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Background/Objectives: Thiadiazine thione (THTT) has gained significant interest owing to its pharmacological potentials, particularly its antiparasitic and anti-inflammatory properties. Leishmaniasis is a clinical syndrome caused by infection with Leishmania species and is associated with an inflammatory response and nociception. The available treatments against leishmaniasis are inadequate, as they are associated with high cost, toxicity, and increased resistance. Methods: In the current study, the antileishmanial potential of five Thiadiazine thione derivatives (C1–C5) was evaluated in vivo against Leishmania tropica. Experiments were performed on BALB/c mice infected with promastigotes and treated with THTT derivatives for 15 days. Additionally, the derivatives were evaluated for their anti-inflammatory, antinociceptive, antipyretic, and antisedative properties using standardized models, including carrageenan-induced paw edema, acetic acid-induced abdominal writhes, yeast-induced fever, and white wood apparatus, respectively. Results: Of the tested derivatives, C5 exhibited the most promising results, with a 61.78% reduction in lesion size and significant decrease in parasite load. Among the derivatives, C1 showed the highest anti-inflammatory activity, with 63.66% inhibition in the paw edema test at the 5th hour post treatment. In the antipyretic assay, C1 and C5 were able to reduce body temperature to a normal level within 1 h of treatment. Furthermore, compounds C4, C2, and C1 showed high nociceptive activity, while C1 and C5 demonstrated the most notable antisedative effects (94 ± 2 and 92 ± 1, respectively), outperforming the standard drug diazepam (13 ± 1). Conclusion: These in vivo findings suggest that THTT derivatives have the potential to serve as a template for developing leishmanicidal drugs, with added anti-inflammatory and analgesic properties. [ABSTRACT FROM AUTHOR]

Background: The overuse of antibiotics has led to lethal multi-antibiotic-resistant microorganisms around the globe, with restricted availability of novel antibiotics. Compared to conventional antibiotics, evolutionarily originated antimicrobial peptides (AMPs) are promising alternatives to address these issues. The gut microbiome of Blattella germanica represents a previously untapped resource of naturally evolving AMPs for developing antimicrobial agents. Results: Using the in-house designed tool "AMPidentifier," AMP candidates were mined from the gut microbiome of B. germanica, and their activities were validated both in vitro and in vivo. Among filtered candidates, AMP1, derived from the symbiotic microorganism Blattabacterium cuenoti, demonstrated broad-spectrum antibacterial activity, low cytotoxicity towards mammalian cells, and a lack of hemolytic effects. Mechanistic studies revealed that AMP1 rapidly permeates the bacterial cell and accumulates intracellularly, resulting in a gradual and mild depolarization of the cell membrane during the initial incubation period, suggesting minimal direct impact on membrane integrity. Furthermore, observations from fluorescence microscopy and scanning electron microscopy indicated abnormalities in bacterial binary fission and compromised cell structure. These findings led to the hypothesis that AMP1 may inhibit bacterial cell wall synthesis. Furthermore, AMP1 showed potent antibacterial and wound healing effects in mice, with comparable performances of vancomycin. Conclusions: This study exemplifies an interdisciplinary approach to screening safe and effective AMPs from natural biological tissues, and our identified AMP 1 holds promising potential for clinical application. Bfzw53yZZxeQJxRuWThBYF Video Abstract [ABSTRACT FROM AUTHOR]

Abstract Background The overuse of antibiotics has led to lethal multi-antibiotic-resistant microorganisms around the globe, with restricted availability of novel antibiotics. Compared to conventional antibiotics, evolutionarily originated antimicrobial peptides (AMPs) are promising alternatives to address these issues. The gut microbiome of Blattella germanica represents a previously untapped resource of naturally evolving AMPs for developing antimicrobial agents. Results Using the in-house designed tool “AMPidentifier,” AMP candidates were mined from the gut microbiome of B. germanica, and their activities were validated both in vitro and in vivo. Among filtered candidates, AMP1, derived from the symbiotic microorganism Blattabacterium cuenoti, demonstrated broad-spectrum antibacterial activity, low cytotoxicity towards mammalian cells, and a lack of hemolytic effects. Mechanistic studies revealed that AMP1 rapidly permeates the bacterial cell and accumulates intracellularly, resulting in a gradual and mild depolarization of the cell membrane during the initial incubation period, suggesting minimal direct impact on membrane integrity. Furthermore, observations from fluorescence microscopy and scanning electron microscopy indicated abnormalities in bacterial binary fission and compromised cell structure. These findings led to the hypothesis that AMP1 may inhibit bacterial cell wall synthesis. Furthermore, AMP1 showed potent antibacterial and wound healing effects in mice, with comparable performances of vancomycin. Conclusions This study exemplifies an interdisciplinary approach to screening safe and effective AMPs from natural biological tissues, and our identified AMP 1 holds promising potential for clinical application. Graphical Abstract Video Abstract

Iron deficiency anemia is a global health concern, affecting around 2 billion people. Oral iron therapy often causes severe gastro‐intestinal issues. Eruca sativa, member of the Brassicaceae family, is valued in traditional medicine and renowned for its rich iron and vitamin C content. This study aims to evaluate the anti‐anemic properties of E. sativa extract in vivo and identify its compounds targeting anemia mechanisms using network pharmacology. Thirty‐two Sprague–Dawley rats (200 ± 250 g) were split into two distinct groups, iron‐deficient and iron‐sufficient. Three different doses (200, 400, and 800 mg/kg) of aqueous extract of E. sativa were checked against anemia by studying hematological, oxidative stress, and histopathological parameters. GC–MS analysis of E. sativa revealed its phytochemical profile, followed by ADME screening. Network pharmacology explored targets related to iron deficiency anemia, with oral bioavailability and drug likeness assessment for compounds. The administration of extracts significantly improved various blood parameters, including osmotic fragility, Hb, RBCs, MCV, PCV, and alkaline phosphatase; catalase activity; and histopathological parameters such as liver in both iron‐deficient and iron‐sufficient rats (p <.001). Seventy‐nine compounds were identified in E. sativa aqueous extract, with only six of them found to be bioavailable and drug‐like against multiple targets. Gene ontology and pathway analysis revealed their diverse molecular, biological, and cellular functions. One gene EGFR was found to have functional association with ID anemia, suggesting potential for using E. sativa extracts. The study concludes that E. sativa extract has potential for iron deficiency anemia treatment, offering hope for future pharmaceutical interventions. [ABSTRACT FROM AUTHOR]

Background/Objectives: Thiadiazine thione (THTT) has gained significant interest owing to its pharmacological potentials, particularly its antiparasitic and anti-inflammatory properties. Leishmaniasis is a clinical syndrome caused by infection with Leishmania species and is associated with an inflammatory response and nociception. The available treatments against leishmaniasis are inadequate, as they are associated with high cost, toxicity, and increased resistance. Methods: In the current study, the antileishmanial potential of five Thiadiazine thione derivatives (C1–C5) was evaluated in vivo against Leishmania tropica. Experiments were performed on BALB/c mice infected with promastigotes and treated with THTT derivatives for 15 days. Additionally, the derivatives were evaluated for their anti-inflammatory, antinociceptive, antipyretic, and antisedative properties using standardized models, including carrageenan-induced paw edema, acetic acid-induced abdominal writhes, yeast-induced fever, and white wood apparatus, respectively. Results: Of the tested derivatives, C5 exhibited the most promising results, with a 61.78% reduction in lesion size and significant decrease in parasite load. Among the derivatives, C1 showed the highest anti-inflammatory activity, with 63.66% inhibition in the paw edema test at the 5th hour post treatment. In the antipyretic assay, C1 and C5 were able to reduce body temperature to a normal level within 1 h of treatment. Furthermore, compounds C4, C2, and C1 showed high nociceptive activity, while C1 and C5 demonstrated the most notable antisedative effects (94 ± 2 and 92 ± 1, respectively), outperforming the standard drug diazepam (13 ± 1). Conclusion: These in vivo findings suggest that THTT derivatives have the potential to serve as a template for developing leishmanicidal drugs, with added anti-inflammatory and analgesic properties.

Chemotherapy currently available for leishmaniasis treatment has many adverse side effects and drug resistance. Therefore, the identification of new targets and the development of new drugs are urgently needed. Previously, we reported the synthesis of a N-(2-methoxyphenyl)-1-methyl-1H-benzimidazol-2-amine, named compound 8, with an IC50 value in the micromolar range against L. mexicana, it also inhibited 68.27% the activity of recombinant L. mexicana arginase. Herein, we report studies carried out to characterize the mechanism of action of compound 8, as well as its in vivo leishmanicidal activity. It was shown in our ultrastructural studies that compound 8 induces several changes, such as membrane blebbing, the presence of autophagosomes, membrane detachment and mitochondrial and kinetoplast disorganization, among others. Compound 8 triggers the production of ROS and parasite apoptosis. It reduced 71% of the parasite load of L. mexicana in an experimental model of cutaneous leishmaniasis in comparison with a control. Altogether, the data obtained suggest the potential use of compound 8 in the treatment of cutaneous leishmaniasis. [ABSTRACT FROM AUTHOR]

A promising therapeutic window and cost-effectiveness are just two of the potential advantages of using naturally derived drugs. Fisetin (3,3′,4′,7-tetrahydroxyflavone) is a natural flavonoid of the flavonol group, commonly found in fruit and vegetables. In recent years, fisetin has gained wide attention across the scientific community because of its broad spectrum of pharmacological properties, including cytotoxic activity against most abundant cancers. By stimulating or inhibiting selected molecular targets or biochemical processes, fisetin could affect the reduction of metastasis or cancer progression, which indicates its chemotherapeutic or chemopreventive role. In this review, we have summarized the results of studies on the anticancer effects of fisetin on selected female malignancies, both in in vitro and in vivo tests, i.e., breast, cervical, and ovarian cancer, published over the past two decades. Until now, no article dedicated exclusively to the action of fisetin on female malignancies has appeared. This review also describes a growing number of nanodelivery systems designed to improve the bioavailability and solubility of this natural compound. The reported low toxicity and activity of fisetin on cancer cells indicate its valuable potential, but large-scale clinical trials are urgently needed to assess real chemotherapeutic efficacy of this flavonoid. [ABSTRACT FROM AUTHOR]

FIBRINOLYTIC enzyme production from Scopulariopsis brevicaulis OS 3456 isolated from a local soil sample was studied. The enzyme was purified by ammonium sulfate precipitation and gel filtration chromatography using Sephadex G-100, increasing its specific activity to 370 U/mg with a yield of 1.5% and a purification fold of 3.4. The molecular weight of the purified enzyme was 61.5 kDa determined by SDS-PAGE analysis. The optimum temperature of the enzyme was 37oC, and it was stable over a pH range of 5.0-9.0 with maximum stability at pH 7.0. The activity was increased in the presence of ß-mercaptoethanol, Mn2+, Ba2+, triton X-100, and xylene by 137.1, 51.6, 41.4, 37.5, and 23%, respectively. Furthermore, the enzyme activity was inhibited by Cd2+, Al3+, EDTA, PMSF, and acetone. The in vitro thrombolytic activity of the undiluted purified enzyme (370 U/mg) was found to be 100%. Meanwhile, in the cases of 185, 92.5, 46.25, 23.125, and 11.562 U/mg, the clot lysis percentage was 76.8, 67.4, 57.8, 39.5, and 28%, respectively. A carrageenan-induced tail thrombosis model was applied to test the in vivo thrombolytic activity of the enzyme. The result indicated no obvious thrombus in the tails of mice treated with the tested enzyme (370 U/mg). However, when the enzyme was diluted, its thrombolytic activity decreased gradually. All these results explore the promising thrombolytic activity of the extracted fibrinolytic enzyme. Hence, more purification steps and more experimental animal studies are required in the future for its use as a commercial drug. [ABSTRACT FROM AUTHOR]

COST Action CA17140 Cancer Nanomedicine—from the bench to the bedside (Nano2Clinic,) is the first, pan-European interdisciplinary network of representatives from academic institutions and small and medium enterprises including clinical research organizations (CROs) devoted to the development of nanosystems carrying anticancer drugs from their initial design, preclinical testing of efficacy, pharmacokinetics and toxicity to the preparation of detailed protocols needed for the first phase of their clinical studies. By promoting scientific exchanges, technological implementation, and innovative solutions, the action aims at providing a timely instrument to rationalize and focus research efforts at the European level in dealing with the grand challenge of nanomedicine translation in cancer, one of the major and societal-burdening human pathologies. Within CA17140, dendrimers in all their forms (from covalent to self-assembling dendrons) play a vital role as powerful nanotheranostic agents in oncology; therefore, the purpose of this review work is to gather and summarize the major results in the field stemming from collaborative efforts in the framework of the European Nano2Clinic COST Action. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general show extremely low aqueous solubility, which adversely affects the drug-like properties. To improve the compounds physicochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb lower than 0.01 µM. The representative compound 37 displays improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute infection mouse model. [ABSTRACT FROM AUTHOR]

Antibacterial peptides are endogenous polypeptides produced by multicellular organisms to protect the host against pathogenic microbes, they show broad spectrum antimicrobial activities against various microorganisms and possess low propensity for developing resistance. The purpose of this study is to develop recombinant antibacterial peptide cathelicidin-BF by genetic engineering and protein engineering technology, and study its antibacterial activity in vitro and in vivo, so as to provide reference for the production and application of recombinant antibacterial peptide cathelicidin-BF. In this study, on account of Pichia pastoris eukaryotic expression system, we expressed and prepared antibacterial peptide cathelicidin-BF. Then, the minimum inhibitory concentration of antibacterial peptide cathelicidin-BF and the comparison with the antibacterial activity of antibiotics were determined through the antibacterial experiment in vitro. Chickens as infection model were used to verify the antibacterial peptide activity in vivo. The results show that the bacteriostatic ability of antibacterial peptide cathelicidin-BF is similar to that of antibiotics in certain concentration, and can reach the treatment level of antibiotics. Although the mode of administration of antibacterial peptide is still limited, this study can provide reference for the future research of antibacterial peptide. [ABSTRACT FROM AUTHOR]

Leishmaniasis and trypanosomiasis rank among lethal vector-borne parasitic diseases that are endemic in tropical and sub-tropical countries. There are currently no preventive vaccines against them, and once diagnosed, a handful of less effective drugs clinically accessible are the only therapeutic options offered to treat these ailments. And although curable, the eradication and elimination of these diseases are hampered by the emergence of multidrug-resistant strains of the causal pathogens. Hence, there is accrued necessity for the development of new, effective, and affordable drugs. In recent decades, several molecular scaffolds, including nitroaromatics, endoperoxides, etc., have been attempted as building blocks to generate new effective clinical antitrypanosomatid agents with low toxicity so far to no avail. In this regard, a series of nitroindolylazine derivatives was synthesised in a three-step process involving nucleophilic substitution (S N), hydrazination and Schiff base condensation reactions, and was evaluated against various Leishmania and Trypanosoma species and strains. Several promising hits portraying leishmanicidal and trypanocidal with in vitro submicromolar activities, and devoid of toxicity on mammalian cells were uncovered. Among these, nitrofurylazine 11 (Tc IC 50 : 0.08 ± 0.03 μM) and nitrothienylazine 13 (Tc IC 50 : 0.09 ± 0.01 μM) were evaluated in vivo against Trypanosoma congolense , the causative agent of nagana , which is livestock most virulent trypanosome species in mice-infected preliminary study. However, only partial efficacy was observed as all mice succumbed due to high parasitemia within 13 days post-infection during the treatment. The translational potential of antileishmanial and antichagasic hits, as well as further identification of their molecular targets, will be assessed in future research. A series of 5-nitroindolylazines was synthesised and screened for trypanosomaticidal activity. Azines 11 and 13 were unveiled as hits with micro-to nanomolar activity. [Display omitted] • A series of 21 novel 5-nitroindolylazines were synthesised in three steps • The azines were assessed in vitro and in vivo for trypanosomaticidal activity • Several micromolar active leishmanicidal and trypanocidal hits were uncovered • Nitrofuryl 11 and nitrothienyl 13 were identified with micro-to nanomolar dual activity • No in vivo efficacy was observed with 11 & 13 in T. congolense- infected mice [ABSTRACT FROM AUTHOR]

Phytochemical properties have recently increased the popularity of plant polysaccharides as wound dressing materials. This work aims at studying the structural characteristics of polysaccharides extracted from Moringa leaves (Moringa Leaves Water Soluble Polysaccharide: MLWSP), and its antioxidant activities, cytotoxic effects, and laser burn wound healing effects in rats. This MLWSP was structurally characterized. Results showed 175.21 KDa and 18.6%, respectively, for the molecular weight and the yield of the novel extracted polysaccharide. It is a hetero-polysaccharide containing arabinose, rhamnose, and galactose. XRD suggested a semi-crystalline structure of the studied polymer and FT-IR results revealed a typical polysaccharide structure. It is composed of 50 to 500 µm rocky-shaped units with rough surfaces and it was found to inhibit the proliferation of the human colon (HCT-116) (IC50 = 36 ± 2.5 µg/mL), breast (MCF-7) (IC50 = 48 ± 3.2), and ovary cancers (IC50 = 24 ± 8.1). The MLWSP showed significant antioxidant effects compared to Trolox (CI50 = 0.001 mg/g). Moreover, promising wound healing results were displayed. The effect of MLWSP hydrogel application on laser burn injuries stimulated wound contraction, re-epithelization, and remodeling phases 8 days after treatment. The wound healing potential of MLWSP may be due to its significant antioxidant activity and/or the huge amount of monosaccharide molecules. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-β-D-ribose 2’-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general show extremely low aqueous solubility, which adversely affects the drug-like properties. To improve the compounds physicochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb lower than 0.01 µM. The representative compound 37 displays improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute infection mouse model.

[Display omitted] • A series of novel 1-amido-2-oxo-4-thio-deoxypyranoses were efficiently synthesized for first time from easily available α, β-unsaturated ketone. • The most active compounds C16 , C18 , C20 and C32 exhibited strong anti-proliferative activity with IC 50 values of 1 ∼ 2 μM. • Compound 20 as a potent ligand and inhibitor of TRIP13 exhibited anticancer efficacy both in vitro and in vivo. • All the results suggested that the 1-amido-2-oxo-4-thio-deoxypyranoses are promising lead compounds for developing carbohydrate-based TRIP13 inhibitor drugs, which are in structure totally different from already reported inhibitors. This study reported the design and synthesis of novel 1-amido-2-one-4-thio-deoxypyranose as inhibitors of potential drug target TRIP13 for developing new mechanism-based therapeutic agents in the treatment of multiple myeloma (MM). In comparison with the positive control DCZ0415 , the most active compounds C16 , C18 , C20 and C32 exhibited strong anti-proliferative activity against human MM cell lines (ARP-1 and NCI-H929) with IC 50 values of 1 ∼ 2 μM. While the surface plasmon resonance (SPR) and ATPase activity assays demonstrated that the representative compound C20 is a potent inhibitor of TRIP13, C20 also showed good antitumor activity in vivo on BALB/c nude mice xenografted with MM tumor cells. An initial structure–activity study showed that the carbonyl group is crucial for anticancer activity. Overall, this study provided novel 1-amido-2-one-4-thio-deoxypyranoses, which are entirely different from previously reported potent inhibitor structures of TRIP13, and thus would aid the development of carbohydrate-based novel agents in MM pharmacotherapy. [ABSTRACT FROM AUTHOR]

Baccharis mattogrosensis is a species from Asteraceae which has been used in Brazilian folk medicine to treatment of several illnesses, including those caused by parasites. In the present work, the MeOH extract of aerial parts of B. mattogrosensis was subjected to chromatographic fractionation to afford three flavonoids: apigenin (1), quercetin (2), and kaempferol (3) as well as a mixture three chlorogenic acids: 3,4-O-dicaffeoylquinic (4), 3,5-O-dicaffeoylquinic (5), and 4,5-O-dicaffeoylquinic (6) acids. When tested in vitro, kaempferol (3) exhibited activity against Schistosoma mansoni with EC 50 =81.86 μM, whereas compounds 1, 2, 4-6 showed to be inactives. Considering this result, the effects of kaempferol (3) against S. mansoni infection using an experimental approach (in vivo assay) was tested at first time. Using a single oral dose (400 mg/kg) of kaempferol (3) to S. mansoni-infected mice reduced the worm burden by 25.5 %. Similarly, the number of eggs, which are responsible for a variety of pathologies and transmission of schistosomiasis, was decreased by 28.8 % in treated mice. Collectively, although kaempferol (3) is partially active when administered orally in a mouse model of schistosomiasis, our results suggest that this compound could be, in future studies, administered in different forms, such as nanoformulation., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

The viral pandemic has resulted in a growing demand for antiviral drugs. The existing small‐molecule antiviral drugs are limited, due to their incidence of drug resistance and adverse side effects. As potential drugs, antiviral peptides have the benefits of high activity, high stability, and few side effects. Furthermore, the diversity of acquisition methods allows antiviral peptides to be quickly designed and yielded. The drug properties (such as high bioavailability and in vivo stability) of antiviral peptides can be improved by the developed modifications. Currently, two peptide antiviral drugs have been approved for the treatment of acquired immunodeficiency syndrome (AIDS). Many antiviral peptides have entered clinical trials for the treatment of diseases caused by viruses. In addition, new antiviral peptides are continuously being identified and validated against virus infections. Given the benefits of antiviral peptides, they will become major antiviral drugs to combat new outbreaks caused by unknown viruses in the future. This review provides an overview of recent developments in antiviral peptides with in vivo activity. [ABSTRACT FROM AUTHOR]

Phytochemical properties have recently increased the popularity of plant polysaccharides as wound dressing materials. This work aims at studying the structural characteristics of polysaccharides extracted from Moringa leaves (Moringa Leaves Water Soluble Polysaccharide: MLWSP), and its antioxidant activities, cytotoxic effects, and laser burn wound healing effects in rats. This MLWSP was structurally characterized. Results showed 175.21 KDa and 18.6%, respectively, for the molecular weight and the yield of the novel extracted polysaccharide. It is a hetero-polysaccharide containing arabinose, rhamnose, and galactose. XRD suggested a semi-crystalline structure of the studied polymer and FT-IR results revealed a typical polysaccharide structure. It is composed of 50 to 500 µm rocky-shaped units with rough surfaces and it was found to inhibit the proliferation of the human colon (HCT-116) (IC50 = 36 ± 2.5 µg/mL), breast (MCF-7) (IC50 = 48 ± 3.2), and ovary cancers (IC50 = 24 ± 8.1). The MLWSP showed significant antioxidant effects compared to Trolox (CI50 = 0.001 mg/g). Moreover, promising wound healing results were displayed. The effect of MLWSP hydrogel application on laser burn injuries stimulated wound contraction, re-epithelization, and remodeling phases 8 days after treatment. The wound healing potential of MLWSP may be due to its significant antioxidant activity and/or the huge amount of monosaccharide molecules.

The pharmacokinetics of CYP2C9 substrates is characterized by substantial interethnic variability. The objective of the study was to compare CYP2C9 activity by using Phenytoin Metabolic Ratio (PMR) between Ethiopian and non-Ethiopian Jews. PMR was derived from the ratio of p-HPPH in 24 h urine collection to plasma phenytoin, 12 h (PMR24/12) or 24 h (PMR24/24) after the administration of 300 mg phenytoin. Analysis of CYP2C9*2, *3, *5, *6, *8, and *11 was carried by direct sequencing. PMR was significantly correlated with CYP2C9 genotype in both groups (p < 0.002). Mean PMR values were similar among Ethiopians and non-Ethiopians despite the fact that the fraction of non-carriers of CYP2C9 variant alleles was significantly different (85 vs. 53%, respectively, p < 0.001). However, among non-carriers of CYP2C9*2, *3, *5, *6, *8, and *11 variant alleles, PMR24/12 and PMR24/24 values were 30 and 34% greater respectively in the non-Ethiopians group (p < 0.001). In conclusion—CYP2C9 activity as measured by PMR is similar in Ethiopian and non-Ethiopian Jews. However, among non-carriers of CYP2C9 variant alleles accounting for 85% of Ethiopian Jews, CYP2C9 activity is decreased by approximately one third as compared with non-Ethiopian Jews. Unique genetic CYP2C9 polymorphisms occurring only in Ethiopians may account for this difference.

Ammar Almaaytah,1 Qosay Albalas,2 Karem H Alzoubi3 1Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Medicinal Chemistry and Pharmacognosy, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid, Jordan Background: The consistent upsurge in antimicrobial resistance globally is threatening the world population with the prospect of facing the post-antibiotic era. Dry pipelines and a drastic decrease of antimicrobial drug development accompany this rise in antimicrobial resistance. Governments and health authorities are calling for the development of novel classes of antimicrobial agents that would tackle this problem. Antimicrobial peptides represent a promising group of molecules for antimicrobial drug development due to their potency and rapid mode of killing. However, several obstacles, such as high mammalian cell toxicity and lack of target selectivity, have challenged the development of such agents. Methods: We have recently designed a novel hybrid peptide named H4 that exhibits potent antimicrobial activity and low toxicity in vitro. In order to confirm the potential therapeutic efficacy and safety of the peptide, we evaluated the in vivo activity and toxicity of H4 against Staphylococcus aureus peritonitis mice model. Results: Our results indicate that H4 is highly potent in eradicating bacterial infections in vivo with an effective dose50 value of 4.55±0.89 mg/kg. Additionally, the acute systemic toxicity results indicate that the peptide exhibits a high therapeutic index with no significant negative effects on the function of major body organs. Conclusion: H4 is a novel hybrid peptide with great potential for antimicrobial drug development. Keywords: antimicrobial peptides, hybrid peptides, in vivo activity, hybridization, antimicrobial resistance, drug development

The pharmacokinetics of CYP2C9 substrates is characterized by substantial interethnic variability. The objective of the study was to compare CYP2C9 activity by using Phenytoin Metabolic Ratio (PMR) between Ethiopian and non-Ethiopian Jews. PMR was derived from the ratio of p-HPPH in 24 h urine collection to plasma phenytoin, 12 h (PMR24/12) or 24 h (PMR24/24) after the administration of 300 mg phenytoin. Analysis of CYP2C9*2, *3, *5, *6, *8 , and *11 was carried by direct sequencing. PMR was significantly correlated with CYP2C9 genotype in both groups (p < 0.002). Mean PMR values were similar among Ethiopians and non-Ethiopians despite the fact that the fraction of non-carriers of CYP2C9 variant alleles was significantly different (85 vs. 53%, respectively, p < 0.001). However, among non-carriers of CYP2C9*2, *3, *5, *6, *8, and *11 variant alleles, PMR24/12 and PMR24/24 values were 30 and 34% greater respectively in the non-Ethiopians group (p < 0.001). In conclusion—CYP2C9 activity as measured by PMR is similar in Ethiopian and non-Ethiopian Jews. However, among non-carriers of CYP2C9 variant alleles accounting for 85% of Ethiopian Jews, CYP2C9 activity is decreased by approximately one third as compared with non-Ethiopian Jews. Unique genetic CYP2C9 polymorphisms occurring only in Ethiopians may account for this difference. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb), causative agent of tuberculosis (TB) and non-tubercular mycobacterial (NTM) pathogens such as Mycobacterium abscessus are one of the most critical concerns worldwide due to increased drug-resistance resulting in increased morbidity and mortality. Therefore, focusing on developing novel therapeutics to minimize the treatment period and reducing the burden of drug-resistant Mtb and NTM infections are an urgent and pressing need. In our previous study, we identified anti-mycobacterial activity of orally bioavailable, non-cytotoxic, polycationic phosphorus dendrimer 2G0 against Mtb. In this study, we report ability of 2G0 to potentiate activity of multiple classes of antibiotics against drug-resistant mycobacterial strains. The observed synergy was confirmed using time-kill kinetics and revealed significantly potent activity of the combinations as compared to individual drugs alone. More importantly, no re-growth was observed in any tested combination. The identified combinations were further confirmed in intra-cellular killing assay as well as murine model of NTM infection, where 2G0 potentiated the activity of all tested antibiotics significantly better than individual drugs. Taken together, this nanoparticle with intrinsic antimycobacterial properties has the potential to represents an alternate drug candidate and/or a novel delivery agent for antibiotics of choice for enhancing the treatment of drug-resistant mycobacterial pathogens. [Display omitted] • 2G0 is efficacious against mycobacterial pathogens including M. abscessus. • 2G0 synergizes with various antibiotics against mycobacterial pathogens. • 2G0 in combination leads to increased cellular lysis as seen by SEM. • 2G0 in combination significantly reduces frequency of resistant mutants. • 2G0 in combination is efficacious in rescuing mice from NTM infection. [ABSTRACT FROM AUTHOR]

Zinc doped copper oxide nanocomposites (Zn-CuO NPs) is a novel doped metal nanomaterial synthesized by our group using the sonochemical method. Our previous studies have shown that Zn-CuO NPs could inhibit cancer cell proliferation by inducing apoptosis via ROS-mediated pathway. In the present study, we studied the anticancer effect of Zn-CuO NPs on human pancreatic cancer cells. MTS assay revealed that Zn-CuO NPs was able to inhibit cancer cell growth. TEM, flow cytometry and fluorescence microscope analysis showed that Zn-CuO NPs induced autophagy significantly; the number of autophagosomes increased obviously in cells treated with Zn-CuO NPs. Western blot analysis revealed that treatment with the NPs resulted in activation of AMPK/mTOR pathway in both AsPC-1 and MIA Paca-2 cells in dose dependent manners. Moreover, in the presence of AMPK activator AMPKinone, the protein level of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I increased, while the protein expression of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I decreased in the presence of AMPK inhibitor Compound C. In vivo study using xenograft mice revealed that Zn-CuO NPs significantly inhibited tumor growth with low toxicity. Our study confirms that Zn-CuO NPs inhibit the tumor growth both in vitro and in vivo for pancreatic cancer. AMPK/mTOR pathway plays an important role in the NPs induced inhibition of tumor growth.

Zinc doped copper oxide nanocomposites (Zn-CuO NPs) is a novel doped metal nanomaterial synthesized by our group using the sonochemical method. Our previous studies have shown that Zn-CuO NPs could inhibit cancer cell proliferation by inducing apoptosis via ROS-mediated pathway. In the present study, we studied the anticancer effect of Zn-CuO NPs on human pancreatic cancer cells. MTS assay revealed that Zn-CuO NPs was able to inhibit cancer cell growth. TEM, flow cytometry and fluorescence microscope analysis showed that Zn-CuO NPs induced autophagy significantly; the number of autophagosomes increased obviously in cells treated with Zn-CuO NPs. Western blot analysis revealed that treatment with the NPs resulted in activation of AMPK/mTOR pathway in both AsPC-1 and MIA Paca-2 cells in dose dependent manners. Moreover, in the presence of AMPK activator AMPKinone, the protein level of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I increased, while the protein expression of p-AMPK, p-ULK1, Beclin-1 and LC3-II/LC3-I decreased in the presence of AMPK inhibitor Compound C. In vivo study using xenograft mice revealed that Zn-CuO NPs significantly inhibited tumor growth with low toxicity. Our study confirms that Zn-CuO NPs inhibit the tumor growth both in vitro and in vivo for pancreatic cancer. AMPK/mTOR pathway plays an important role in the NPs induced inhibition of tumor growth. [ABSTRACT FROM AUTHOR]

Diabetes mellitus, one of the major health challenges of the 21st century, is associated with numerous biomedical complications including retinopathy, neuropathy, nephropathy, cardiovascular diseases and liver disorders. To control the chronic hyperglycemic condition, the development of potential inhibitors of drug targets such as α -glucosidase and α -amylase remains a promising strategy and focus of continuous efforts. Therefore, in the present work, a concise library of isobenzofuranone derivatives (3a-q) was designed and synthesized using Suzuki-Miyaura cross-coupling approach. The biological potential of these heterocyclic compounds against carbohydrate-hydrolyzing enzymes; α -glucosidase and α -amylase, was examined. In vitro inhibitory results demonstrated that the tested isobenzofuranones were considerably more effective and potent inhibitors than the standard drug, acarbose. Compound 3d having an IC 50 value of 6.82 ± 0.02 μM was emerged as the lead candidate against α -glucosidase with ⁓127-folds strong inhibition than acarbose. Similarly, compound 3g demonstrated ⁓11-folds higher inhibition strength against α -amylase when compared with acarbose. Both compounds were tested in vivo and results demonstrate that the treatment of diabetic rats with α -amylase inhibitor show more pronounced histopathological normalization in kidney and liver than with α -glucosidase inhibitor. The Lineweaver-Burk plot revealed an uncompetitive mode of inhibition for 3d against α -glucosidase whereas compound 3g exhibited mixed inhibition against α -amylase. Furthermore, in silico molecular docking and dynamics simulations validated the in vitro data for these compounds whereas pharmacokinetics profile revealed the druglike properties of potent inhibitors. [Display omitted] • A concise library of isobenzofuranone derivatives was designed and synthesized. • Assessment of inhibitory potential against α -glucosidase and α -amylase. • Kinetics experiments were performed to elucidate the mode of action. • In vivo testing on rats to explore the effect of our lead compounds. • In silico molecular docking and dynamics simulations were performed. [ABSTRACT FROM AUTHOR]

New anticancer ruthenium(II/III) complexes [RuCl2(DMSO)2(Hapbim)] (1) and [RuCl3(DMSO) (Hapbim)] (2) (Hapbim = 2-aminophenyl benzimidazole) have been synthesized and characterized, and their chemotherapeutic potential evaluated. The interaction of the compounds with DNA was studied by both UV-Visible and fluorescence spectroscopies, revealing intercalation of both the Hapbim ligand and the Ru complexes. The in vitro cytotoxicity of the compounds was tested on human breast cancer (MCF7), human colorectal cancer (Caco2), and normal human liver cell lines (THLE-2), with compound (2) the most potent against cancer cells. The cytotoxic effect of (2) is shown to correlate with the ability of the Ru(III) complex to induce apoptosis and to cause cell-cycle arrest in the G2/M phase. Notably, both compounds were inactive in the noncancerous cell line. The anticancer effect of (2) has also been studied in an EAC (Ehrlich Ascites Carcinoma) mouse model. Significantly, the activity of the complex was more pronounced in vivo, with removal of the cancer burden at doses that resulted in only low levels of hepatotoxicity and nephrotoxicity. An apoptosis mechanism was determined by the observation of increased Bax and caspase 3 and decreased Bcl2 expression. Furthermore, (2) decreased oxidative stress and increased the levels of antioxidant enzymes, especially SOD, suggesting the enhancement of normal cell repair. Overall, compound (2) shows great potential as a chemotherapeutic candidate, with promising activity and low levels of side effects.

A three-component reaction between diamines (diaminobenzenes, diaminocyclohexanes, and piperazines), triethyl orthoformate, and diethyl phosphite was studied in some detail. In the case of 1,3- and 1,4-diamines and piperazines, products of the substitution of two amino moieties—the corresponding tetraphosphonic acids—were obtained. In the cases of 1,2-diaminobenzene, 1,2-diaminocyclohexanes and 1,2-diaminocyclohexenes, only one amino group reacted. This is most likely the result of the formation of hydrogen bonding between the phosphonate oxygen and a hydrogen of the adjacent amino group, which caused a decrease in the reactivity of the amino group. Most of the obtained compounds inhibited the proliferation of RAW 264.7 macrophages, PC-3 human prostate cancer cells, and MCF-7 human breast cancer cells, with 1, trans-7, and 16 showing broad nonspecific activity, which makes these compounds especially interesting in the context of anti-osteolytic treatment and the blocking of interactions and mutual activation of osteoclasts and tumor metastatic cells. These compounds exhibit similar activity to zoledronic acid and higher activity than incadronic acid, which were used as controls. However, studies of sheep with induced osteoporosis carried out with compound trans-7 did not support this assumption.

Cervical cancer is the fourth most common cancer that affects women, mainly through human papilloma virus (HPV) infection with high-risk HPV16 and HPV18. The present study investigated the in vitro anticancer activity and mechanism of action of a proanthocyanidin polymer-rich fraction of Stryphnodendron adstringens (F2) in cervical cancer cell lines, including HeLa (HPV18-positive), SiHa (HPV16-positive), and C33A (HPV-negative) cells, and also evaluated in vivo anticancer activity. In vitro, cell viability was determined by the MTT assay. Cell migration was determined by the wound healing assay. The mechanism of action was investigated by performing ultrastructural analysis and evaluating reactive oxygen species (ROS) production, mitochondrial metabolism, lipoperoxidation, BCL-2 family expression, caspase expression, and DNA and cell membrane integrity. In vivo activity was evaluated using the murine Ehrlich solid tumor model. F2 time- and dose-dependently reduced cell viability and significantly inhibited the migration of cervical cancer cells. HeLa and SiHa cells treated with F2 (IC50) exhibited intense oxidative stress (i.e., increase in ROS and decrease in antioxidant species) and mitochondrial damage (i.e., mitochondrial membrane potential depolarization and a reduction of intracellular levels of adenosine triphosphate). Increases in the Bax/BCL-2 ratio and caspase 9 and caspase 3 expression, were observed, with DNA damage that was sufficient to trigger mitochondria-dependent apoptosis. Cell membrane disruption was observed in C33A cells (IC50 and IC90) and HeLa and SiHa cells (IC90), indicating progress to late apoptosis/necrosis. The inhibition of ROS production by N-acetylcysteine significantly suppressed oxidative stress in all three cell lines. In vivo, F2 significantly reduced tumor volume and weight of the Ehrlich solid tumor, and significantly increased lipoperoxidation, indicating that F2 also induces oxidative stress in the in vivo model. These findings indicate that the proanthocyanidin polymer-rich fraction of S. adstringens may be a potential chemotherapeutic candidate for cancer treatment.

NhaD-type antiporters are mainly distributed in various Proteobacteria, especially in marine microorganisms and human pathogens. This distribution as well as the pathogenic properties of these strains suggest that these antiporters contribute to the regulation of high osmoregulation and are potential drug targets. Two NhaD homologs, NhaD1 and NhaD2, from the halotolerant and alkaliphilic Halomonas sp. Y2 exhibits similar, high in vitro activity, but remarkably different in vivo functions. To search for critical domains or residues involved in these differences of physiological functions, various chimeras composed of NhaD1 and NhaD2 segments were generated. Two regions at residues 1–67 and 464–492 were found to be responsible for the robust in vivo function of NhaD2, and region 464–492 is also crucial to the pH response of the antiporter. In particular, the completely abolished activity of KNabc/N463r, highly recovered activity while very weakly recovered ion resistance of the KNabc/N463r-C7 chimera, suggested that transmembrane helix (TM) XIII is crucial for the robust ion resistance of NhaD2. Using site-directed mutagenesis, seven hydrophobic residues in TM XIII were identified as key residues for the ion translocation of NhaD2. Compared with the fluorescence resonance energy transfer (FRET) profile in the wild-type NhaD2, the reduced FRET efficiency of N463r chimeras provided solid evidence for conformational changes in the N463r fusion protein and consequently verified the structural functions of TM XIII in the pH activation and physiological functions of NhaD2.

Molecular mechanism suggests that the incorporation of an antioxidant organic moiety to chromium will be a sound strategy for the synthesis of safer and more effective hypoglycemic compounds. Two Schiff base ligands were derived by condensation of isonicotinyl hydrazide with salicylaldehyde/o-hydroxyacetophenone which further yield four novel chromium(III) complexes of types [Cr(L)Cl2(H2O)] and [Cr(L)2]Cl. The ligands and complexes were characterized by analytical and spectroscopic techniques. DFT study at the basic set B3LYP and TD-SCF/6-311-G level was employed to confirm the geometry of the investigated compounds. Ligands were tested for their antioxidant activity and exhibited good antioxidant activity. Assessment of insulin-like activity of the complexes was initially performed in vitro by measuring the inhibition of α-amylase. The complex with highest in vitro activity was investigated for in vivo antidiabetic activity on the model of STZ-induced diabetic rats, which demonstrated that complex 4 significantly lowers the blood glucose level in rats. Toxicity level and antioxidant activity of the complex were also tested, which exhibit good tolerance level and antioxidant activity. Histological analysis of the pancreas of animals under investigation reveals the good condition of the pancreas treated with the complex. Ligands and complexes were also tested for antibacterial activity against Escherichia coli. [ABSTRACT FROM AUTHOR]

Amino acid (AA) sequences of 807 bioactive peptides from foods of animal origin were examined in order to correlate peptide structure with activity (antihypertensive, antioxidative, immunomodulatory, antimicrobial, hypolipidemic, antithrombotic, and opioid) and stability in vivo. Food sources, such as milk, meat, eggs, and marine products, show different frequencies of bioactive peptides exhibiting specific effects. There is a correlation of peptide structure and effect, depending on type and position of AA. Opioid peptides contain a high percentage of aromatic AA residues, while antimicrobial peptides show an excess of positively charged AAs. AA residue position is significant, with those in the first and penultimate positions having the biggest effects on peptide activity. Peptides that have activity in vivo contain a high percentage (67%) of proline residues, but the positions of proline in the sequence depend on the length of the peptide. We also discuss the influence of processing on activity of these peptides, as well as methods for predicting release from the source protein and activity of peptides. [ABSTRACT FROM AUTHOR]

Cervical cancer is the fourth most common cancer that affects women, mainly through human papilloma virus (HPV) infection with high-risk HPV16 and HPV18. The present study investigated the in vitro anticancer activity and mechanism of action of a proanthocyanidin polymer-rich fraction of Stryphnodendron adstringens (F2) in cervical cancer cell lines, including HeLa (HPV18-positive), SiHa (HPV16-positive), and C33A (HPV-negative) cells, and also evaluated in vivo anticancer activity. In vitro, cell viability was determined by the MTT assay. Cell migration was determined by the wound healing assay. The mechanism of action was investigated by performing ultrastructural analysis and evaluating reactive oxygen species (ROS) production, mitochondrial metabolism, lipoperoxidation, BCL-2 family expression, caspase expression, and DNA and cell membrane integrity. In vivo activity was evaluated using the murine Ehrlich solid tumor model. F2 time- and dose-dependently reduced cell viability and significantly inhibited the migration of cervical cancer cells. HeLa and SiHa cells treated with F2 (IC50) exhibited intense oxidative stress (i.e., increase in ROS and decrease in antioxidant species) and mitochondrial damage (i.e., mitochondrial membrane potential depolarization and a reduction of intracellular levels of adenosine triphosphate). Increases in the Bax/BCL-2 ratio and caspase 9 and caspase 3 expression, were observed, with DNA damage that was sufficient to trigger mitochondria-dependent apoptosis. Cell membrane disruption was observed in C33A cells (IC50 and IC90) and HeLa and SiHa cells (IC90), indicating progress to late apoptosis/necrosis. The inhibition of ROS production by N-acetylcysteine significantly suppressed oxidative stress in all three cell lines. In vivo, F2 significantly reduced tumor volume and weight of the Ehrlich solid tumor, and significantly increased lipoperoxidation, indicating that F2 also induces oxidative stress in the in vivo model. These findings indicate that the proanthocyanidin polymer-rich fraction of S. adstringens may be a potential chemotherapeutic candidate for cancer treatment. [ABSTRACT FROM AUTHOR]

NhaD-type antiporters are mainly distributed in various Proteobacteria, especially in marine microorganisms and human pathogens. This distribution as well as the pathogenic properties of these strains suggest that these antiporters contribute to the regulation of high osmoregulation and are potential drug targets. Two NhaD homologs, NhaD1 and NhaD2, from the halotolerant and alkaliphilic Halomonas sp. Y2 exhibits similar, high in vitro activity, but remarkably different in vivo functions. To search for critical domains or residues involved in these differences of physiological functions, various chimeras composed of NhaD1 and NhaD2 segments were generated. Two regions at residues 1-67 and 464-492 were found to be responsible for the robust in vivo function of NhaD2, and region 464-492 is also crucial to the pH response of the antiporter. In particular, the completely abolished activity of KNabc/N463r, highly recovered activity while very weakly recovered ion resistance of the KNabc/N463r-C7 chimera, suggested that transmembrane helix (TM) XIII is crucial for the robust ion resistance of NhaD2. Using site-directed mutagenesis, seven hydrophobic residues in TM XIII were identified as key residues for the ion translocation of NhaD2. Compared with the fluorescence resonance energy transfer (FRET) profile in the wild-type NhaD2, the reduced FRET efficiency of N463r chimeras provided solid evidence for conformational changes in the N463r fusion protein and consequently verified the structural functions of TM XIII in the pH activation and physiological functions of NhaD2. [ABSTRACT FROM AUTHOR]

We evaluated the in vivo efficacy of humanized exposures of cefiderocol, a novel siderophore cephalosporin, against a test panel of P. aeruginosa (PSA) previously shown to develop resistance to 2 preclinical candidate siderophores (MB-1 and SMC-3176). In the thigh infection model, the PSA bacterial density in untreated controls grew from 5.54 ± 0.23 to 8.68 ± 0.57 log10 CFU over 24 h. The humanized cefiderocol exposure resulted in >1 log10 CFU reduction in all 8 isolates, while MB-1 and SMC-3176 exhibited variable activity similar to that previously reported. Humanized exposures of cefepime and levofloxacin, acting as positive antimicrobial controls displayed activity consistent with that of the bacterial phenotypic susceptibility profiles. Cefiderocol manifested in vivo efficacy against all PSA isolates including those resistant to cefepime and levofloxacin in contrast to its predecessor siderophore compounds. These preclinical data are supportive of further evaluation of cefiderocol in the treatment of P. aeruginosa. [ABSTRACT FROM AUTHOR]

LCB01-0648 is a novel oxazolidinone compound that shows potent antibacterial activities against most Gram-positive cocci, including the multi-drug resistant Staphylococcus aureus. In this study, in vivo activity of LCB01-0699, a LCB01-0648 prodrug, against S. aureus was evaluated in comparison with that of Linezolid. The results of the systemic infection study demonstrated that LCB01-0699 was more potent than Linezolid against methicillin-susceptible and -resistant S. aureus strains. The in vivo efficacy of LCB01-0699 against methicillin-susceptible and -resistant S. aureus strains in a skin infection model showed more potent activity than Linezolid. LCB01-0699 shows potent in vivo activity against methicillin-susceptible and -resistant S. aureus strains, suggesting that LCB01-0699 would be a novel candidate for the treatment of these infectious diseases caused by S. aureus. [ABSTRACT FROM AUTHOR]

Syncarpamide 1 , a norepinephrine alkaloid isolated from the leaves of Zanthoxylum syncarpum (Rutaceae) exhibited promising antiplasmodial activities against Plasmodium falciparum with reported IC 50 values of 2.04 μM (D6 clone), 3.06 μM (W2 clone) and observed by us 3.90 μM (3D7 clone) and 2.56 μM (K1 clone). In continuation of our work on naturally occurring antimalarial compounds, synthesis of syncarpamide 1 and its enantiomer, ( R )- 2 using Sharpless asymmetric dihydroxylation as a key step has been accomplished. In order to study structure-activity-relationship (SAR) in detail, a library of 55 compounds ( 3 – 57 ), which are analogues/homologues of syncarpamide 1 were synthesized by varying the substituents on the aromatic ring, by changing the stereocentre at the C-7 and/or by varying the acid groups in the ester and/or amide side chain based on the natural product lead molecule and further assayed in vitro against 3D7 and K1 strains of P. falciparum to evaluate their antiplasmodial activities. In order to study the effect of position of functional groups on antiplasmodial activity profile, a regioisomer ( S )- 58 of syncarpamide 1 was synthesized however, it turned out to be inactive against both the strains. Two compounds, ( S )- 41 and its enantiomer, ( R )- 42 having 3,4,5-trimethoxy cinnamoyl groups as side chains showed better antiplasmodial activity with IC 50 values of 3.16, 2.28 μM (3D7) and 1.78, 2.07 μM (K1), respectively than the natural product, syncarpamide 1 . Three compounds ( S )- 13 , ( S )- 17 , ( S )- 21 exhibited antiplasmodial activities with IC 50 values of 6.39, 6.82, 6.41 μM against 3D7 strain, 4.27, 7.26, 2.71 μM against K1 strain and with CC 50 values of 147.72, 153.0, >200 μM respectively. The in vitro antiplasmodial activity data of synthesized library suggests that the electron density and possibility of resonance in both the ester and amide side chains increases the antiplasmodial activity as compared to the parent natural product 1 . The natural product syncarpamide 1 and four analogues/homologues out of the synthesized library of 55, ( S )- 41 , ( R )- 42 , ( S )- 55 and ( S )- 57 were assayed in vivo assay against chloroquine-resistant P. yoelii (N-67) strain of Plasmodium . However, none of the five molecules, 1 , ( S )- 41 , ( R )- 42 , ( S )- 55 and ( S )- 57 exhibited any promising in vivo antimalarial activity against P. yoelii (N-67) strain. Compounds 4 , 6 , 7 and 11 showed high cytotoxicities with CC 50 values of 5.87, 5.08, 6.44 and 14.04 μM, respectively. Compound 6 was found to be the most cytotoxic as compared to the standard drug, podophyllotoxin whereas compounds 4 and 7 showed comparable cytotoxicities to podophyllotoxin. [ABSTRACT FROM AUTHOR]

A series of 3-carbamate and 29-ester celastrol derivatives (compounds 1 – 26 ) were designed and synthesized. These analogues were evaluated for their cytotoxic activities against several cancer cell lines. Cytotoxicity data revealed that the properties of substituents and substitution position had important influence on cytotoxic activity. Modification of C-3 hydroxyl with size-limited groups did not reduce the activity obviously. The introduction of polarity group like piperazine could improve the solubility. Compound 23 was chosen to further evaluate anti-tumor efficacy in vivo . It showed higher inhibition rate and better safety than celastrol during in vivo experiment by intragastric administration. The preliminary antitumor studies of compound 23 in vivo showed that it might be promising for the development of new antitumor agents. [ABSTRACT FROM AUTHOR]

Background: Chagas disease is a life-threatening illness caused by Trypanosoma cruzi . The involvement of serine-/arginine-rich protein kinase in the T. cruzi life cycle is significant. Aims: To synthesize, characterize and evaluate the trypanocidal activity of diamides inspired by kinase inhibitor, SRPIN340. Material & Methods: Synthesis using a three-step process and characterization by infrared, nuclear magnetic resonance and high-resolution mass spectrometry were conducted. The selectivity index was obtained by the ratio of CC 50 /IC 50 in two in vitro models. The most active compound, 3j , was evaluated using in vitro cytokine assays and assessing in vivo trypanocidal activity. Results: 3j activity in the macrophage J774 lineage showed an anti-inflammatory profile, and mice showed significantly reduced parasitemia and morbidity at low compound dosages. Conclusion: Novel diamide is active against T. cruzi in vitro and in vivo .

Breast cancer (BrCa) remains an unmet medical need despite the revolutionary development of antibody treatments and protein kinase inhibitors. In the current study, a series of novel substituted pyridopyrazine derivatives have been rationally designed and evaluated as multi-kinase inhibitors in the PI3K pathway. The target compounds were prepared from 6-amino-2-picoline, which upon nitration and selective reduction was converted to suitably substituted 6-methyl-7-aminopyrido[2,3- b ]pyrazines. Suitable manipulation of the former amines provided the designed analogues, which were then assessed in vitro against several BrCa cell lines using the MTT cytotoxicity assay. The most potent compounds underwent evaluation in a broad spectrum of protein kinases, while their pharmacokinetic parameters were measured by LC-MS/MS. In vivo evaluation of a hit compound ( 14a ) was performed in a HER2 amplified BrCa xenograft model (HCC1954) and efficacy was determined using Western blot based phosphokinase assays and immunohistochemistry. This derivative showed low micromolar cytotoxic potency in all BrCa cell lines, a mild inhibition of the PI3Kα wild type and H1047R mutated enzyme and excellent pharmacokinetic parameters following oral and intraperitoneal administration at the designed dose of 10 mg/kg, with absence of in vivo phenotypic toxicity. Interestingly, compound 14a inhibited the growth of xenografted tumors. Analysis of excised tumors from the treated animals showed a significantly reduced population of Ki-67 positive cells, as well as downregulated levels of phosphorylated AKT, ERK1/2 and SRC compared to vehicle treated animals. Finally, the specificity of 14a was assessed in a panel of 31 kinases where a mild, but direct, inhibition of the MET receptor tyrosine kinase was observed. [ABSTRACT FROM AUTHOR]

Solanum surattense is one of the most potent plants of Solanaceae family used commonly as drug in ayurveda. Its different plant parts (stem, leaves, root and fruit) have remarkable potential against gram positive, gram negative fungal pathogenic microbes and anthelmintic, anti-convulsant, anti-hyperlipidemic, anti-malarial, anti-urolithiatic, natriuretic, anti-ulcer, wound healing, anti-asthmatic, hypoglycemic, antioxidant, hepatoprotective activity and cytotoxicity. Different activities have documented that S. surattense possesses alkaloids, saponins, steroids, tannins, flavonoids, glycosides, oleanic acid, proteins, phenolic compounds and amino acids. The aim of present study is to facilitate and to provide organised information on the pharmacological aspects of S. surattense. The variety of S. surattense constituents showed its large prospective in providing precursors for the synthesis of useful drugs and its significant medicinal potential proved it to be an important prebiotic as well. The present review therefore assists in closing the gap in knowledge by highlighting the usefulness of this underutilised plant S. surattense. [ABSTRACT FROM AUTHOR]

The design, synthesis, in vitro and in vivo evaluation of 6-substituted benzimidazole with 1, 4-disubsituted or 1, 5-disubsituted indole derivatives as novel angiotensin II receptor antagonists are outlined. Radioligand binding assays showed that several 6-substituted benzimidazole derivatives displayed high affinities binding to the angiotensin II type 1 receptor at the same order of magnitude to telmisartan. The biological evaluation on spontaneously hypertensive rats showed that 2-[4-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole-1-yl]methyl]-1 H -indol-1-yl]benzoic acid, 1c , could cause significant decrease on MBP in a dose dependent manner. Its maximal response lowered 53 mmHg of MBP at 5 mg/kg and 64 mmHg of MBP at 10 mg/kg after oral administration, and the significant antihypertensive effect lasted beyond 24 h, which was better than both losartan and telmisartan. A study designed to determine acute toxicity showed that 1c had low acute toxicity with no significant changes in the weight and no obvious untoward reactions. The encouraging results make 1c an effective and durable anti-hypertension drug candidate and deserve further investigation for therapeutic application. [ABSTRACT FROM AUTHOR]

Herein a series of 4-aminoquinolines were synthesized in an attempt to optimize and study the structural features related to LABIO-17 biological activity, a Mycobacterium tuberculosis NADH-dependent enoyl-acyl carrier protein reductase (Mt InhA) inhibitor previously identified by a virtual-ligand-screening approach. Structure-activity relationships led to novel submicromolar inhibitors of Mt InhA and potent antitubercular agents. The lead compound is 87-fold more potent as enzymatic inhibitors and 32-fold more potent against M. tuberculosis H37Rv strain in comparison with LABIO-17. These molecules were also active against multidrug-resistant strains, devoid of apparent toxicity to mammalian cells and showed favorable in vitro ADME profiles. Additionally, these compounds were active in an intracellular model of tuberculosis (TB) infection, showed no genotoxicity signals, satisfactory absorption parameters and absence of in vivo acute toxicity. Finally, treatment with selected 4-aminoquinoline for two weeks produced bacteriostatic effect in a murine model of TB. Taken together, these findings indicate that this chemical class may furnish candidates for the future development of drug-sensitive and drug-resistant tuberculosis treatments. [Display omitted] • InhA enzyme inhibition and thermodynamics of ligand binding of best candidates. • 4-aminoquinolines that inhibit in vitro Mycobacterium tuberculosis growth. • 4-aminoquinolines against drug-resistant strains of Mycobacterium tuberculosis. • High selectivity index of 4-aminoquinolines. • Bacteriostatic effect of 4-aminoquinoline in M. tuberculosis mouse infection model. [ABSTRACT FROM AUTHOR]

[Display omitted] • Zein-based matrices are formed with plasticizing ionic liquid and glycerol. • The active ingredients keep their biological activity after thermal treatment. • The release of [Lidocainium] and [Ibuprofenate] is studied under digestive conditions. • Zein matrices undergo gastric and intestinal phases without noticeable erosion. • Release kinetics are controlled by diffusion and swelling mechanisms. An in vitro approach is proposed to study the release of an Active Pharmaceutical Ingredient-Ionic Liquid (API-IL) from a natural biopolymer matrix based on zein, a maize storage protein. Zein can be processed in the molten state with 20 w% [Lidocainium][Ibuprofenate] added as API-IL also acting as plasticizer and potentially co-plasticized by glycerol. The thermal stability of the matrix is checked, as well as the in vivo biological activity of the API-IL confirming anesthetic and anti-inflammatory activities. Model tablets are thermomolded at 130 °C (∅20 mm, 0.2 mm thick) and submitted to simulated digestion based on the INFOGEST static protocol of gastrointestinal food digestion at 37 °C (2 h under gastric conditions followed by 2 h under intestinal ones). The release of the API-IL is evaluated by HPLC-UV to dissociate lidocainium, that shows a progressive release (35 % after 2 h and 60 % after 4 h digestion), from ibuprofenate, that is mainly released under intestinal conditions due to low solubility in acidic conditions. The monitoring of the tablets reveals release mechanisms based on diffusion without noticeable erosion of the matrix. These results demonstrate the interest of this thermoplastic material to provide a relevant drug delivery system. [ABSTRACT FROM AUTHOR]

• The peptide PSAIWF-NH 2 is comparable to bevacizumab in terms of activity. • The hexapeptide can be easily obtained by a simple solid-phase synthesis protocol. • The carboxyamidated analogues shows high cell viability and low cytotoxic potential. • The amount of peptide released from implants is capable of angiogenic inhibition. The search for new inhibitors of tyrosine kinase receptors involved in angiogenesis is a frequent topic in the design of antiangiogenic drugs. Michaloski and coworkers have obtained the peptide sequences PCAIWF-OH and PSAIWF-OH that showed potential inhibition of VEGF receptors. The present work describes the obtention of these peptides and their carboxyamidated analogues, which are prepared by a more efficient method. Their antiangiogenic activities were evaluated in vivo using the chicken embryo chorioallantoic membrane model. Assays with ARPE-19 cells were carried out to evaluate toxicity. PSAIWF-NH 2 showed the higher inhibition of angiogenesis, at levels comparable to the bevacizumab. This carboxyamidated analogue carrying a serine has the advantage of not undergoing dimerization and it can be obtained by a more efficient and cheaper synthetic method. Retinal cells displayed in general high cell viability in the presence of the four peptides. PSAIWF-NH 2 presented the highest angiogenic inhibition and the lowest toxicity. To evaluate the feasibility of prolonged and controlled release, PSAIWF-NH 2 was incorporated into PLGA implants. The delivery profile was characterized by two phases, initially marked by a burst of release, followed by the sustained release of lower quantities during 36 days. Peptide concentrations were kept at levels that showed angiogenic inhibition. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract: Branched peptides have been found to be useful in several research fields however their synthesis and purification is complicated. Here we present a novel and facile synthesis of tetra branched derivatives of nociceptin/orphanin FQ (N/OFQ). Three N/OFQ tetra branched derivatives were prepared using novel cores (PWT1, PWT2 and PWT3) containing a maleimido moiety. [Cys18]N/OFQ-NH2 was linked to the cores via thiol-Michael reaction characterized by high yield and purity of the desired final product. In the electrically stimulated mouse vas deferens PWT-N/OFQ derivatives mimicked the inhibitory action of the natural sequence showing similar maximal effects and 3 fold higher potencies. The NOP selective antagonist SB-612111 antagonized the effects of N/OFQ and PWT derivatives with similar pK B values (8.02–8.48). In vivo after supraspinal administration PWT2-N/OFQ stimulated food intake in mice mimicking the action of N/OFQ. Compared to the natural peptide PWT2-N/OFQ was 40 fold more potent and elicited larger effects. These findings suggest that the PWT chemical strategy can be successfully applied to biologically active peptides to generate, with unprecedented high purity and yield, tetra branched derivatives displaying an in vitro pharmacological profile similar to that of the natural sequence associated, in vivo, to increased potency and effectiveness. [Copyright &y& Elsevier]

Abstract: Matriptase is a serine protease implicated in cancer invasion and metastasis. Expression of matriptase is frequently dysregulated in human cancers and matriptase has been reported to activate latent growth factors such as hepatocyte growth factor/scatter factor, and proteases such as urokinase plasminogen activator suggesting that matriptase inhibitors could have therapeutic potential in treatment of cancer. Here we report a structure-based approach which led to the discovery of selective and potent matriptase inhibitors with benzene as central core having 1,3,5 tri-substitution pattern. X-ray crystallography of one of the potent analogs in complex with matriptase revealed strong hydrogen bonding and salt-bridge interactions in the S1 pocket, as well as strong CH–π contacts between the P2/P4 cyclohexyl and Trp215 side-chain. An additional interaction of the pendant amine at cyclohexyl with Gln175 side-chain results in substantial improvement in matriptase inhibition and selectivity against other related serine proteases. Compounds 15 and 26 showed tumor growth inhibition in a subcutaneous DU-145 prostate cancer mouse model. These compounds could be useful as tools to further explore the biology of matriptase as a drug target. [Copyright &y& Elsevier]

Abstract: Chagas disease is today one of the most important neglected diseases for its upcoming expansion to non-endemic areas and has become a threat to blood recipients in many countries. In this study, the trypanocidal activity of ten derivatives of a family of aza-scorpiand like macrocycles is evaluated against Trypanosoma cruzi in vitro and in vivo murine model in which the acute and chronic phases of Chagas disease were analyzed. The compounds 4, 3 and 1 were found to be more active against the parasite and less toxic against Vero cells than the reference drug benznidazole, 4 being the most active compound, particularly in the chronic phase. While all these compounds showed a remarkable degree of inhibition of the Fe-SOD enzyme of the epimastigote forms of T. cruzi, they produced a negligible inhibition of human CuZn-SOD and Mn-SOD from Escherichia coli. The modifications observed by 1H NMR and the amounts of excreted catabolites by the parasites after treatment suggested that the mechanism of action could be based on interactions of the side chains of the compounds with enzymes of the parasite metabolism. The ultrastructural alterations observed in treated epimastigote forms confirmed that the compounds having the highest activity are those causing the largest cell damage. A complementary histopathological analysis confirmed that the compounds tested were significantly less toxic to mammals than the reference drug. [Copyright &y& Elsevier]

Background: Because Plasmodium falciparum displays increase tolerance against the recommended artemisinin combination therapies (ACT), new classes of anti-malarial drugs are urgently required. Previously synthesized artemisinin-aminoquinoline hybrids were evaluated to ascertain whether the potent low nanomolar in vitro anti-plasmodial activity would carry over in vivo against Plasmodium vinckei. A snapshot pharmacokinetic analysis was carried out on one of the hybrids to obtain an indication of the pharmacokinetic properties of this class of anti-malarial drugs. Methods: In vitro activity of hybrids 2 and 3 were determined against the 3D7 strain of P. falciparum. Plasmodium vinckei-infected mice were treated with hybrids 1 - 3 for four days at a dosage of 0.8 mg/kg, 2.5 mg/kg, 7.5 mg/kg or 15 mg/kg intraperitoneally (ip), or orally (per os) with 2.7 mg/kg, 8.3 mg/kg, 25 mg/kg or 50 mg/kg. Artesunate was used as reference drug. A snapshot oral and IV pharmacokinetic study was performed on hybrid 2. Results: Hybrids 1 - 3 displayed potent in vivo anti-malarial activity with ED50 of 1.1, 1.4 and <0.8 mg/kg by the ip route and 12, 16 and 13 mg/kg per os, respectively. Long-term monitoring of parasitaemia showed a complete cure of mice (without recrudescence) at 15 mg/kg via ip route and at 50 mg/kg by oral route for hybrid 1 and 2, whereas artesunate was only able to provide a complete cure at 30 mg/kg ip and 80 mg/kg per os. Conclusions: These compounds provide a new class of desperately needed anti-malarial drug. Despite a short half-life and moderate oral bioavailability, this class of compounds was able to cure malaria in mice at very low dosages. The optimum linker length for anti-malarial activity was found to be a diaminoalkyl chain consisting of two carbon atoms either methylated or unmethylated. [ABSTRACT FROM AUTHOR]