A literature review on pharmacological aspects, docking studies, and synthetic approaches of quinazoline and quinazolinone derivatives.

Quinazoline and quinazolinone derivatives piqued medicinal chemistry interest in developing novel drug candidates owing to their pharmacological potential. They are important chemicals for the synthesis of a variety of physiologically significant and pharmacologically useful molecules. Quinazoline and quinazolinone derivatives have anticancer, anti-inflammatory, antidiabetic, anticonvulsant, antiviral, and antimicrobial potential. The increased understanding of quinazoline and quinazolinone derivatives in biological activities provides opportunities for new medicinal products. The present review focuses on novel advances in the synthesis of these important scaffolds and other medicinal aspects involving drug design, structure-activity relationship, and action mechanisms of quinazoline and quinazolinone derivatives to help in the development of new quinazoline and quinazolinone derivatives.

Design and construction of novel pyridine-pyrimidine hybrids as selective COX-2 suppressors: anti-inflammatory potential, ulcerogenic profile, molecular modeling and ADME/Tox studies.

NSAIDs represent a mainstay in pain and inflammation suppression, and their actions are mainly based on inhibiting COX-1 and COX-2 enzymes.Due to the adverse effects of these drugs, especially on the stomach and heart, scientists efforts have been directed to manufacture selective COX-2 without cardiovascular side effects and with minimal effects on the stomach. The cardiovascular side effects are thought to be related to the chemical composition rather than mechanism of action of these drugs.Novel pyridopyrimidines, 9a-j, were prepared and their chemical structures were confirmed by NMR, mass and IR Spectra, and elemental analysis. The effect of the 9a-j compounds on COX-1 and COX-2 was assessed and it was found that 2-hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-d)pyrimidin-4-one (9d) was the most potent COX-2 inhibitor (IC50 = 0.54 uM) compared to celecoxib (IC50 = 1.11 uM) with selectivity indices of 6.56 and 5.12, respectively.The in vivo inhibition of paw edema of novel compounds 9a-j was measured using carrageenan-induced paw edema method, and that 2-hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-d)pyrimidin-4-one (9d) showed the best inhibitory activity in comparison with the other compounds and celecoxib.The gastroprotective effect of the potent derivatives 9d, 9e, 9f, 9 g and 9h was investigated. 2-Hydrazino-5-(4-methoxyphenyl)-7-phenyl-3H-pyrido[2,3-d)pyrimidin-4-one (9d) and 7-(chlorophenyl)-hydrazino-5-(4-methoxyphenyl)-3H-pyrido[2,3-d)pyrimidin-4-one (9e) showed ulcer indices comparable to celecoxib (1 and 0.5 vs 0.5, respectively). Docking studies were carried out and they confirmed the mechanistic action of the designed compoundsCommunicated by Ramaswamy H. Sarma.

Tunable Polymeric Mixed Micellar Nanoassemblies of Lutrol F127/Gelucire 44/14 for Oral Delivery of Praziquantel: A Promising Nanovector against Hymenolepis nana in Experimentally-Infected Rats.

Hymenolepiasis represents a parasitic infection of common prevalence in pediatrics with intimidating impacts, particularly amongst immunocompromised patients. The present work aimed to snowball the curative outcomes of the current mainstay of hymenolepiasis chemotherapy, praziquantel (PRZ), through assembly of polymeric mixed micelles (PMMs). Such innovative nano-cargo could consolidate PRZ hydrosolubility, extend its circulation time and eventually upraise its bioavailability, thus accomplishing a nanoparadigm for hymenolepiasis tackling at lower dose levels. For consummating this goal, PRZ-PMMs were tailored via thin-film hydration technique integrating a binary system of Lutrol F127 and Gelucire 44/14. Box-Behnken design was planned for optimizing the nanoformulation variables employing Design-Expert® software. Also, in Hymenolepis nana-infected rats, the pharmacodynamics of the optimal micellar formulation versus the analogous crude PRZ suspension were scrutinized on the 1st and 3rd days after administration of a single oral dose (12.5 or 25 mg/kg). Moreover, in vitro ovicidal activity of the monitored formulations was estimated utilizing Fuchsin vital stain. Furthermore, the in vivo pharmacokinetics were assessed in rats. The optimum PRZ-PMMs disclosed conciliation between thermodynamic and kinetic stability, high entrapment efficiency (86.29%), spherical nanosized morphology (15.18 nm), and controlled-release characteristics over 24 h (78.22%). 1H NMR studies verified PRZ assimilation within the micellar core. Additionally, the in vivo results highlighted a significant boosted efficacy of PRZ-PMMs manifested by fecal eggs output and worm burden reduction, which was clearly evident at the lesser PRZ dose, besides a reversed effect for the intestinal histological disruptions. At 50 µg/mL, PRZ-PMMs increased the percent of non-viable eggs to 100% versus 47% for crude PRZ, whilst shell destruction and loss of embryo were only clear with the applied nano-cargo. Moreover, superior bioavailability by 3.43-fold with elongated residence time was measured for PRZ-PMMs compared to PRZ suspension. Practically, our results unravel the potential of PRZ-PMMs as an oral promising tolerable lower dose nanoplatform for more competent PRZ mass chemotherapy.

Bilosomes as a promising nanoplatform for oral delivery of an alkaloid nutraceutical: improved pharmacokinetic profile and snowballed hypoglycemic effect in diabetic rats.

Diabetes mellitus is a life-threatening metabolic disease. At the moment, there is no effective treatment available to combat it. In this study, we aimed to develop berberine-loaded bilosomes (BER-BLS) to boost the oral bioavailability and therapeutic efficacy of berberine, a natural antidiabetic medication. The BER-BLS was fabricated using a thin-film hydration strategy and optimized using a central composite design (face-centered). The average vesicle size, entrapment efficiency, and surface charge of the optimized BER-BLS preparation were 196.5 nm, 89.7%, (-) 36.4 mV, respectively. In addition, it exhibited higher stability and better-sustained release of berberine than the berberine solution (BER-SOL). BER-BLS and BER-SOL were administered to streptozocin-induced diabetic rats. The optimized BER-BLS formulation had a significant hypoglycemic impact, with a maximum blood glucose decrease of 41%, whereas BER-SOL only reduced blood glucose by 19%. Furthermore, the pharmacological effect of oral BER-BLS and BER-SOL corresponded to 99.3% and 31.7%, respectively, when compared to subcutaneous insulin (1 IU). A pharmacokinetic analysis found a 6.4-fold rise in the relative bioavailability of berberine in BER-BLS when compared to BER-SOL at a dosage of 100 mg/kg body weight. Histopathological investigation revealed that BER-BLS is suitable for oral administration. Our data demonstrate that BLS is a potential nanocarrier for berberine administration, enhancing its oral bioavailability and antidiabetic activity.

Facile Conversion of the Quinone-Semicarbazone Chromophore of Naftazone into a Fluorescent Quinol-Semicarbazide: Kinetic Study and Analysis of Naftazone in Pharmaceuticals and Human Serum.

Naftazone is a quinone-semi carbazone drug that possesses a strong orange color, and hence it was usually analyzed colorimetrically or by HPLC-UV. However, these methods are not sensitive enough to determine naftazone in biological samples. Naftazone lacks intrinsic fluorescence and does not possess easily derivatizable functional groups. In this contribution, we introduced the first spectrofluorimetric method for naftazone assay through reduction-elicited fluorogenic derivatization through the reduction of its quinone-semicarbazone moiety to the corresponding quinol-semicarbazide derivative by potassium borohydride as a reduction probe. The solvent-dependent fluorescence of the reaction product was studied in various protic and aprotic solvents. Eventually, the fluorescence of the reduced naftazone was measured in 2-propanol at λemission of 350 nm after excitation at λecxitation of 295 nm. The relative fluorescence intensity was linearly correlated to the drug concentration (r = 0.9995) from 10.0 to 500 ng/mL with high sensitivity, where the lower detection limit was 2.9 ng/mL. Hence, the method was effectively applied for naftazone tablets quality control with a mean %recovery of 100.3 ± 1.5, and the results agreed with those of the comparison HPLC-UV method. Furthermore, a new salting-out assisted liquid-liquid extraction (SALLE) method was established for naftazone extraction from human serum, followed by its determination using the developed reduction-based fluorogenic method. The developed SALLE method showed excellent recovery for naftazone from human serum (92.3-106.5%) with good precision (RSD ≤ 6.8%). Additionally, the reaction of naftazone with potassium borohydride was kinetically monitored, and it was found to follow pseudo-first-order kinetics with an activation energy of 43.8 kcal/mol. The developed method's greenness was approved using three green analytical chemistry metrics.

Intranasal Delivery of Granisetron to the Brain via Nanostructured Cubosomes-Based In Situ Gel for Improved Management of Chemotherapy-Induced Emesis.

This research aimed to boost granisetron (GS) delivery to the brain via the intranasal route to better manage chemotherapy-induced emesis. Glycerol monooleate (GMO), Poloxamer 407 (P 407) and Tween 80 (T 80) were used to formulate GS-loaded cubosomes (GS-CBS) utilizing a melt dispersion-emulsification technique. GS-CBS were characterized by testing particle diameter, surface charge and entrapment efficiency. The formulations were optimized using a Box-Behnken statistical design, and the optimum formula (including GMO with a concentration of 4.9%, P 407 with a concentration of 10%, and T 80 with a concentration of 1%) was investigated for morphology, release behavior, ex vivo permeation through the nasal mucosa, and physical stability. Moreover, the optimal formula was incorporated into a thermosensitive gel and subjected to histopathological and in vivo biodistribution experiments. It demonstrated sustained release characteristics, increased ex vivo permeability and improved physical stability. Moreover, the cubosomal in situ gel was safe and biocompatible when applied to the nasal mucosa. Furthermore, compared to a drug solution, the nose-to-brain pathway enhanced bioavailability and brain distribution. Finally, the cubosomal in situ gel may be a potential nanocarrier for GS delivery to the brain through nose-to-brain pathway.

Innovative pulmonary targeting of terbutaline sulfate-laded novasomes for non-invasive tackling of asthma: statistical optimization and comparative in vitro/in vivo evaluation.

Asthma represents a globally serious non-communicable ailment with significant public health outcomes for both pediatrics and adults triggering vast morbidity and fatality in critical cases. The ß2-adrenoceptor agonist, terbutaline sulfate (TBN), is harnessed as a bronchodilator for monitoring asthma noising symptoms. Nevertheless, the hepatic first-pass metabolism correlated with TBN oral administration mitigates its clinical performance. Likewise, the regimens of inhaled TBN dosage forms restrict its exploitation. Consequently, this work is concerned with the assimilation of TBN into a novel non-phospholipid nanovesicular paradigm termed novasomes (NVS) for direct and effective TBN pulmonary targeting. TBN-NVS were tailored based on the thin film hydration method and Box-Behnken design was applied to statistically optimize the formulation variables. Also, the aerodynamic pattern of the optimal TBN-NVS was explored via cascade impaction. Moreover, comparative pharmacokinetic studies were conducted using a rat model. TBN elicited encapsulation efficiency as high as 70%. The optimized TBN-NVS formulation disclosed an average nano-size of 223.89 nm, ζ potential of -31.17 mV and a sustained drug release up to 24 h. Additionally, it manifested snowballed in vitro lung deposition behavior in cascade impactor with a fine particle fraction of 86.44%. In vivo histopathological studies verified safety of intratracheally-administered TBN-NVS. The pharmacokinetic studies divulged 3.88-fold accentuation in TBN bioavailability from the optimum TBN-NVS versus the oral TBN solution. Concisely, the results proposed that NVS are an auspicious nanovector for TBN pulmonary delivery with integral curbing of the disease owing to target specificity.

Lipid Nanocarriers Overlaid with Chitosan for Brain Delivery of Berberine via the Nasal Route.

This research aimed to design, optimize, and evaluate berberine-laden nanostructured lipid carriers overlaid with chitosan (BER-CTS-NLCs) for efficient brain delivery via the intranasal route. The nanostructured lipid carriers containing berberine (BER-NLCs) were formulated via hot homogenization and ultrasonication strategy and optimized for the influence of a variety of causal variables, including the amount of glycerol monostearate (solid lipid), poloxamer 407 (surfactant) concentration, and oleic acid (liquid lipid) amount, on size of the particles, entrapment, and the total drug release after 24 h. The optimal BER-NLCs formulation was then coated with chitosan. Their diameter, in vitro release, surface charge, morphology, ex vivo permeability, pH, histological, and in vivo (pharmacokinetics and brain uptake) parameters were estimated. BER-CTS-NLCs had a size of 180.9 ± 4.3 nm, sustained-release properties, positive surface charge of 36.8 mV, and augmented ex-vivo permeation via nasal mucosa. The histopathological assessment revealed that the BER-CTS-NLCs system is safe for nasal delivery. Pharmacokinetic and brain accumulation experiments showed that animals treated intranasally with BER-CTS-NLCs had substantially greater drug levels in the brain. The ratios of BER brain/blood levels at 30 min, AUCbrain/AUCblood, drug transport percentage, and drug targeting efficiency for BER-CTS-NLCs (IN) were higher compared to BER solution (IN), suggesting enhanced brain targeting. The optimized nanoparticulate system is speculated to be a successful approach for boosting the effect of BER in treating CNS diseases, such as Alzheimer's disease, through intranasal therapy.

Surface-Modified Bilosomes Nanogel Bearing a Natural Plant Alkaloid for Safe Management of Rheumatoid Arthritis Inflammation.

Rheumatoid arthritis (RA) is a chronic inflammatory illness affecting the joints. The characteristic of RA is gradual joint deterioration. Current RA treatment alleviates signs such as inflammation and pain and substantially slows the progression of the disease. In this study, we aimed to boost the transdermal delivery of berberine (a natural product) by encapsulating it in chitosan, surface-modified bilosomes nanogel for better management of the inflammation of RA. The chitosan-coated bilosomes loaded with berberine (BER-CTS-BLS) were formulated according to the thin-film hydration approach and optimized for various causal variables, considering the effect of lipid, sodium deoxycholate, and chitosan concentrations on the size of the particles, entrapment, and the surface charge. The optimized BER-CTS-BLS has 202.3 nm mean diameter, 83.8% entrapment, and 30.8 mV surface charge. The optimized BER-CTS-BLS exhibited a delayed-release profile in vitro and increased skin permeability ex vivo. Additionally, histological examination revealed that the formulated BLS had no irritating effects on the skin. Furthermore, the optimized BER-CTS-BLS ability to reduce inflammation was evaluated in rats with carrageenan-induced paw edema. Our results demonstrate that the group treated with topical BER-CTS-BLS gel exhibited a dramatic reduction in rat paw edema swelling percentage to reach 24.4% after 12 h, which was substantially lower than other groups. Collectively, chitosan-coated bilosomes containing berberine have emerged as a promising therapeutic approach to control RA inflammation.

Utilization of Polymeric Micelles as a Lucrative Platform for Efficient Brain Deposition of Olanzapine as an Antischizophrenic Drug via Intranasal Delivery.

Schizophrenia is a mental disorder characterized by alterations in cognition, behavior and emotions. Oral olanzapine (OZ) administration is extensively metabolized (~up to 40% of the administrated dose). In addition, OZ is a P-glycoproteins substrate that impairs the blood-brain barrier (BBB) permeability. To direct OZ to the brain and to minimize its systemic side effects, the nasal pathway is recommended. OZ-loaded polymeric micelles nano-carriers were developed using suitable biodegradable excipients. The developed micelles were physicochemically investigated to assess their appropriateness for intranasal delivery and the potential of these carriers for OZ brain targeting. The selected formula will be examined in vivo for improving the anti-schizophrenic effects on a schizophrenia rat model. The binary mixture of P123/P407 has a low CMC (0.001326% w/v), which helps in maintaining the formed micelles' stability upon dilution. The combination effect of P123, P407 and TPGS led to a decrease in micelle size, ranging between 37.5-47.55 nm and an increase in the EE% (ranging between 68.22-86.84%). The selected OZ-PM shows great stability expressed by a suitable negative charge zeta potential value (-15.11 ± 1.35 mV) and scattered non-aggregated spherical particles with a particle size range of 30-40 nm. OZ-PM maintains sustained drug release at the application site with no nasal cytotoxicity. In vivo administration of the selected OZ-PM formula reveals improved CNS targeting and anti-schizophrenia-related deficits after OZ nasal administration. Therefore, OZ-PM provided safe direct nose-to-brain transport of OZ after nasal administration with an efficient anti-schizophrenic effect.

A carvedilol analogue, VK-II-86, prevents hypokalaemia-induced ventricular arrhythmia through novel multi-channel effects.

BACKGROUND AND PURPOSE: QT prolongation and intracellular Ca2+ loading with diastolic Ca2+ release via ryanodine receptors (RyR2) are the predominant mechanisms underlying hypokalaemia-induced ventricular arrhythmia. We investigated the antiarrhythmic actions of two RyR2 inhibitors: dantrolene and VK-II-86, a carvedilol analogue lacking antagonist activity at ß-adrenoceptors, in hypokalaemia. EXPERIMENTAL APPROACH: Surface ECG and ventricular action potentials (APs) were recorded from whole-heart murine Langendorff preparations. Ventricular arrhythmia incidence was compared in hearts perfused with low [K+ ], and those pretreated with dantrolene or VK-II-86. Whole-cell patch clamping was used in murine and canine ventricular cardiomyocytes to study effects of dantrolene and VK-II-86 on AP parameters in low [K+ ] and effects of VK-II-86 on the inward rectifier current (IK1 ), late sodium current (INa_L ) and the L-type Ca2+ current (ICa ). Effects of VK-II-86 on IKr were investigated in transfected HEK-293 cells. A fluorogenic probe quantified the effects of VK-II-86 on oxidative stress in hypokalaemia. KEY RESULTS: Dantrolene reduced the incidence of ventricular arrhythmias induced by low [K+ ] in explanted murine hearts by 94%, whereas VK-II-86 prevented all arrhythmias. VK-II-86 prevented hypokalaemia-induced AP prolongation and depolarization but did not alter AP parameters in normokalaemia. Hypokalaemia was associated with decreased IK1 and IKr , and increased INa-L , and ICa . VK-II-86 prevented all hypokalaemia-induced changes in ion channel activity and oxidative stress. CONCLUSIONS AND IMPLICATIONS: VK-II-86 prevents hypokalaemia-induced arrhythmogenesis by normalizing calcium homeostasis and repolarization reserve. VK-II-86 may provide an effective treatment in hypokalaemia and other arrhythmias caused by delayed repolarization or Ca2+ overload.

Novel Chitosan-Coated Niosomal Formulation for Improved Management of Bacterial Conjunctivitis: A Highly Permeable and Efficient Ocular Nanocarrier for Azithromycin.

In the present study, we aimed to formulate, optimize, and characterize azithromycin chitosan coated niosomes (AZM-CTS-NSM) as a novel colloidal system that increases precorneal residence period, eye permeation, and bioavailability. AZM-NSM was formulated via a modified thin-film hydration strategy and then coated with CTS. We assessed the influence of the cholesterol: surfactant molar ratio, CTS concentration, and surfactant type on particle diameter, entrapment, zeta potential, and NSM adhesion force to the corneal mucosal membrane and employed a central composite design (CCD). The resulting optimized AZM-CTS-NSM has a mean diameter of 376 nm, entrapment of 74.2%, surface charge of 32.1 mV, and mucoadhesion force of 3114 dyne/cm2. The optimized AZM-CTS-NSM demonstrated a prolonged in vitro release behavior. When compared with commercial eye drops, the optimized AZM-CTS-NSM produced a 2.61-fold increase in the apparent permeability coefficient, significantly improving corneal permeability. Additionally, ocular irritation was assessed, with no major irritant effects found to be induced by the formulated NSM. Compared with AZM commercial drops, the optimized AZM-CTS-NSM revealed ˃ 3-fold increase in AZM concentration in the rabbit eyes. Collectively, these findings indicate that CTS-NSM is a potentially valuable ocular nanocarrier that could augment the efficacy of AZM.

Inhibition of aggregation of amyloid-ß through covalent modification with benzylpenicillin; potential relevance to Alzheimer's disease.

The pathogenesis of Alzheimer's disease (AD) is correlated with the misfolding and aggregation of amyloid-beta protein (Aß). Here we report that the antibiotic benzylpenicillin (BP) can specifically bind to Aß, modulate the process of aggregation and supress its cytotoxic effect, initially via a reversible binding interaction, followed by covalent bonding between specific functional groups (nucleophiles) within the Aß peptide and the beta-lactam ring. Mass spectrometry and computational docking supported covalent modification of Aß by BP. BP was found to inhibit aggregation of Aß as revealed by the Thioflavin T (ThT) fluorescence assay and atomic force microscopy (AFM). In addition, BP treatment was found to have a cytoprotective activity against Aß-induced cell cytotoxicity as shown by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) cell toxicity assay. The specific interaction of BP with Aß suggests the possibility of structure-based drug design, leading to the identification of new drug candidates against AD. Moreover, good pharmacokinetics of beta-lactam antibiotics and safety on long-time use make them valuable candidates for drug repurposing towards neurological disorders such as AD.

Plant-Derived Natural Products in Cancer Research: Extraction, Mechanism of Action, and Drug Formulation.

Cancer is one of the main causes of death globally and considered as a major challenge for the public health system. The high toxicity and the lack of selectivity of conventional anticancer therapies make the search for alternative treatments a priority. In this review, we describe the main plant-derived natural products used as anticancer agents. Natural sources, extraction methods, anticancer mechanisms, clinical studies, and pharmaceutical formulation are discussed in this review. Studies covered by this review should provide a solid foundation for researchers and physicians to enhance basic and clinical research on developing alternative anticancer therapies.

Resveratrol-mediated cleavage of amyloid ß1-42 peptide: potential relevance to Alzheimer's disease.

Aggregation of amyloid ß1-42 (Aß1-42) peptide within the brain is considered one of the main causes of the neuropathological changes associated with Alzheimer's disease. Resveratrol is a well-known antioxidant but has also been reported to bind to Aß1-42 peptide, thereby reducing aggregation. However, little is known of the precise mechanism by which resveratrol reduces Aß1-42 peptide aggregation. Using the thioflavin-T assay, the ability of resveratrol to reduce the extent of Aß1-42 peptide aggregation was investigated. The findings of the present study demonstrate that interaction of resveratrol with Aß1-42 peptide resulted in the cleavage of Aß1-42 peptide into smaller fragments, as detected by matrix assisted laser desorption ionization-time of flight mass spectrometry. Atomic force microscopy analyses revealed Aß1-42 peptide, under control conditions, aggregated into oligomers, protofibrils, and fibrils, whereas there was a distinct lack of these structures when Aß1-42 peptide was incubated with resveratrol. Following 10 days incubation of Aß1-42 peptide with resveratrol, particles with a mean z-height of 1.940 nm (range 0.675-3.275 nm) were observed, which are characteristic of shorter peptide species. In cell-based studies, resveratrol significantly reduced the cytotoxicity of Aß1-42 peptide toward SH-SY5Y human neuroblastoma cells, suggesting a protective effect of the polyphenol. We therefore propose a novel mechanism by which resveratrol disrupts Aß1-42 aggregation by mediating fragmentation of Aß1-42 into smaller peptides, which have no propensity to aggregate further.

Evaluation of analogues of furan-amidines as inhibitors of NQO2.

Inhibitors of the enzyme NQO2 (NRH: quinone oxidoreductase 2) are of potential use in cancer chemotherapy and malaria. We have previously reported that non-symmetrical furan amidines are potent inhibitors of NQO2 and here novel analogues are evaluated. The furan ring has been changed to other heterocycles (imidazole, N-methylimidazole, oxazole, thiophene) and the amidine group has been replaced with imidate, reversed amidine, N-arylamide and amidoxime to probe NQO2 activity, improve solubility and decrease basicity of the lead furan amidine. All compounds were fully characterised spectroscopically and the structure of the unexpected product N-hydroxy-4-(5-methyl-4-phenylfuran-2-yl)benzamidine was established by X-ray crystallography. The analogues were evaluated for inhibition of NQO2, which showed lower activity than the lead furan amidine. The observed structure-activity relationship for the furan-amidine series with NQO2 was rationalized by preliminary molecular docking and binding mode analysis. In addition, the oxazole-amidine analogue inhibited the growth of Plasmodium falciparum with an IC50 value of 0.3 µM.

Targeting γ-aminobutyric acid (GABA) carriers to the brain: potential relevance as antiepileptic pro-drugs.

The search for antiepileptic compounds with more selective activity continues to be an area of intensive investigation in medicinal chemistry. 3,5-Disubstituted tetrahydro-2H-1,3,5-thiadiazine-2-thione (THTT) derivatives, 3a-g, potential prodrugs incorporating the neurotransmitter GABA were synthesized and studied for crossing the blood-brain barrier (BBB). Compounds were prepared from primary amines and carbon disulfide to give dithiocarbamates 2a-g which upon reaction in situ with formaldehyde provided the intermediates Ia-g. Addition of Ia-g onto GABA furnished the title compounds 3a-g. The structures were verified by spectral data and the amounts of the compounds in the brain were investigated by using HPLC. The concentration profiles of the tested compounds in mice brain were determined and the in vivo anticonvulsant activity was measured.