Novel 2-alkythio-4-chloro-N-[imino(heteroaryl)methyl]benzenesulfonamide Derivatives: Synthesis, Molecular Structure, Anticancer Activity and Metabolic Stability.

A series of novel 2-alkythio-4-chloro-N-[imino-(heteroaryl)methyl]benzenesulfonamide derivatives, 8-24, were synthesized in the reaction of the N-(benzenesulfonyl)cyanamide potassium salts 1-7 with the appropriate mercaptoheterocycles. All the synthesized compounds were evaluated for their anticancer activity in HeLa, HCT-116 and MCF-7 cell lines. The most promising compounds, 11-13, molecular hybrids containing benzenesulfonamide and imidazole moieties, selectively showed a high cytotoxic effect in HeLa cancer cells (IC50: 6-7 µM) and exhibited about three times less cytotoxicity against the non-tumor cell line HaCaT cells (IC50: 18-20 µM). It was found that the anti-proliferative effects of 11, 12 and 13 were associated with their ability to induce apoptosis in HeLa cells. The compounds increased the early apoptotic population of cells, elevated the percentage of cells in the sub-G1 phase of the cell cycle and induced apoptosis through caspase activation in HeLa cells. For the most active compounds, susceptibility to undergo first-phase oxidation reactions in human liver microsomes was assessed. The results of the in vitro metabolic stability experiments indicated values of the factor t½ for 11-13 in the range of 9.1-20.3 min and suggested the hypothetical oxidation of these compounds to sulfenic and subsequently sulfinic acids as metabolites.

New 2-[(4-Amino-6-N-substituted-1,3,5-triazin-2-yl)methylthio]-N-(imidazolidin-2-ylidene)-4-chloro-5-methylbenzenesulfonamide Derivatives, Design, Synthesis and Anticancer Evaluation.

In the search for new compounds with antitumor activity, new potential anticancer agents were designed as molecular hybrids containing the structures of a triazine ring and a sulfonamide fragment. Applying the synthesis in solution, a base of new sulfonamide derivatives 20-162 was obtained by the reaction of the corresponding esters 11-19 with appropriate biguanide hydrochlorides. The structures of the compounds were confirmed by spectroscopy (IR, NMR), mass spectrometry (HRMS or MALDI-TOF/TOF), elemental analysis (C,H,N) and X-ray crystallography. The cytotoxic activity of the obtained compounds toward three tumor cell lines, HCT-116, MCF-7 and HeLa, was examined. The results showed that some of the most active compounds belonged to the R1 = 4-trifluoromethylbenzyl and R1 = 3,5-bis(trifluoromethyl)benzyl series and exhibited IC50 values ranging from 3.6 µM to 11.0 µM. The SAR relationships were described, indicating the key role of the R2 = 4-phenylpiperazin-1-yl substituent for the cytotoxic activity against the HCT-116 and MCF-7 lines. The studies regarding the mechanism of action of the active compounds included the assessment of the inhibition of MDM2-p53 interactions, cell cycle analysis and apoptosis induction examination. The results indicated that the studied compounds did not inhibit MDM2-p53 interactions but induced G0/G1 and G2/M cell cycle arrest in a p53-independent manner. Furthermore, the active compounds induced apoptosis in cells harboring wild-type and mutant p53. The compound design was conducted step by step and assisted by QSAR models that correlated the activity of the compounds against the HCT-116 cell line with molecular descriptors.

Modeling of Anticancer Sulfonamide Derivatives Lipophilicity by Chemometric and Quantitative Structure-Retention Relationships Approaches.

Sulfonamides are a classic group of chemotherapeutic drugs with a broad spectrum of pharmacological action, including anticancer activity. In this work, reversed-phase high-performance liquid chromatography and biomimetic chromatography were applied to characterize the lipophilicity of sulfonamide derivatives with proven anticancer activities against human colon cancer. Chromatographically determined lipophilicity parameters were compared with obtained logP, employing various computational approaches. Similarities and dissimilarities between experimental and computational logP were studied using principal component analysis, cluster analysis, and the sum of ranking differences. Furthermore, quantitative structure-retention relationship modeling was applied to understand the influences of sulfonamide's molecular properties on lipophilicity and affinity to phospholipids.

A multicentre retrospective observational study on Polish experience of pirfenidone therapy in patients with idiopathic pulmonary fibrosis: the PolExPIR study.

BACKGROUND: Pirfenidone is an antifibrotic agent approved for the treatment of idiopathic pulmonary fibrosis (IPF). The drug is available for Polish patients with IPF since 2017. The PolExPIR study aimed to describe the real-world data (RWD) on the Polish experience of pirfenidone therapy in IPF with respect to safety and efficacy profiles. METHODS: This was a multicentre, retrospective, observational study collecting clinical data of patients with IPF receiving pirfenidone from January 2017 to September 2019 across 10 specialized pulmonary centres in Poland. Data collection included baseline characteristics, pulmonary function tests (PFTs) results and six-minute walk test (6MWT). Longitudinal data on PFTs, 6MWT, adverse drug reactions (ADRs), treatment persistence, and survival were also collected up to 24 months post-inclusion. RESULTS: A total of 307 patients receiving pirfenidone were identified for analysis. The mean age was 68.83 (8.13) years and 77% were males. The median time from the first symptoms to IPF diagnosis was 15.5 (9.75-30) months and from diagnosis to start of pirfenidone treatment was 6 (2-23) months. Patients were followed on treatment for a median of 17 (12-22.75) months. Seventy-four patients (24.1%) required dose adjustments and 35 (11.4%) were chronically treated with different than the full recommended dose. A total of 141 patients (45.92%) discontinued therapy due to different reasons including ADRs (16.61%), death (8.79%), disease progression (6.51%), patient's own request (5.54%), neoplastic disease (3.91%) and lung transplantation (0.33%). Over up to 24 months of follow-up, the pulmonary function remained largely stable. The median annual decline in forced vital capacity (FVC) during the first year of pirfenidone therapy was -20 ml (-200-100) and during the second year was -120 ml (-340-30). Over a study period, 33 patients (10.75%) died. CONCLUSIONS: The PolExPIR study is a source of longitudinal RWD on pirfenidone therapy in the Polish cohort of patients with IPF supporting its long-term acceptable safety and efficacy profiles and reinforce findings from the previous randomised clinical trials and observational studies.

Synthesis, Antitumor Evaluation, Molecular Modeling and Quantitative Structure-Activity Relationship (QSAR) of Novel 2-[(4-Amino-6-N-substituted-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-N-(1H-benzo[d]imidazol-2(3H)-ylidene)Benzenesulfonamides.

A series of novel 2-[(4-amino-6-R2-1,3,5-triazin-2-yl)methylthio]-4-chloro-5-methyl-N-(5-R1-1H-benzo[d]imidazol-2(3H)-ylidene)benzenesulfonamides 6-49 was synthesized by the reaction of 5-substituted ethyl 2-{5-R1-2-[N-(5-chloro-1H-benzo[d]imidazol-2(3H)-ylidene)sulfamoyl]-4-methylphenylthio}acetate with appropriate biguanide hydrochlorides. The most active compounds, 22 and 46, showed significant cytotoxic activity and selectivity against colon (HCT-116), breast (MCF-7) and cervical cancer (HeLa) cell lines (IC50: 7-11 µM; 15-24 µM and 11-18 µM), respectively. Further QSAR (Quantitative Structure-Activity Relationships) studies on the cytotoxic activity of investigated compounds toward HCT-116, MCF-7 and HeLa were performed by using different topological (2D) and conformational (3D) molecular descriptors based on the stepwise multiple linear regression technique (MLR). The QSAR studies allowed us to make three statistically significant and predictive models for them. Moreover, the molecular docking studies were carried out to evaluate the possible binding mode of the most active compounds, 22 and 46, within the active site of the MDM2 protein.

N-(2-Arylmethylthio-4-Chloro-5-Methylbenzenesulfonyl)amide Derivatives as Potential Antimicrobial Agents-Synthesis and Biological Studies.

Rising resistance of pathogenic bacteria reduces the options of treating hospital and non-hospital bacterial infections. There is a need to search for newer chemotherapies that will show antimicrobial ability against planktonic cells as well as bacterial biofilms. We have synthesized a series of N-(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl)amides, namely, molecular hybrids, which include a 2-mercaptobenzenosulfonamide fragment and either cinnamic or cyclohexylpropionic acid residues. The antimicrobial activity of compounds 8‒17 was evaluated on Gram-positive, Gram-negative bacteria and fungal species. Experiments took into account investigation of antibacterial activity against planktonic cells as well as biofilms. Compounds 8‒17 showed high bacteriostatic activity against staphylococci, with the most active molecules 10 and 16 presenting low MIC values of 4-8 µg/mL against reference methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive S. aureus (MSSA) strains as well as clinical isolates. Compounds 10 and 16 also showed an ability to inhibit biofilms formed by MRSA and MSSA. The potential of 10 and 16 as antibiofilm agents was supported by cytotoxicity assays that indicated no cytotoxic effect either on normal cells of human keratinocytes or on human cancer cells, including cervical, colon, and breast cancer lines.

Target-based drug discovery through inversion of quantitative structure-drug-property relationships and molecular simulation: CA IX-sulphonamide complexes.

In this work, a target-based drug screening method is proposed exploiting the synergy effect of ligand-based and structure-based computer-assisted drug design. The new method provides great flexibility in drug design and drug candidates with considerably lower risk in an efficient manner. As a model system, 45 sulphonamides (33 training, 12 testing ligands) in complex with carbonic anhydrase IX were used for development of quantitative structure-activity-lipophilicity (property)-relationships (QSPRs). For each ligand, nearly 5,000 molecular descriptors were calculated, while lipophilicity (logkw) and inhibitory activity (logKi) were used as drug properties. Genetic algorithm-partial least squares (GA-PLS) provided a QSPR model with high prediction capability employing only seven molecular descriptors. As a proof-of-concept, optimal drug structure was obtained by inverting the model with respect to reference drug properties. 3509 ligands were ranked accordingly. Top 10 ligands were further validated through molecular docking. Large-scale MD simulations were performed to test the stability of structures of selected ligands obtained through docking complemented with biophysical experiments.

Synthesis, Molecular Structure, Anticancer Activity, and QSAR Study of N-(aryl/heteroaryl)-4-(1H-pyrrol-1-yl)Benzenesulfonamide Derivatives.

A series of N-(aryl/heteroaryl)-4-(1H-pyrrol-1-yl)benzenesulfonamides were synthesized from 4-amino-N-(aryl/heteroaryl)benzenesulfonamides and 2,5-dimethoxytetrahydrofuran. All the synthesized compounds were evaluated for their anticancer activity on HeLa, HCT-116, and MCF-7 human tumor cell lines. Compound 28, bearing 8-quinolinyl moiety, exhibited the most potent anticancer activity against the HCT-116, MCF-7, and HeLa cell lines, with IC50 values of 3, 5, and 7 µM, respectively. The apoptotic potential of the most active compound (28) was analyzed through various assays: phosphatidylserine translocation, cell cycle distribution, and caspase activation. Compound 28 promoted cell cycle arrest in G2/M phase in cancer cells, induced caspase activity, and increased the population of apoptotic cells. Relationships between structure and biological activity were determined by the QSAR (quantitative structure activity relationships) method. Analysis of quantitative structure activity relationships allowed us to generate OPLS (Orthogonal Projections to Latent Structure) models with verified predictive ability that point out key molecular descriptors influencing benzenosulfonamide's activity.

Novel 5-Substituted 2-(Aylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl)benzenesulfonamides: Synthesis, Molecular Structure, Anticancer Activity, Apoptosis-Inducing Activity and Metabolic Stability.

A series of novel 5-substituted 2-(arylmethylthio)-4-chloro-N-(5-aryl-1,2,4-triazin-3-yl) benzenesulfonamide derivatives 27-60 have been synthesized by the reaction of aminoguanidines with an appropriate phenylglyoxal hydrate in glacial acetic acid. A majority of the compounds showed cytotoxic activity toward the human cancer cell lines HCT-116, HeLa and MCF-7, with IC50 values below 100 µM. It was found that for the analogues 36-38 the naphthyl moiety contributed significantly to the anticancer activity. Cytometric analysis of translocation of phosphatidylserine as well as mitochondrial membrane potential and cell cycle revealed that the most active compounds 37 (HCT-116 and HeLa) and 46 (MCF-7) inhibited the proliferation of cells by increasing the number of apoptotic cells. Apoptotic-like, dose dependent changes in morphology of cell lines were also noticed after treatment with 37 and 46. Moreover, triazines 37 and 46 induced caspase activity in the HCT-116, HeLa and MCF-7 cell lines. Selected compounds were tested for metabolic stability in the presence of pooled human liver microsomes and NADPH, both R² and Ar = 4-CF3-C6H4 moiety in 2-(R²-methylthio)-N-(5-aryl-1,2,4-triazin-3-yl)benzenesulfonamides simultaneously increased metabolic stability. The results pointed to 37 as a hit compound with a good cytotoxicity against HCT-116 (IC50 = 36 µM), HeLa (IC50 = 34 µM) cell lines, apoptosis-inducing activity and moderate metabolic stability.

Synthesis of Novel Pyrido[4,3-e][1,2,4]triazino[3,2-c][1,2,4]thiadiazine 6,6-dioxide Derivatives with Potential Anticancer Activity.

A series of novel 3-/2,3-substituted pyrido[4,3-e][1,2,4]triazino[3,2-c][1,2,4]thiadiazine 6,6-dioxides 4-28 have been synthesized by the reaction of 3-amino-2-(4-thioxo-1,4-dihydropyridin-3-yl-sulfonyl)guanidine with either 2-oxoalkanoic acids and its esters, or phenylglyoxylic hydrates in glacial acetic acid. Some of them exhibited reasonable or moderate anticancer activity toward human cancer cell lines, HCT-116, MCF-7 and HeLa. The structure of this novel heterocyclic ring system was confirmed by ¹D-NMR and ²D-NMR spectroscopic data including COSY, ROESY and HMBC, elemental analyses and MS spectrometry.

Synthesis and QSAR study of novel 6-chloro-3-(2-Arylmethylene-1-methylhydrazino)-1,4,2-benzodithiazine 1,1-dioxide derivatives with anticancer activity.

A series of new 6-chloro-3-(2-arylmethylene-1-methylhydrazino)-1,4,2-benzodithiazine 1,1-dioxide derivatives were effectively synthesized from N-methyl-N-(6-chloro-1,1-dioxo-1,4,2-benzodithiazin-3-yl)hydrazines. The intermediate compounds as well as the products, were evaluated for their cytotoxic effects toward three human cancer cell lines. All compounds shown moderate or weak cytotoxic effects against the tested cancer cell lines, but selective cytotoxic effects were observed. Compound 16 exhibited the most potent cytotoxic activity against the HeLa cell line, with an IC50 value of 10 µM, while 14 was the most active against the MCF-7 and HCT-116 cell lines, affording IC50 values of 15 µM and 16 µM, respectively. The structure-activity relationship was evaluated based on QSAR methodology. The QSAR MCF-7 model indicated that natural charge on carbon atom C13 and energy of highest occupied molecular orbital (HOMO) are highly involved in cytotoxic activity against MCF-7 cell line. The cytotoxic activity of compounds against HCT-116 cell line is dependent on natural charge on carbon atom C13 and electrostatic charge on nitrogen atom N10. The obtained QSAR models could provide guidelines for further development of novel anticancer agents.

Synthesis, Molecular Structure, Metabolic Stability and QSAR Studies of a Novel Series of Anticancer N-Acylbenzenesulfonamides.

A series of novel N-acyl-4-chloro-5-methyl-2-(R¹-methylthio)benzenesulfonamides 18-47 have been synthesized by the reaction of N-[4-chloro-5-methyl-2-(R¹-methylthio) benzenesulfonyl]cyanamide potassium salts with appropriate carboxylic acids. Some of them showed anticancer activity toward the human cancer cell lines MCF-7, HCT-116 and HeLa, with the growth percentages (GPs) in the range from 7% to 46%. Quantitative structure-activity relationship (QSAR) studies on the cytotoxic activity of N-acylsulfonamides toward MCF-7, HCT-116 and HeLa were performed by using topological, ring and charge descriptors based on the stepwise multiple linear regression technique (MLR). The QSAR studies revealed three predictive and statistically significant models for the investigated compounds. The results obtained with these models indicated that the anticancer activity of N-acylsulfonamides depends on topological distances, number of ring system, maximum positive charge and number of atom-centered fragments. The metabolic stability of the selected compounds had been evaluated on pooled human liver microsomes and NADPH, both R¹ and R² substituents of the N-acylsulfonamides simultaneously affected them.

N-Substituted N'-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)guanidines--Antibacterial, Cytotoxic Activities and Some Structure-Activity Relationships.

A series of N-substituted N'-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)guanidine derivatives bearing sulfonamide moiety have been screened in vitro for antibacterial activity against isolates from patients with infections of oral cavity, respiratory tract and intestinal tract. The majority of compounds exhibited good antibacterial potency. 1-[4-Chloro-5-methyl-2-(4-trifluoromethylbenzylthio)benzenesulfonyl]-3-(3-sulfamoylphenyl)guanidine (13) showed very strong activity, with MIC ≤ 6.2 µg/ml against eleven bacteria strains belonged to Gram-positive anaerobes and aerobes. Furthermore, compound 13 exhibited promising activity toward highly resistant microorganisms such as methicillin-resistant Staphylococcus aureus and Enterococcusfaecalis. It was found that Parvimonas micra, Finegoldia magna, Peptostreptococcus anaerobius, Propionibacterium acnes showed the highest susceptibility toward the investigated guanidines.

Synthesis and anti-yeast evaluation of novel 2-alkylthio-4-chloro-5-methyl-N-[imino-(1-oxo-(1H)-phthalazin-2-yl)methyl]benzenesulfonamide derivatives.

Pathogenic fungi are one of the main causes of hospital-related infections. Since conventional antifungals have become less effective because of the increasing fungal resistance to the standard drugs, the need for new agents is becoming urgent. Herein we report a synthesis of a series of novel N-[imino-(1-oxo-(1H)-phthalazin-2-yl)methyl]-benzenesulfonamide derivatives with in vitro activity against yeast-like fungi isolated from the oral cavity and respiratory tract of patients with candidiasis. These compounds were synthesized by the one-step or two-step reactions of 1-(2-alkylthiobenzensulfonyl)-2-aminoguanidines with the appropriate ortho-carbonyl benzoic acids. The biological study revealed that new derivatives have shown significant growth-inhibitory activity, superior or comparable, than those of the reference drug fluconazole. The most promising activities were observed against Candida albicans, with inhibition at least 1-3 (12.5%-37.5%) of the eight tested strains at the low MIC level of ≤6.2-25 µg/mL.

Modification of gradient HPLC method for determination of small molecules' affinity to human serum albumin under column safety conditions: Robustness and chemometrics study.

In the early stages of drug discovery, beyond the biological activity screening, determining the physicochemical properties that affect the distribution of molecules in the human body is an essential step. Plasma protein binding (PPB) is one of the most important investigated endpoints. Nevertheless, the methodology for measuring %PPB is significantly less popular and standardized than other physicochemical properties, like lipophilicity. Here, we proposed how to modify protocols presented by Valko into column safety conditions and evaluated their robustness using fractional factorial design. For robustness testing, four factors were selected: column temperature, mobile phase flow rate, maximum isopropanol concentration in the mobile phase, and buffer pH. Elaborate methods have been applied for the analysis of HSA affinity for three groups of antibiotic-oriented substances that vary in chemical structure: fluoroquinolones, sulfonamides, and tetrazole derivatives. Furthermore, based on the reversed-phase chromatography the workflow of pilot studies was proposed to select molecules that have high affinity to HSA and can not be eluted from the HSA column using the concentration of organic modifier recommended by the column manufacturer.

Synthesis and antibacterial activity of novel 4-chloro-2-mercaptobenzenesulfonamide derivatives.

Few series of novel 4-chloro-2-mercaptobenzenesulfonamides have been synthesized by the reactions of N-(benzenesulfonyl)cyanamide potassium salts 7-15 with corresponding hydrazinecarbodithioic acid esters, 1-substituted carbothioic acid hydrazides, methyl 3-aminothiophene-2-carboxylate, methyl 2-aminobenzoate, 2-aminophenol or 2-aminothiophenol. The synthesized compounds (16-49) were screened in vitro for their antibacterial activity. Some of the tested compounds 16, 17, 23, 24, 31, 32 and 48 showed the promising activity against many of anaerobic Gram-positive bacteria strains.

A Real-World Multicenter Retrospective Observational Study on Polish Experience with Nintedanib Therapy in Patients with Idiopathic Pulmonary Fibrosis: The PolExNIB Study.

Nintedanib is a disease-modifying agent licensed for the treatment of IPF. Data on Polish experience with nintedanib in IPF are lacking. The present study aimed to describe the safety and efficacy profiles of nintedanib in a large real-world cohort of Polish patients with IPF. This was a multicenter, retrospective, observational study of IPF patients treated with nintedanib between March 2018 and October 2021. Data collection included baseline clinical characteristics, results of pulmonary function tests (PFTs), and a six-minute walk test (6MWT). Longitudinal data on PFTs, 6MWT, adverse drug reactions (ADRs), and treatment persistence were also retrieved. A total of 501 patients (70% male) with a median age of 70.9 years (IQR 65-75.7) were included in this study. Patients were followed on treatment for a median of 15 months (7-25.5). The majority of patients (66.7%) were treated with the full recommended dose of nintedanib and 33.3% of patients were treated with a reduced dose of a drug. Intermittent dose reductions or drug interruptions were needed in 20% of patients. Over up to 3 years of follow-up, pulmonary function remained largely stable with the minority experiencing disease progression. The most frequent ADRs included diarrhea (45.3%), decreased appetite (29.9%), abdominal discomfort (29.5%), weight loss (32.1%), nausea (20.8%), fatigue (19.2%), increased liver aminotransferases (15.4%), and vomiting (8.2%). A total of 203 patients (40.5%) discontinued nintedanib treatment due to diverse reasons including ADRs (10.2%), death (11.6%), disease progression (4.6%), patient's request (6.6%), and neoplastic disease (2.2%). This real-world study of a large cohort of Polish patients with IPF demonstrates that nintedanib therapy is safe, and is associated with acceptable tolerance and disease stabilization. These data support the findings of previously conducted clinical trials and observational studies on the safety and efficacy profiles of nintedanib in IPF.

Therapeutic decisions in a cohort of patients with idiopathic pulmonary fibrosis: a multicenter, prospective survey from Poland.

Background: Pirfenidone and nintedanib are considered as the standard of care in idiopathic pulmonary fibrosis (IPF), but there is no consensus as to which of these two agents should be regarded as first-line treatment. Objective: To provide real-world data on therapeutic decisions of pulmonary specialists, particularly the choice of the antifibrotic drug in patients with IPF. Methods: This was a multicenter, prospective survey collecting clinical data of patients with IPF considered as candidates for antifibrotic treatment between September 2019 and December 2020. Clinical characteristics and information on the therapeutic approach were retrieved. Statistical evaluation included multiple logistic regression analysis with stepwise model selection. Results: Data on 188 patients [74.5% male, median age 73 (interquartile range, 68-78) years] considered for antifibrotic therapy were collected. Treatment was initiated in 138 patients, while 50 patients did not receive an antifibrotic, mainly due to the lack of consent for treatment and IPF severity. Seventy-two patients received pirfenidone and 66 received nintedanib. Dosing protocol (p < 0.01) and patient preference (p = 0.049) were more frequently associated with the choice of nintedanib, while comorbidity profile (p = 0.0003) and concomitant medication use (p = 0.03) were more frequently associated with the choice of pirfenidone. Age (p = 0.002), lung transfer factor for carbon monoxide (TLCO) (p = 0.001), and gastrointestinal bleeding (p = 0.03) were significantly associated with the qualification for the antifibrotic treatment. Conclusion: This real-world prospective study showed that dose protocol and patient preference were more frequently associated with the choice of nintedanib, while the comorbidity profile and concomitant medication use were more frequently associated with the choice of pirfenidone. Age, TLCO, and history of gastrointestinal bleeding were significant factors influencing the decision to initiate antifibrotic therapy.

Simultaneous activation of muscarinic and GABAB receptors as a bidirectional target for novel antipsychotics.

Recent preclinical studies point to muscarinic and GABAB receptors as novel therapeutic targets for the treatment of schizophrenia. This study was aimed to assess the role of muscarinic and GABAB receptor interactions in animal models of schizophrenia, using positive allosteric modulators (PAMs) of GABAB receptor (GS39783), muscarinic M4 (VU0152100) and M5 (VU0238429) receptor, and partial allosteric agonist of M1 receptor (VU0357017). DOI-induced head twitches, social interaction and novel object recognition tests were used as the models of schizophrenia. Analyses of DOI-induced increases in sEPSCs (spontaneous excitatory postsynaptic currents) were performed as complementary experiments to the DOI-induced head twitch studies. Haloperidol-induced catalepsy and the rotarod test were used to examine the adverse effects of the drugs. All three activators of muscarinic receptors were active in DOI-induced head twitches. When administered together with GS39783 in subeffective doses, only the co-administration of VU0152100 and GS39783 was effective. The combination also reduced the frequency but not the amplitude of DOI-induced sEPSCs. Neither VU0357017 nor VU0238429 were active in social interaction test when given alone, and also the combination of VU0152100 and GS39783 failed to reverse MK-801-induced deficits observed in this test. All muscarinic activators when administered alone or in combination with GS39783 reversed the MK-801-induced disruption of memory in the novel object recognition test, and their actions were blocked by specific antagonists. None of the tested compounds or their combinations influenced the motor coordination of the animals. The compounds had no effect on haloperidol-induced catalepsy and did not induce catalepsy when administered alone. Pharmacokinetic analysis confirmed lack of possible drug-drug interactions after combined administration of GS39783 with VU0357017 or VU0152100; however, when the drug was co-administered with VU0238429 its ability to pass the blood-brain barrier slightly decreased, suggesting potential drug-drug interactions. Our data show that modulation of cholinergic and GABAergic systems can potentially be beneficial in the treatment of the positive and cognitive symptoms of schizophrenia without inducing the adverse effects typical for presently used antipsychotics.

Cysteine cathepsins as a prospective target for anticancer therapies-current progress and prospects.

Cysteine cathepsins (CTS), being involved in both physiological and pathological processes, play an important role in the human body. During the last 30 years, it has been shown that CTS are highly upregulated in a wide variety of cancer types although they have received a little attention as a potential therapeutic target as compared to serine or metalloproteinases. Studies on the increasing problem of neoplastic progression have revealed that secretion of cell-surface- and intracellular cysteine proteases is aberrant in tumor cells and has an impact on their growth, invasion, and metastasis by taking part in tumor angiogenesis, in apoptosis, and in events of inflammatory and immune responses. Considering the role of CTS in carcinogenesis, inhibition of these enzymes becomes an attractive strategy for cancer therapy. The downregulation of natural CTS inhibitors (CTSsis), such as cystatins, observed in various types of cancer, supports this claim. The intention of this review is to highlight the relationship of CTS with cancer and to present illustrations that explain how some of their inhibitors affect processes related to neoplastic progression.