A Series of Ferulic Acid Amides Reveals Unexpected Peroxiredoxin 1 Inhibitory Activity with in†vivo Antidiabetic and Hypolipidemic Effects.

Insulin resistance is a major pathophysiological feature in the development of type 2 diabetes (T2DM). Ferulic acid is known for attenuating the insulin resistance and reducing the blood glucose in T2DM rats. In this work, we designed and synthesized a library of new ferulic acid amides (FAA), which could be considered as ring opening derivatives of the antidiabetic PPARγ agonists Thiazolidinediones (TZDs). However, since these compounds displayed weak PPAR transactivation capacity, we employed a proteomics approach to unravel their molecular target(s) and identified the peroxiredoxin 1 (PRDX1) as a direct binding target of FAAs. Interestingly, PRDX1, a protein with antioxidant and chaperone activity, has been implied in the development of T2DM by inducing hepatic insulin resistance. SPR, mass spectrometry-based studies, docking experiments and in vitro inhibition assay confirmed that compounds VIe and VIf bound PRDX1 and induced a dose-dependent inhibition. Furthermore, VIe and VIf significantly improved hyperglycemia and hyperlipidemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats as confirmed by histopathological examinations. These results provide guidance for developing the current FAAs as new potential antidiabetic agents.

Synthesis and Antifungal Potential of Some Novel Benzimidazole-1,3,4-Oxadiazole Compounds.

Discovery of novel anticandidal agents with clarified mechanisms of action, could be a rationalist approach against diverse pathogenic fungal strains due to the rise of resistance to existing drugs. In support to this hypothesis, in this paper, a series of benzimidazole-oxadiazole compounds were synthesized and subjected to antifungal activity evaluation. In vitro activity assays indicated that some of the compounds exhibited moderate to potent antifungal activities against tested Candida species when compared positive control amphotericin B and ketoconazole. The most active compounds 4h and 4p were evaluated in terms of inhibitory activity upon ergosterol biosynthesis by an LC-MS-MS method and it was determined that they inhibited ergosterol synthesis concentration dependently. Docking studies examining interactions between most active compounds and lanosterol 14-α-demethylase also supported the in vitro results.

Corrigendum to "Toxic Effects of Trazodone on Male Reproductive System via Disrupting Hypothalamic-Pituitary-Testicular Axis and Inducing Testicular Oxidative Stress".

[This corrects the article DOI: 10.1155/2018/7196142.].

Evidence for cardiotoxicity associated with sertraline in rats.

Sertraline is an antidepressant that is frequently prescribed to treat depression, obsessive-compulsive disorder, panic disorder, and anxiety. This drug had a safe cardiotoxicity profile, until the reporting of cases of sertraline-associated cardiotoxicities in the early 2000s. Since then, there have been conflicting results on the cardiotoxicity of this drug. In the study reported here we aimed to identify the cardiotoxic effects of sertraline by evaluating serum cardiac biomarkers, such as serum aspartate aminotransferase (AST), creatinine phosphokinase-myoglobin band (CK-MB), lactate dehydrogenase (LDH), and cardiac troponin T (cTn-T) levels as well as electrocardiographic parameters, DNA damage in cardiomyocytes, and histological findings of heart tissue in rats that were administered oral doses of 5, 10, or 20 mg kg-1 of sertraline for 28 days. Additionally, to investigate the possible mechanisms underlying cardiotoxicity, glutathione and malondialdehyde levels in cardiac tissue were determined to evaluate oxidative stress. According to our results, AST, LDH, and cTn-T levels were significantly increased in the 10 and 20 mg kg-1 sertraline groups when compared to the control group. Heart rates were increased, PR intervals prolonged, a short QTc value was observed, and T-wave amplitudes were decreased significantly in the 20 mg kg-1 sertraline group when compared to the control group. Significant DNA damage was observed in the high-dose groups. Histopathological investigations also revealed some degenerative changes in the 10 and 20 mg kg-1 sertraline groups. Glutathione levels were significantly decreased in the 10 and 20 mg kg-1 sertraline groups when compared with the control group. In conclusion, our findings support the cardiotoxic potential of sertraline and also suggest that oxidative stress may play a role in the toxicity of sertraline.

Toxic Effects of Trazodone on Male Reproductive System via Disrupting Hypothalamic-Pituitary-Testicular Axis and Inducing Testicular Oxidative Stress.

Depression and anxiety are recognized as public health problems. Epidemiological studies have shown that depression and anxiety often occur during reproductive ages between 20 and 60 years of age in males. Trazodone is one of the most frequently prescribed drugs in the treatment of depression and anxiety. Drugs used in repeated doses also play a role in the etiology of infertility. In our study, it was aimed to identify the possible toxic effects of trazodone on male rats and elucidate the underlying mechanisms. Vehicle or trazodone (5, 10, and 20 mg/kg/day) was administered to rats for 28 consecutive days (n = 8 per group). At the end of that period, sperm concentration, motility, morphology, and DNA damage were determined and testicular morphology was assessed histopathologically in rats. Additionally, we investigated hormonal status by determining serum testosterone, FSH, and LH levels and oxidative stress by determining glutathione and malondialdehyde levels in testicular tissue to elucidate mechanisms of possible reproductive toxicity. According to our results, sperm concentration, sperm motility, and normal sperm morphology were decreased; sperm DNA damage was increased in trazodone-administered groups. Degenerative findings on the testicular structure were observed after trazodone administration in rats. Additionally, serum FSH, LH, and testosterone levels were elevated in the trazodone-administered groups. Increased MDA levels were the signs of enhanced oxidative stress after trazodone administration in testis tissues. Thus, we concluded that trazodone induced reproductive toxicity in male rats; this reproductive toxicity was accompanied by oxidative stress and hormonal changes, which are considered as important causes of reproductive disorders.

Synthesis and Evaluation of a Series of 1,3,4-Thiadiazole Derivatives as Potential Anticancer Agents.

BACKGROUND AND METHODS: In an attempt to develop potent antitumor agents, the synthesis of a series of N-(6-substituted benzothiazol-2-yl)-2-[(5-(arylamino)-1,3,4-thiadiazol-2-yl)thio]acetamides (1-14) was described and their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma, HepG2 human hepatocellular carcinoma and NIH/3T3 mouse embryonic fibroblast cell lines were investigated using MTT assay. RESULTS: Phenyl-substituted compounds (8-14) were found to be more effective than naphthyl-substituted compounds (1-7) on cancer cells. Compounds 8, 9, 10, 12, 13 and 14 were identified as the most potent anticancer agents on MCF-7 and HepG2 cell lines and therefore their effects on DNA synthesis and apoptosis/necrosis in MCF-7 cell line were evaluated. Among these compounds, N-(6-methoxybenzothiazol-2-yl)-2-[(5- (phenylamino)-1,3,4-thiadiazol-2-yl)thio]acetamide (13) was the most selective anticancer agent against MCF-7 and HepG2 cell lines with a SI value of 100. On the other hand, compounds 8, 9, 10, 12, 13 and 14 inhibited DNA synthesis in MCF-7 cell line in a dose-dependent manner. Flow cytometric analyses clearly indicated that the compounds showed significant anticancer activity against MCF-7 cell line via the induction of apoptosis dose dependently. CONCLUSION: According to in vitro assays, compounds 8, 9, 10, 12, 13 and 14 stand out as promising candidates for further studies.

Synthesis and Anticandidal Activity of New Imidazole-Chalcones.

In the present work, 15 new 1-(4-(1H-imidazol-1-yl)phenyl)-3-(4-substituedphenyl)prop-2-en-1-one derivatives (3a−3o) were synthesized to evaluate their antifungal activity. Structures of newly synthesized imidazole derivatives (3a−3o) were characterized by IR, ¹H-NMR, 13C-NMR, and LCMSMS spectroscopic methods. The anticandidal activity of compounds (3a−3o) against C. albicans (ATCC 24433), C. krusei (ATCC 6258), C. parapsilosis (ATCC 22019), and C. glabrata (ATCC 90030) was elucidated according to the EUCAST definitive (EDef 7.1) method. Consistent with the activity studies, 3a−3d were found to be more potent derivatives with their MIC50 values (0.78 µg/mL−3.125 µg/mL) against Candida strains. Compound 3c indicated similar antifungal activity to ketoconazole against all Candida species and was evaluated as the most active derivative in the series. Effects of the most potent derivatives 3a−3d on ergosterol biosynthesis were observed by LC-MS-MS method, which is based on quantification of the ergosterol level in C. krusei. Moreover, these compounds were subjected to a cytotoxicity test for the preliminary toxicological profiles and were found as non-cytotoxic. Furthermore, docking studies for the most active derivative 3c were performed to evaluate its binding modes on lanosterol 14-α-demethylase. In addition to in vitro tests, docking studies also revealed that Compound 3c is a potential ergosterol biosynthesis inhibitor.

Synthesis and Evaluation of Heterocycles Based Chalcone Derivatives as Antiproliferative Agents.

BACKGROUND: The lack of selectivity and development of drug-resistance encourage researchers to search for novel, more efficient and multi-targeted agents with less toxicity. OBJECTIVE: In this paper, a series of novel chalcone derivatives bearing diverse heterocycles have been synthesized and evaluated for their antiproliferative activity against A549 (Human Lung Adenocarcinoma) and C6 (Rat Brain Glioma) cells. METHOD: Structures of the title compounds (3-18) were verified by FT-IR, 1H NMR, 13C NMR, HRMS spectral data and elemental analyses. Antiproliferative activities of the compounds were evaluated using MTT assay, BrdU method, and flow cytometric analysis. RESULTS: Compounds 9 and 15 were revealed as the most promising cytotoxic agents due to their selectivity towards A549 cells with lower IC50 values (IC50=0.05 µM and IC50=0.0316 µM) than cisplatin (IC50=0.06 µM). Flow cytometric analysis of compounds 9 and 15 showed that they affected lung cancer cells by the apoptotic pathway. CONCLUSION: It is concluded that this study will contribute to the research of novel antiproliferative agents.

Design, synthesis and biological assessment of new thiazolylhydrazine derivatives as selective and reversible hMAO-A inhibitors.

In the recent works, it was shown that numerous thiazolylhydrazine derivatives display hMAO inhibitory activity in the range of micromolar concentration. Hence, in the present study a new series of new thiazole-hydrazines (3a-3n) were designed, synthesized, characterized and screened for their hMAO-A and hMAO-B inhibitory activity by an in vitro flurometric method. The enzyme inhibition assay revealed that most of the synthesized compounds have selective inhibition potency against hMAO-A. The compounds 3f and 3h showed promising hMAO-A inhibition with an IC50 values of 0.012 µM and 0.011 µM and significant selectivity indexes of 1214 and 1601 towards hMAO-A, respectively. The mechanism of hMAO-A inhibition of compounds 3f and 3h was investigated by Lineweaver-Burk graphics and reversible-competitive inhibition of hMAO-A was determined. Cytotoxicity and genotoxicity studies were carried out and the compound 3h was found as non-cytotoxic and non-genotoxic. Theoretical calculation of ADME properties suggested that synthesized compounds may have a good pharmacokinetic profile. The docking study of compound 3f and 3h revealed that there is a strong interaction between the active sites of hMAO-A and analyzed compound.

A New Series of Pyrrole-Based Chalcones: Synthesis and Evaluation of Antimicrobial Activity, Cytotoxicity, and Genotoxicity.

In an effort to develop new potent antimicrobial and anticancer agents, new pyrrole-based chalcones were designed and synthesized via the base-catalyzed Claisen-Schmidt condensation of 2-acetyl-1-methylpyrrole with 5-(aryl)furfural derivatives. The compounds were evaluated for their in vitro antimicrobial effects on pathogenic bacteria and Candida species using microdilution and ATP luminescence microbial cell viability assays. MTT assay was performed to determine the cytotoxic effects of the compounds on A549 human lung adenocarcinoma, HepG2 human hepatocellular carcinoma, C6 rat glioma, and NIH/3T3 mouse embryonic fibroblast cell lines. 1-(1-Methyl-1H-pyrrol-2-yl)-3-(5-(4-chlorophenyl)furan-2-yl)prop-2-en-1-one (7) and 1-(1-methyl-1H-pyrrol-2-yl)-3-(5-(2,5-dichlorophenyl)furan-2-yl)prop-2-en-1-one (9) were found to be the most potent antifungal agents against Candida krusei and therefore these compounds were chosen for flow cytometry analysis and Ames MPF assay. ATP bioluminescence assay indicated that the antifungal activity of compounds 7 and 9 against C. krusei was significantly higher than that of other compounds and the reference drug (ketoconazole), whereas flow cytometry analysis revealed that the percentage of dead cells treated with compound 7 was more than that treated with compound 9 and ketoconazole. According to Ames MPF assay, compounds 7 and 9 were found to be non-genotoxic against TA98 and TA100 with/without metabolic activation. MTT assay indicated that 1-(1-methyl-1H-pyrrol-2-yl)-3-(5-(2-nitrophenyl)furan-2-yl)prop-2-en-1-one (3) showed more selective anticancer activity than cisplatin against the HepG2 cell line. On the other hand, 1-(1-methyl-1H-pyrrol-2-yl)-3-(5-(4-nitrophenyl)furan-2-yl)prop-2-en-1-one (1) was found to be more effective and selective on the A549 cell line than cisplatin.

Novel Benzylidene Thiazolidinedione Derivatives as Partial PPARγ Agonists and their Antidiabetic Effects on Type 2 Diabetes.

Peroxisome proliferator-activated receptor γ (PPARγ) has received significant attention as a key regulator of glucose and lipid homeostasis. In this study, we synthesized and tested a library of novel 5-benzylidene-thiazolidin-2,4-dione (BTZD) derivatives bearing a substituent on nitrogen of TZD nucleus (compounds 1a-1k, 2i-10i, 3a, 6a, and 8a-10a). Three compounds (1a, 1i, and 3a) exhibited selectivity towards PPARγ and were found to be weak to moderate partial agonists. Surface Plasmon Resonance (SPR) results demonstrated binding affinity of 1a, 1i and 3a towards PPARγ. Furthermore, docking experiments revealed that BTZDs interact with PPARγ through a distinct binding mode, forming primarily hydrophobic contacts with the ligand-binding pocket (LBD) without direct H-bonding interactions to key residues in H12 that are characteristic of full agonists. In addition, 1a, 1i and 3a significantly improved hyperglycemia and hyperlipidaemia in streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats at a dose of 36 mg/kg/day administered orally for 15 days. Histopathological investigations revealed that microscopic architecture of pancreatic and hepatic cells improved in BTZDs-treated diabetic rats. These findings suggested that 1a, 1i and 3a are very promising pharmacological agents by selectively targeting PPARγ for further development in the clinical treatment of type 2 diabetes mellitus.

Synthesis of Oxadiazole-Thiadiazole Hybrids and Their Anticandidal Activity.

In the field of infection management, it is a major challenge to discover a potent and safe antifungal agent due to the emergence of resistant strains. Hence, the goal of this paper is to design and synthesize novel oxadiazole-thiadiazole hybrid compounds (6a-6s) and evaluate their antifungal activity. The structures of synthesized compounds were elucidated by various methods including FT-IR, ¹H-NMR, 13C-NMR and HR-MS spectral data. Compounds were tested against four Candida species by broth microdilution assay. Compounds 6e, 6k and 6r, bearing a nitro group, showed significant antifungal activity against all fungi with minimum inhibitory concentration (MIC) in the range of 0.78-3.12 µg/mL. These compounds were also screened for their in vitro cytotoxic effects by MTT assay and detected as nontoxic at their active concentrations against Candida strains. To examine the effects of these compounds on ergosterol biosynthesis, the LC-MS-MS method, which is based on quantification of ergosterol level in C. krusei, was carried out. Finally, the most active molecule (6e) was docked in the active site of the lanosterol 14α-demethylase enzyme, and it was determined that there is a strong interaction between the compound and enzyme.

Pharmacological and Toxicological Screening of Novel Benzimidazole-Morpholine Derivatives as Dual-Acting Inhibitors.

The aim of this study was to investigate acetylcholinesterase (AChE), monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme inhibitory, and antimicrobial activities of a new series of 2-(4-substituted phenyl)-1-[2-(morpholin-4-yl)ethyl]-1H-benzimidazole derivatives, for their possible use as multi-action therapeutic agents. Target compounds (n = 15) were synthesized under microwave irradiation conditions in two steps, and their structures were elucidated by FT-IR, ¹H-NMR, 13C-NMR and high resolution mass spectroscopic analyses. Pharmacological screening studies revealed that two of the compounds (2b and 2j) have inhibitory potential on both COX-1 and COX-2 enzymes. In addition, cytotoxic and genotoxic properties of the compounds 2b, 2j and 2m were investigated via the well-known MTT and Ames tests, which revealed that the mentioned compounds are non-cytotoxic and non-genotoxic. As a concise conclusion, two novel compounds were characterized as potential candidates for treatment of frequently encountered inflammatory diseases.

Synthesis and Evaluation of New Oxadiazole, Thiadiazole, and Triazole Derivatives as Potential Anticancer Agents Targeting MMP-9.

Matrix metalloproteinases (MMPs) are important proteases involved in tumor progression including angiogenesis, tissue invasion, and migration. Therefore, MMPs have been reported as potential diagnostic and prognostic biomarkers in many types of cancer. New oxadiazole, thiadiazole, and triazole derivatives were synthesized and evaluated for their anticancer effects on A549 human lung adenocarcinoma and C6 rat glioma cell lines. In order to examine the relationship between their anticancer activity and MMP-9, the compounds were evaluated for their inhibitory effects on MMPs. N-(1,3-Benzodioxol-5-ylmethyl)-2-{[5,[5-(((5,6,7,8-tetrahydronaphthalen-2-yl)oxy)methyl)-1,3,4-oxadiazol-2-yl]thio}acetamide (8) and N-(1,3-benzodioxol-5-ylmethyl)-2-[(5-phenyl-1,3,4-oxadiazol-2-yl)thio]acetamide (9) revealed promising cytotoxic effects on A549 and C6 cell lines similar to cisplatin without causing any toxicity towards NIH/3T3 mouse embryonic fibroblast cell line. Compounds 8 and 9 were also the most effective MMP-9 inhibitors in this series. Moreover, docking studies pointed out that compounds 8 and 9 had good affinity to the active site of the MMP-9 enzyme. The molecular docking and in vitro studies suggest that the MMP-9 inhibitory effects of compounds 8 and 9 may play an important role in lung adenocarcinoma and glioma treatment.

Citalopram Induces Reproductive Toxicity in Male Rats.

BACKGROUND: Citalopram hydrobromide (CTL) has been shown to cause sexual dysfunction; however, its reproductive toxicity potential has not been sufficiently elucidated in men. Therefore, we aimed to clarify the toxic effects of CTL on the reproductive system of male rats. METHODS: For this purpose, CTL was administered at 5, 10, and 20 mg/kg/day to rats orally for 28 days. Sperm concentration, motility, and morphology were investigated using a computer-assisted sperm analysis system, and sperm DNA damage was detected using a Comet assay. The testes were histopathologically examined. Serum follicle-stimulating hormone, luteinizing hormone, and testosterone levels were measured and the oxidative status of testes was investigated. RESULTS: Our results showed that sperm concentration was reduced, and abnormal sperm morphology and sperm DNA damage were increased in CTL-administered groups. Additionally, histopathological changes were observed in the testes of CTL-administered rats. Luteinizing hormone levels were increased in CTL-administered groups, while testosterone levels were increased in the 5 and 10 mg/kg CTL-administered groups. Decreased glutathione signaled enhanced oxidative stress in the 10 and 20 mg/kg CTL-administered groups. CONCLUSION: Thus, we concluded that CT induced testicular damage in male rats; this testicular damage was accompanied by oxidative stress and hormonal changes, which are considered as the important causes of reproductive disorders. Birth Defects Research 109:475-485, 2017. © 2017 Wiley Periodicals, Inc.

Reproductive toxicity after levetiracetam administration in male rats: Evidence for role of hormonal status and oxidative stress.

Levetiracetam (LEV) is an antiepileptic drug commonly used in the treatment of epilepsy because of its excellent safety profile in all age groups. It is remarkable that there are no studies evaluating the toxic effects of this drug on the male reproductive system, as it is commonly used in male patients of reproductive age. From this point of view, our aim was to evaluate the possible toxic effects of LEV on the male reproductive system. Therefore, LEV was administered to male rats orally at 50, 150, and 300 mg/kg for 70 consecutive days. At the end of this period, alterations to body and organ weights were calculated, and sperm concentration, motility, and morphology were investigated by a computer-assisted sperm analysis system. Sperm DNA damage was determined by comet assay and histopathological examination of the testes was carried out. Serum testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels were measured by ELISAs to determine the effects of hormonal status, while glutathione, superoxide dismutase, catalase, and malondialdehyde levels in the testes were measured by colorimetric assay kits to determine the role of oxidative status in potential toxicity. According to the results, sperm quality was decreased by LEV treatment in a dose-dependent manner. LEV induced significant DNA damage in the 150 and 300 mg/kg LEV-administered groups. Histopathology of the testes showed that LEV resulted in testicular injury in the 300 mg/kg LEV-administered group. Serum testosterone, FSH, and LH levels were significantly decreased in the 300 mg/kg LEV-administered group. Glutathione, superoxide dismutase, and catalase levels were significantly decreased in all experimental groups while malondialdehyde levels were significantly increased in 150 and 300 mg/kg LEV-administered groups. According to these results, it was determined that LEV administration decreased sperm quality and it was alleged that hormonal alteration and oxidative stress are potential contributors to reproductive toxicity.

Cytotoxic, Antiproliferative and Apoptotic Effects of Perillyl Alcohol and Its Biotransformation Metabolite on A549 and HepG2 Cancer Cell Lines.

BACKGROUND: A monoterpene, perillyl alcohol, has attracted attention in medicinal chemistry since it exhibited chemo-preventive and therapeutic properties against a variety of cancers. OBJECTIVE: In the present work, it was aimed to obtain derivatives of perillyl alcohol through microbial biotransformation and investigate their anticancer activities against A549 and HepG2 cancer cell lines. METHOD: Biotransformation studies were carried out in a α-medium for 7 days at 25oC. XTT assay was performed to investigate the anticancer activities of perillyl alcohol and its biotransformation metabolite, dehydroperillic acid, against A549 and HepG2 cell lines and their selectivity using healthy cell line, NIH/3T3. Cell proliferation ELISA, BRDU (colorimetric) assay was used for measurement of proliferation in replicative cells in which DNA synthesis occurs. Flow cytometric analyses were also carried out for measuring apoptotic cell percentages, caspase 3 activation and mitochondrial membrane potential. RESULTS: Biotransformation of perillyl alcohol with Fusarium culmorum yielded dehydroperillic acid in a yield of 20.4 %. In in vitro anticancer studies, perillyl alcohol was found to exert cytotoxicity against HepG2 cell line with an IC50 value of 409.2 µg/mL. However, this effect was not found to be selective because of its higher IC50 (250 µg/mL) value against NIH/3T3 cell line. On the other hand, dehydroperillic acid was found to be effective and also selective against A549 cell line with an IC50 value of 125 µg/mL and a selectivity index (SI) value of 400. Apoptosis inducing effects of dehydroperillic acid was better in A549 cell line. CONCLUSION: Dehydroperillic acid may be a good candidate for therapy of lung adenocarcinoma and may show this anticancer activity by inducing apoptosis.

Matrix metalloproteinases are possible targets in monocrotaline-induced pulmonary hypertension: investigation of anti-remodeling effects of alagebrium and everolimus.

OBJECTIVE: In our study, sildenafil alone and everolimus or alagebrium in combination with sildenafil were investigated in terms of their additional therapeutic and anti-remodeling activity in monocrotaline-induced pulmonary hypertension (PH) model in rats. In particular, the inter-relationships between PH and matrix metalloproteinases (MMPs) were investigated. METHODS: The pulmonary artery responses of male Sprague Dawley rats were recorded using myography, and the quantities and activities of MMPs were analyzed in homogenates of the pulmonary arteries and lungs by enzyme-linked immunosorbent assays, activity assays, and gelatin zymography techniques. RESULTS: Our results indicated that the therapeutic effects of sildenafil were accompanied by its suppressor effects on MMP activity. It was also shown that everolimus or alagebrium in combination with sildenafil showed additional regulatory effects on MMPs as well as functional responses on pulmonary artery pressure. Therefore, the enzymes in the MMP superfamily are likely to be target molecules for the treatment of PH. CONCLUSION: In conclusion, MMPs were involved in the pathogenesis of PH, and our results suggested that the addition of everolimus or alagebrium to sildenafil therapy may be beneficial in PH. Our results indicated that agents that limit pulmonary vascular hypertrophy and inflammation via their anti-remodeling effects significantly ameliorate mortality and morbidity in PH.

Synthesis and Evaluation of A New Series of Thiazole Derivatives as Potential Antitumor Agents and MMP Inhibitors.

BACKGROUND: In recent years, the relationship between overexpression of matrix metalloproteinases (MMPs) and tumor invasion/metastasis has prompted researchers to develop MMP inhibitors as anticancer drugs. OBJECTIVE: The aim of this study was to design and synthesize new thiazole-based anticancer agents targeting MMPs. METHOD: New thiazole derivatives were synthesized and investigated for their cytotoxic effects on A549 human lung adenocarcinoma, MCF-7 human breast adenocarcinoma and NIH/3T3 mouse embryonic fibroblast cell lines using MTT assay. The potential inhibitory effects of the best candidates on gelatinases (MMP-2, MMP-9), and collagenases (MMP-1, MMP-8, MMP-13) were evaluated. RESULTS: Ethyl 2-[2-((4-amino-5-(phenoxymethyl)-4H-1,2,4-triazol-3-yl)thio)acetamido]-4-methylthiazole-5-carboxylate (3) was found to be the most promising anticancer agent against MCF-7 cell line due to its selective inhibitory effect on MCF-7 cells with an IC50 value of 20.6±0.3 µg/mL when compared with cisplatin (IC50= 35.31±0.51 µg/mL). Compound 3 also showed multiple MMP (MMP-1, MMP-8 and MMP-9) inhibitory activity (10.56±1.70, 20 and 7.28±1.49%, respectively). CONCLUSION: The notable anticancer activity and selectivity of compound 3 on MCF-7 cell line can be attributed to multiple MMP inhibition potential.