazolyl-thio)- quinazolin-4-ones as a new class of DHFR inhibitors

A new series of 2-(1,3,4-thiadiazolyl- or 4-methyl-thiazolyl)thio-6-substituted-quinazolin-4-one analogs was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 29, 34, and 39 proved to be the most active DHFR inhibitors with IC50 values range of 0.1-0.6 μM. Compounds 28, 31 and 33 showed remarkable broad-spectrum antimicrobial activity comparable to the known antibiotic Gentamicin. Compounds 26, 33, 39, 43, 44, 50, 55 and 63 showed broad spectrum antitumor activity with GI values range of 10.1-100%. Molecular modeling study concluded that recognition with key amino acid Glu30, Phe31 and Phe34 is essential for binding. ADMET properties prediction of the active compounds suggested that compounds 29 and 34 could be orally absorbed with diminished toxicity.

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, biological evaluation and molecular docking studies of thiazole-based pyrrolidinones and isoindolinediones as anticonvulsant agents

A series of new 1-(thiazol-2-yl)pyrrolidin-2-one 5a–m and 2-(thiazol-2-yl)isoindoline-1,3-dione 6a–n derivatives were synthesized and evaluated for anticonvulsant activity. The activity was established in three seizure models: PTZ, picrotoxin and MES. Selected compounds were elected for neurotoxicity by the rotarod test. The most active compound of the series was 1-(4-(naphthalen-2-yl)thiazol-2-yl)pyrrolidin-2-one (5g), showing a PTZ effect dose (ED50) value of 18.4xa0mg/kg in mice. The median toxic dose (TD50) was 170.2xa0mg/kg, which provided a protection index (PIxa0=xa0TD50/ED50) of 9.2. A computational study was also carried out, including prediction of pharmacokinetic properties and docking studies. The structural assignments of the newly synthesized compounds were elucidated on the basis of spectroscopic data and single-crystal X-ray crystallography.Graphical AbstractA series of new thiazole-based pyrrolidinones 5a–m and isoindolinediones 6a–l were synthesized and tested as anticonvulsant. The most active compound was 1-(4-(naphthalen-2-yl)thiazol-2-yl)pyrrolidin-2-one (5g), showing ED50 value 18.4xa0mg/kg.

Synthesis, biological evaluation and molecular modeling study of new (1,2,4-triazole or 1,3,4-thiadiazole)-methylthio-derivatives of quinazolin-4(3H)-one as DHFR inhibitors

A new series of 2-mercapto-quinazolin-4-one analogues was designed, synthesized and evaluated for their in vitro DHFR inhibition, antitumor and antimicrobial activity. Compound 17 proved to be the most active DHFR inhibitor with IC50 value of 0.01μM, eight fold more active than methotrexate (MTX). Compounds 16 and 24 showed antitumor activity against human Caco2 colon and MCF-7 breast tumor cell lines with IC50 values of 25.4 and 9.5μg/ml, respectively. Compounds 15, 20, 21 and 30 showed considerable activity against the Gram-positive bacteria Staphylococcus aureus while 24 and 30 proved active against Bacillus subtilis with a magnitude of potency comparable to the broad spectrum antibiotic Ciprofloxacin. Strong activity was observed for 13, 14, 19, 20 and 24 against Candida albicans and Aspergillus flavus. Compound 17 shared a similar molecular docking mode with MTX and made a critical hydrogen bond and arene-arene interactions via Ala9 and Phe34 amino acid residues, respectively.

Synthesis, biological evaluation and molecular modeling study of thiadiazolo[3,2-a][1,3]diazepine analogues of HIE-124 as a new class of short acting hypnotics.

A new series of 6,7-dihydro-[1,3,4]thiadiazolo[3,2-a][1,3]diazepine analogues were synthesized, and biological evaluated. Compound GS-62 (33) exhibited potent inxa0vivo short acting hypnotic activity with onset time, duration of sleep and therapeutic index of 6.4xa0±xa00.2, 94.8xa0±xa05.3xa0min, 6.62, respectively), in comparison to thiopental sodium (6). Compounds 33 did not show any sign of acute tolerance reported with the maintenance dose of 6. Meanwhile 33 potentiated the inxa0vivo hypnotic effect of 6 in an equimolar amounts (0.06xa0mmol) combination showing an onset and duration of 7.5xa0±xa01.3, 62.5xa0±xa05.9xa0min, respectively. This combination allowed the use of lower doses of both drugs to avoid the undesirable side effects. Docking studies revealed favorable interactions and binding to BDZ binding site of the GABAA receptor especially with Arg87, Arg149, and Thr151 amino acid residues.

Synthesis, biological evaluation and molecular modeling study of some new thiazolodiazepine analogs as CNS active agents

New derivatives of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diazepin-3-carboxylate (HIE-124, 3), were synthesized as continuation to our previous patented efforts. Compounds 15 and 20 showed marginal hypnotic potency compared to 3. Compounds 15 (0.78mmol/kg) and 20 (0.39mmol/kg) showed remarkable 100% protection against PTZ induced convulsions with two and four fold increase in activity than sodium valproate (1.38mmol/kg), respectively. Molecular modeling studies showed hydrogen bonding interaction between 15 and Thr56 residues at the binding site of GABAA. Superposition, flexible alignment and surface mapping of 15, 20 and diazepam supports their biological resemblance where ADMET study suggested that those compounds could be used as oral anticonvulsants.

Thiadiazolodiazepine analogues as a new class of neuromuscular blocking agents: Synthesis, biological evaluation and molecular modeling study.

The synthesis, biological evaluation and molecular modeling study of 6,7-dihydro-[1,3,4] thiadiazolo[3,2-a][1,3]diazepine analogues as new class of neuromuscular blocking agents are described. The new compounds act via competitive mechanism with ACh which could be reversed by the anticholinesterase - Physostigmine. Compounds GS-53 (30) and AAH1 (33) induced dose-dependent neuromuscular blockade with onset time of 3 and 10xa0min, ED50 0.15 and 0.36xa0mmol/kg i.p., respectively, in rats. Compound 30 proved to be as twice as potent as 33 with rapid onset and shorter duration (Pxa0<xa00.05). Docking profile of 30 and 33 closely resembles HIE-124 (3), in α7β2 nAChR receptor. Molecular modeling analysis indicated that hydrogen bonding to Thr120 and Thr124 beside hydrophobic interactions play effective role incorporating the active ligands to nAChR. The obtained model could be useful for further development of new skeletal muscle relaxants.

Synthesis, biological evaluation and molecular modeling study of some new methoxylated 2-benzylthio-quinazoline-4(3H)-ones as nonclassical antifolates.

A new series of 2,3,6-substituted-quinazolin-4-ones was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 28 and 61 proved to be active DHFR inhibitors with IC50 0.02 and 0.01μM, respectively. Molecular modeling studies concluded that recognition with the key amino acid Phe34 is essential for binding and hence DHFR inhibition. Compounds 34, 56 and 66 showed broad spectrum antimicrobial activity comparable to Gentamicin and Ciprofloxacin. Compounds 40 and 64 showed broad spectrum antitumor activity toward several tumor cell lines and proved to be 10 fold more active than 5-FU, with GI50 MG-MID values of 2.2 and 2.4μM, respectively.

Selective Analysis of Dopamine Receptor Antagonist LE300 and its N-Methyl Metabolite in Mouse Sera at the Trace Level by HPLC–Fluorescence Detection

A highly selective, sensitive, and reliable high-performance liquid chromatography (HPLC) method was developed and validated for the simultaneous determination of a novel type of dopamine receptor antagonist LE300 and its N-methyl metabolite in mouse sera. LE300, its N-methyl metabolite, and verapamil (an internal standard) were detected using excitation and emission wavelengths of 275 and 340xa0nm, respectively. HPLC analysis using a deproteinization procedure was performed by injecting an aliquot of the supernatant into the chromatographic system. Chromatographic separation was achieved on a reversed-phase Spherisorb Cyano (CN) column with a mobile phase consisting of acetonitrile:50xa0mM phosphate buffer pH 3.5 (70:30, v/v) pumped at a flow rate of 1.0 mLxa0min−1. Regression analyses showed excellent linearity (rxa0=xa00.999) for concentrations of LE300 ranging from 4 to 500xa0ngxa0mL−1 and for concentrations of its N-methyl metabolite of 6–600xa0ngxa0mL−1. The HPLC-FLD method had limits of detection of 1.6xa0ngxa0mL−1 for LE300 and 2.4 ngxa0mL−1 for its N-methyl metabolite in mouse sera. The precision results, expressed as the intraday and interday relative standard deviation (RSD) values, ranged from 0.65 to 2.85xa0% (repeatability) and from 0.37 to 2.62xa0% (intermediate precision) for LE300 and its N-methyl metabolite, respectively; these values are in line with ICH guidelines. The assay was successfully applied in a pharmacokinetic study. The mean values of Tmax and Cmax were 2xa0h and 25.03xa0±xa05.60xa0ngxa0mL−1 for LE300 and 3xa0h and 19.92xa0±xa02.88xa0ngxa0mL−1 for its N-methyl metabolite, respectively.

Thiazolo[4,5-d]pyridazine analogues as a new class of dihydrofolate reductase (DHFR) inhibitors: Synthesis, biological evaluation and molecular modeling study

A new series of 1,3-thiazoles and thiazolo[4,5-d]pyridazine both bearing the 2-thioureido function were designed, synthesized and evaluated for their invitro DHFR inhibition and antitumor activities. Compound 26 proved to be the most active DHFR inhibitor (IC50 of 0.06μM). Compound 4, 20 and 21 showed in vitro antitumor activity against a collection of cancer cell lines. Compound 26 proved lethal to HS 578T breast cancer cell line with IC50 value of 0.8μM, inducing cell cycle arrest and apoptosis. Molecular modeling studies concluded that recognition with key amino acids Phe 31 and Arg 22 is essential for DHFR binding. The obtained model could be useful for the development of new class of DHFR inhibitors.