Development Of New Compounds Research Articles

Microwave Assisted Synthesis, Antimicrobial and Anti-inflammatory Potential of Some Novel 1,2,4-triazole Derivatives

<p>A series of 1,2,4-triazole derivatives were synthesized under microwave irradiation and characterized by IR, 1H-NMR, and mass spectral data. Pathogenic microorganisms are causative agents for different types of serious infectious diseases. Despite advancements in medication, bacterial infections continue to be a growing problem in health care. As more and more bacteria become resistant to antibiotics used in therapy there is considerable interest in the development of new compounds with antimicrobial activity. Inflammation is a central part of the response to injury and infection in the immune system. It may become problematic if the inflammatory process continues for too long. External infections involving the skin and wound are the most frequent complications affecting humans and animals. The compounds containing a heterocyclic ring play an important role among organic compounds with biological activity used as drugs in human, veterinary medicine or as insecticides and pesticides in agriculture. The compounds were evaluated for their in antimicrobial and anti-inflammatory activity against some strains of bacteria. The pharmacological evaluation of 1,2,4-triazole derivatives revealed that, among all the compounds screened compound code 2b showed leading antibacterial activity against the selected pathogenic strains of bacteria and compound code 2e were found to have promising anti-inflammatory activity.</p>

Selective JAK1 Inhibitors for the Treatment of Atopic Dermatitis: Focus on Upadacitinib and Abrocitinib

Atopic dermatitis is a common, chronic, immune-mediated disease associated with several comorbidities. Elevated levels of T helper (Th)2, Th22, and also some Th1 and Th17 cytokines are found in atopic dermatitis skin lesions. Similar to psoriasis, there is a tendency towards increased use of more targeted therapies. However, there are still several unmet needs in the treatment of atopic dermatitis concerning long-term efficacy, tolerability, safety, route of administration, and cost. The increased knowledge of atopic dermatitis pathogenesis and the role of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways hasallowed the development of new compounds to inhibit this intracellular signaling pathway implicated in atopic dermatitis-related immune responses. Currently, JAK inhibitors are an important focus of therapeutic research for atopic dermatitis. Upadacitinib and abrocitinib are oral small molecules that inhibit the JAK/STAT pathway by selectively blocking JAK1. Data from phase II and III trials are encouraging, revealing that JAK1 inhibitors are effective and well-tolerated agents for moderate-to-severe atopic dermatitis. Selective JAK1 inhibitors may represent an important therapeutic option to be included in the treatment algorithm of atopic dermatitis, owing to oral administration and a favorable safety and tolerability profile. In this article, we review the current evidence on the efficacy and safety of oral selective JAK1 inhibitors for the treatment of atopic dermatitis.

Comparative chemometric and quantitative structure-retention relationship analysis of anisotropic lipophilicity of 1-arylsuccinimide derivatives determined in high-performance thin-layer chromatography system with aprotic solvents

Numerous structurally different amides and imides including succinimide derivatives exhibit diverse bioactive potential. The development of new compounds requires rationalization in the design in order to provide structural changes that guarantee favorable physico-chemical properties, pharmacological activity and safety. In the present research, a comprehensive study with comparison of the chromatographic lipophilicity and other physico-chemical properties of five groups of 1-arylsuccinimide derivatives was conducted. The chemometric analysis of their physico-chemical properties was carried out by using unsupervised (hierarchical cluster analysis and principal component analysis) and supervised pattern recognition methods (linear discriminant analysis), while the correlations between the in silico molecular features and chromatographic lipophilicity were examined applying linear and non-linear Quantitative Structure-Retention Relationship (QSRR) approaches. The main aim of the conducted research was to determine similarities and dissimilarities among the studied 1-arylsuccinimides, to point out the molecular features which have significant influence on their lipophilicity, as well as to establish high-quality QSRR models which can be used in prediction of chromatographic lipophilicity of structurally similar 1-arylsuccinimides. This study is a continuation of analysis and determination of the physico-chemical properties of 1-arylsuccinimides which could be important guidelines in further in vitro and eventually in vivo studies of their biological potential.

An influenza A hemagglutinin small-molecule fusion inhibitor identified by a new high-throughput fluorescence polarization screen

Influenza hemagglutinin (HA) glycoprotein is the primary surface antigen targeted by the host immune response and a focus for development of novel vaccines, broadly neutralizing antibodies (bnAbs), and therapeutics. HA enables viral entry into host cells via receptor binding and membrane fusion and is a validated target for drug discovery. However, to date, only a very few bona fide small molecules have been reported against the HA. To identity new antiviral lead candidates against the highly conserved fusion machinery in the HA stem, we synthesized a fluorescence-polarization probe based on a recently described neutralizing cyclic peptide P7 derived from the complementarity-determining region loops of human bnAbs FI6v3 and CR9114 against the HA stem. We then designed a robust binding assay compatible with high-throughput screening to identify molecules with low micromolar to nanomolar affinity to influenza A group 1 HAs. Our simple, low-cost, and efficient in vitro assay was used to screen H1/Puerto Rico/8/1934 (H1/PR8) HA trimer against ∼72,000 compounds. The crystal structure of H1/PR8 HA in complex with our best hit compound F0045(S) confirmed that it binds to pockets in the HA stem similar to bnAbs FI6v3 and CR9114, cyclic peptide P7, and small-molecule inhibitor JNJ4796. F0045 is enantioselective against a panel of group 1 HAs and F0045(S) exhibits in vitro neutralization activity against multiple H1N1 and H5N1 strains. Our assay, compound characterization, and small-molecule candidate should further stimulate the discovery and development of new compounds with unique chemical scaffolds and enhanced influenza antiviral capabilities.

Synthesis, investigation of biological effects and in silico studies of new benzimidazole derivatives as aromatase inhibitors.

Inhibition of aromatase enzymes is very important in the prevention of estrogen-related diseases and the regulation of estrogen levels. Aromatase enzyme is involved in the final stage of the biosynthesis of estrogen, in the conversion of androgens to estrogen. The development of new compounds for the inhibition of aromatase enzymes is an important area for medicinal chemists in this respect. In the present study, new benzimidazole derivatives have been designed and synthesized which have reported anticancer activity in the literature. Their anticancer activity was evaluated against human A549 and MCF-7 cell lines by MTT assay. In the series, concerning MCF-7 cell line, the most potent compounds were the 4-benzylpiperidine derivatives 2c, 2g, and 2k with IC50 values of 0.032±0.001, 0.024±0.001, and 0.035±0.001µM, respectively, compared to the reference drug cisplatin (IC50=0.021±0.001µM). Then, these compounds were subject to further in silico aromatase enzyme inhibition assays to determine the possible binding modes and interactions underlying their activity. Thanks to molecular docking studies, the effectiveness of these compounds against aromatase enzyme could be simulated. Consequently, it has been found that these compounds can be settled very properly to the active site of the aromatase enzyme.

Vorinostat is genotoxic and epigenotoxic in the mouse bone marrow cells at the human equivalent doses

Vorinostat was approved as the first histone deacetylase inhibitor for the management of cutaneous T cell lymphoma. However, it’s in vivo genetic and epigenetic effects on non-cancerous cells remain poorly understood. As genetic and epigenetic changes play a critical role in the pathogenesis of carcinogenesis, we investigated whether vorinostat induces genetic and epigenetic alterations in mouse bone marrow cells. Bone marrow cells were isolated 24 h following the last oral administration of vorinostat at the doses of 25, 50, or 100 mg/kg/day for five days (approximately equal to the recommended human doses). The cells were then used to assess clastogenicity and aneugenicity by the micronucleus test complemented by fluorescence in situ hybridization assay; DNA strand breaks, oxidative DNA strand breaks, and DNA methylation by the modified comet assay; apoptosis by annexin V/PI staining analysis and the occurrence of the hypodiploid DNA content; and DNA damage/repair gene expression by polymerase chain reaction (PCR) Array. The expression of the mRNA transcripts were also confirmed by real-time PCR and western blot analysis. Vorinostat caused structural chromosomal damage, numerical chromosomal abnormalities, DNA strand breaks, oxidative DNA strand breaks, DNA hypomethylation, and programed cell death in a dose-dependent manner. Furthermore, the expression of numerous genes implicated in DNA damage/repair were altered after vorinostat treatment. Accordingly, the genetic/epigenetic mechanism(s) of action of vorinostat may play a role in its carcinogenicity and support the continued study and development of new compounds with lower toxicity.

Development of a Molecularly Imprinted Sensing Material for Antibiotics Detection

Introduction Antibiotic detection has become a major issue in many fields such as water analysis, food control, health, etc. Besides the immediate dangers, the spread of antibiotics everywhere provokes the phenomenon of bacterial resistance which, on the long run, will cause health issues. Indeed, the excessive use of antibiotics allows the bacteria to mutate and thus develop resistance, requiring the development of new compounds. This work aims to develop and characterize a sensing material to detect multiple antibiotics in liquid phase using various methods. The idea is to conceive low power sensors or even disposable sensors. Therefore, sensors should be low cost and compatible for mass production. The most interesting sensitive materials seem to be molecularly imprinted polymers (also called MIP) using conductive polymers [1],[2]. Synthesis of the MIP Polypyrrole (PPy) is chosen as conductive polymer to be molecularly imprinted. Pyrrole (Py) is used as the cross-linker and pyrrole-3-carboxylic acid as the functional monomer, to obtain chemical interactions between polymer and the target molecule (also called “template”). The synthesis is performed in-situ (also called bulk polymerization) in aqueous media by mixing the target molecule, the functional monomer and the cross-linker with the oxidizer, ammonium persulfate (APS), while pH value is set to around 2.2, well below the template’s pKa to allow better interactions between monomers and the template. While oxidative polymerization takes place, temperature is kept at 30 °C, for 2 hours. The polymer is deposited everywhere in the reactor, and also on the substrates used to get the sensor.The next step, so-called extraction, consists in removing the template from the polymer. It is performed by using a solution of methanol and HCl (9:1) wherein substrates are immersed for 2 hours [3]. Then, substrates are stored in PBS (phosphate buffered saline) solution before being tested. Non-Imprinted Polymers (NIP) are also synthetized following the same steps, except that the template is not present during the synthesis. Measurement methods Polymerization has been performed on various substrates allowing to use multiple sensing methods to explore as much path as possible. Up to now, sensors had been performed and tested on chemoresistive plastic IDE sensors to perform impedimetric measurements, on quartz crystal microbalance substrates to perform mass variation measurements and on glass slide to perform UV/VIS/NIR absorbance measurements (the ultimate goal is to use the sensing material on optical fibers), as shown on Fig.1. Results and Conclusions Sensors are tested in PBS 0.5x solution (half the usual concentration). After the extraction step carried out on the various substrates, detection is performed by adding the target antibiotic into the PBS solution. Fig. 2 shows impedance measurements and this parameter grows nearly linearly as soon as we add a dozen ppb of the antibiotic. Fig.3 shows that for the same measurement method, the NIP nearly doesn’t react when we add the template, which means that the imprinting is functional and significantly increases the performance of the sensor. Fig. 4 and Fig. 5 show the evolution of the NIR spectrum of the sensing layers after contact with the antibiotic, for the MIP ad NIP, respectively. This method exhibits some limitation with a saturation above 50 ppb. Fig.6 shows the mass evolution on a quartz microbalance of the sensitive layer in contact with the target antibiotic and an interferent with the same concentrations to show the sensor specificity. The response shown to the interferent is quite weak in comparison with the one corresponding to the target molecule. In conclusion, the sensors were found to be able to detect concentrations of approximately 15 ppb and are close to the detection limits of conventional methods (10 ppb). In addition, they have proven their specificity to the target molecule by showing no reaction when exposed to the usual interferents. We showed that the MIP is suitable for both impedimetric sensors as well as for optical sensors (optical fibers or dipsticks for instance).

Repurposing a platelet aggregation inhibitor ticagrelor as an antimicrobial against Clostridioides difficile

Drug resistance in Clostridioides difficile becomes a public health concern worldwide, especially as the hypervirulent strains show decreased susceptibility to the first-line antibiotics for C. difficile treatment. Therefore, the simultaneous discovery and development of new compounds to fight this pathogen are urgently needed. In order to determinate new drugs active against C. difficile, we identified ticagrelor, utilized for the prevention of thrombotic events, as exhibiting potent growth-inhibitory activity against C. difficile. Whole-cell growth inhibition assays were performed and compared to vancomycin and metronidazole, followed by determining time-kill kinetics against C. difficile. Activities against biofilm formation and spore germination were also evaluated. Leakage analyses and electron microscopy were applied to confirm the disruption of membrane structure. Finally, ticagrelor’s ability to synergize with vancomycin and metronidazole was determined using checkerboard assays. Our data showed that ticagrelor exerted activity with a MIC range of 20–40 µg/mL against C. difficile. This compound also exhibited an inhibitory effect on biofilm formation and spore germination. Additionally, ticagrelor did not interact with vancomycin nor metronidazole. Our findings revealed for the first time that ticagrelor could be further developed as a new antimicrobial agent for fighting against C. difficile.

Neonicotinoid and sulfoximine pesticides differentially impair insect escape behavior and motion detection

Insect nervous systems offer unique advantages for studying interactions between sensory systems and behavior, given their complexity with high tractability. By examining the neural coding of salient environmental stimuli and resulting behavioral output in the context of environmental stressors, we gain an understanding of the effects of these stressors on brain and behavior and provide insight into normal function. The implication of neonicotinoid (neonic) pesticides in contributing to declines of nontarget species, such as bees, has motivated the development of new compounds that can potentially mitigate putative resistance in target species and declines of nontarget species. We used a neuroethologic approach, including behavioral assays and multineuronal recording techniques, to investigate effects of imidacloprid (IMD) and the novel insecticide sulfoxaflor (SFX) on visual motion-detection circuits and related escape behavior in the tractable locust system. Despite similar LD50 values, IMD and SFX evoked different behavioral and physiological effects. IMD significantly attenuated collision avoidance behaviors and impaired responses of neural populations, including decreases in spontaneous firing and neural habituation. In contrast, SFX displayed no effect at a comparable sublethal dose. These results show that neonics affect population responses and habituation of a visual motion detection system. We propose that differences in the sublethal effects of SFX reflect a different mode of action than that of IMD. More broadly, we suggest that neuroethologic assays for comparative neurotoxicology are valuable tools for fully addressing current issues regarding the proximal effects of environmental toxicity in nontarget species.

In Silico Insights on GD2 : A Potential Target for Pediatric Neuroblastoma.

Originating from the abnormal growth of neuroblasts, pediatric neuroblastoma affects the age group below 15 years. It is an aggressive heterogenous cancer with a high morbidity rate. Biological marker GD2 synthesised by the GD2 gene acts as a powerful predictor of neuroblastoma cells. GD2 gangliosides are sialic acid-containing glycosphingolipids. Differential expression during brain development governs the function of the GD2. The present study explains the interaction of the GD2 with its established inhibitors and discovers the compound having a high binding affinity against the target protein. Technically, during the development of new compounds through docking studies, the best drug among all pre-exist inhibitors was filtered. Hence in reference to the best docked compound, the study proceeded further. The In silico approach provides a platform to determine and establish potential inhibitor against GD2 in Pediatric neuroblastoma. The 3D structure of GD2 protein was modelled by homology base fold methods using Smith-Watermans' Local alignment. A total of 18 established potent compounds were subjected to molecular docking and Etoposide (CID: 36462) manifested the highest affinity. The similarity search presented 336 compounds similar to Etoposide. Through virtual screening, the compound having PubChem ID 10254934 showed a better affinity towards GD2 than the established inhibitor. The comparative profiling of the two compounds based on various interactions such as H-bond interaction, aromatic interactions, electrostatic interactions and ADMET profiling and toxicity studies were performed using various computational tools. The docking separated the virtual screened drug (PubChemID: 10254934) from the established inhibitor with a better re-rank score of -136.33. The toxicity profile of the virtual screened drug was also lesser (less lethal) than the established drug. The virtual screened drug was observed to be bioavailable as it does not cross the blood-brain barrier. Conclusively, the virtual screened compound obtained in the present investigation is better than the established inhibitor and can be further augmented by In vitro analysis, pharmacodynamics and pharmacokinetic studies.

Ab Initio Many-Body Perturbation Theory Calculations of the Electronic and Optical Properties of Cyclometalated Ir(III) Complexes

Cyclometalated Ir(III) compounds are the preferred choice as organic emitters in organic light-emitting diodes. In practice, the presence of the transition metal surrounded by carefully designed ligands allows fine-tuning of the emission frequency as well as good efficiency of the device. To support the development of new compounds, experimental measurements are generally compared with absorption and emission spectra obtained from ab initio calculations. The standard approach for these calculations is time-dependent density functional theory (TDDFT) with a hybrid exchange-correlation functional like B3LYP. Because of the size of these compounds, the application of more complex quantum chemistry approaches can be challenging. In this work, we used many-body perturbation theory approaches, in particular the GW approximation with the Bethe-Salpeter equation (BSE) implemented in Gaussian basis sets, to calculate the quasiparticle properties and the absorption spectra of six cyclometalated Ir(III) complexes, going beyond TDDFT. In the presented results, we compared standard TDDFT simulations with BSE calculations performed on top of perturbative G0W0 and accounting for eigenvalue self-consistency. Moreover, in order to investigate in detail the effect of the DFT starting point, we concentrated on Ir(ppy)3 and performed GW-BSE simulations starting from different DFT exchange-correlation potentials.

In vitro and in vivo antimalarial activity of the volatile oil of Cyperus articulatus (Cyperaceae)

ABSTRACT Malaria is a disease of global tropical distribution, being endemic in more than 90 countries and responsible for about 212 million cases worldwide in 2016. To date, the strategies used to eradicate this disease have been ineffective, without specific preventive measures such as vaccines. Currently, the existing therapeutic arsenal is limited and has become ineffective against the expansion of artemisinin-resistant Plasmodium, demonstrating the need for studies that would allow the development of new compounds against this disease. In this context, we studied the volatile oil obtained from rhizomes of Cyperus articulatus (VOCA), a plant species commonly found in the Amazon region and popularly used as a therapeutic alternative for the treatment of malaria, in order to confirm its potential as an antimalarial agent by in vitro and in vivo assays. We cultured Plasmodium falciparum W2 (chloroquine-resistant) and 3D7 (chloroquine-sensitive) strains in erythrocytes and exposed them to VOCA at different concentrations in 96-well microplates. In vivo antimalarial activity was tested in BALB/c mice inoculated with approximately 106 erythrocytes infected with Plasmodium berghei. VOCA showed a high antimalarial potential against the two P. falciparum strains, with IC50 = 1.21 μg mL-1 for W2 and 2.30 μg mL-1 for 3D7. VOCA also significantly reduced the parasitemia and anemia induced by P. berghei in mice. Our results confirmed the antimalarial potential of the volatile oil of Cyperus articulatus.

Dissecting the Anticancer Mechanism of Trifluoperazine on Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with almost no curative chemotherapeutic treatment. Besides the development of new compounds, repurposing of approved drugs to treat cancer, alone or in combination, has become an attractive strategy, showing many therapeutic and economic advantages. However, it is necessary to improve our knowledge about the mechanism of cell death elicited by approved drugs itself, but also to rationally develop more powerful multidrug treatments. In this work, we focus our attention on determining the mechanism promoting cell death following trifluoperazine (TFP) treatment, which is an antipsychotic drug with strong anticancer activity in PDAC. We demonstrate that TFP induces cell death by apoptosis and necroptosis, which can be partially inhibited by Z-VAD-FMK as well as necrostatin-1, respectively. This cell death promotion is triggered by a poor ATP content, observed in TFP-treated cells as a consequence of a dramatic decrease in OXPHOS metabolism due to mitochondrial stress. Remarkably, mitochondrial homeostasis was seriously affected, and a loss of mitochondrial membrane potential and ROS overproduction was observed. Moreover, this mitochondrial stress was coupled with an ER stress and the activation of the endoplasmic-reticulum-associated protein degradation (ERAD) and the unf olded protein response (UPR) pathways. We took advantage of this information and inhibited this process by using the proteasome inhibitors MG-132 or bortezomib compounds in combination with TFP and found a significant improvement of the anticancer effect of the TFP on primary PDAC-derived cells. In conclusion, this study not only uncovers the molecular mechanisms that are triggered upon TFP-treatment but also its possible combination with bortezomib for the future development of therapies for pancreatic cancer.

Targeting Cancer Resistance via Multifunctional Gold Nanoparticles.

Resistance to chemotherapy is a major problem facing current cancer therapy, which is continuously aiming at the development of new compounds that are capable of tackling tumors that developed resistance toward common chemotherapeutic agents, such as doxorubicin (DOX). Alongside the development of new generations of compounds, nanotechnology-based delivery strategies can significantly improve the in vivo drug stability and target specificity for overcoming drug resistance. In this study, multifunctional gold nanoparticles (AuNP) have been used as a nanoplatform for the targeted delivery of an original anticancer agent, a Zn(II) coordination compound [Zn(DION)2]Cl2 (ZnD), toward better efficacy against DOX-resistant colorectal carcinoma cells (HCT116 DR). Selective delivery of the ZnD nanosystem to cancer cells was achieved by active targeting via cetuximab, NanoZnD, which significantly inhibited cell proliferation and triggered the death of resistant tumor cells, thus improving efficacy. In vivo studies in a colorectal DOX-resistant model corroborated the capability of NanoZnD for the selective targeting of cancer cells, leading to a reduction of tumor growth without systemic toxicity. This approach highlights the potential of gold nanoformulations for the targeting of drug-resistant cancer cells.

TRIM59 inhibits porcine reproductive and respiratory syndrome virus (PRRSV)-2 replication in vitro

Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV), has ranked among the major economically significant pathogen in the global swine industry. The PRRSV nonstructural protein (nsp)11 possesses nidovirus endoribonuclease (NendoU) activity, which is important for virus replication and suppression of the host innate immunity system. Recent proteomic study found that TRIM59 (tripartite motif-containing 59) interacted with the nsp11, albeit the exact role it plays in PRRSV infection remains enigmatic. Herein, we first confirmed the interaction between nsp11 and TRIM59 in co-transfected HEK293T cells and PRRSV-infected pulmonary alveolar macrophages (PAMs). The interacting domains between TRIM59 and nsp11 were further determined to be the N-terminal RING domain in TRIM59 and the C-terminal NendoU domain in nsp11, respectively. Moreover, we reported that overexpression of TRIM59 inhibited PRRSV infection in Marc-145 cells. Conversely, small interfering RNA (siRNA) depletion of TRIM59 resulted in enhanced production of PRRSV in PAMs. Together, these data add TRIM59 as a crucial antiviral component against PRRSV and provide new insights for development of new compounds to reduce PRRSV infection.

Diplatin, a Novel and Low-Toxicity Anti-Lung Cancer Platinum Complex, Activation of Cell Death in Tumors via a ROS/JNK/p53-Dependent Pathway, and a Low Rate of Acquired Treatment Resistance.

Background: Platinum-based drugs prevail as the main treatment of lung cancer; this is caused by their relative effectiveness despite known side effects, such as neurotoxicity. The risk reward of the treatment and side effects is confronted when dosage is considered and when resistance to treatment develops. Development of new compounds that improve effectiveness and safety profiles addresses this ongoing need in clinical practice. Objectives: The novel water-soluble platinum complex, diplatin, was synthesized, and its antitumor potency and toxicology profile were evaluated in murine xenograft tumor models and in lung cancer cell lines. Methods: The effects of diplatin, cisplatin (DDP), and carboplatin (CBP) on the viability of nine lung tumor cell lines and one normal human lung epithelial cell line were evaluated using the MTT assay. Therapeutic index was calculated as LD50/ED50 to identify and compare the ideal therapeutic windows of the above compounds. Diplatin’s antitumor effects were assessed in lung xenograft tumors of nude mice; molecular mechanisms of therapeutic effects were identified. Results: Diplatin had desirable IC50 compared to CBP in a variety of cultured tumor cells, notably lung tumor cells. In the mouse xenograft lung tumor, diplatin led to a substantially improved therapeutic index when compared to the effects of DDP and CBP. Importantly, diplatin inhibited the growth of DDP-resistant lung tumor cells. Diplatin’s mode of action was characterized to be through cell cycle arrest in the G2/M phase and induction of lung tumor apoptosis via ROS/JNK/p53-mediated pathways. Conclusion: Diplatin was observed to have antitumor effects in mice with both greater potency and safety compared with DDP and CBP. These observations indicate that diplatin is promising as a potential treatment in future clinical applications.

Contract Research Organization (CRO): An Important Partner to Biotechnological and Pharmaceutical Companies

With the ever increasing Research and Development cost for the pharmaceutical industries, the cost of bringing a drug to market was increasing drastically. The funds for drug development was drying up and thus to maintain a healthy profit margin , the pharmaceutical companies have adopted to frame out research and development (R&D) to Contract Research Organizations (CRO’s). The CRO’s have become an important partner to biotechnological and pharmaceutical companies, in the development of new compounds and at the same time in drug registration also it has extended its hands. Out of 20, 19 pharmaceutical companies have invested in emerging markets like China, India, Russia and Latin America since clinical research is accessible to these markets due to adoption of ICH and GCPs guidelines. The traditional nature of CRO’s have changed and they will develop into a formidable industry in near future.

Room temperature semiconductor detectors for nuclear security

Preventing radioactive sources from being used for harmful purposes is a global challenge. A requirement for solving the challenge is developing radiation detectors that are efficient, sensitive, and practical. Room temperature semiconductor detectors (RTSDs) are an important class of gamma-ray sensors because they can generate high-resolution gamma-ray spectra at ambient operating temperatures. A number of diverse and stringent requirements must be met for semiconducting materials to serve as sensors in RTSD spectrometers, which limits the number of candidates of interest that receive attention and undergo focused research and development efforts. Despite this, the development of new compounds for sensors in RTSDs is a thriving research field, and a number of materials with stunning potential as RTSD materials have emerged within the last decade. In this perspective, the state of the art in RTSD materials is examined, and emerging semiconducting compounds are reviewed. The highly developed CdTe, CdZnTe, HgI2, and TlBr are first discussed to highlight the potential that can emerge from RTSD compounds in advanced stages of technological development. Thereafter, emerging compounds are reviewed by class from chalcogenides, iodides and chalcohalides, and organic-inorganic hybrid compounds. This work provides both a compilation of the physical and electronic properties of the emerging RTSD candidates and a perspective on the importance of material properties for the future of compounds that can transform the field of radiation detection science.

Old Antiprotozoal Drugs: Are They Still Viable Options for Parasitic Infections or New Options for Other Diseases?

Parasitic diseases, caused by helminths (ascariasis, hookworm, trichinosis, and schistosomiasis) and protozoa (chagas, leishmaniasis, and amebiasis), are considered a serious public health problem in developing countries. Additionally, there is a limited arsenal of anti-parasitic drugs in the current pipeline and growing drug resistance. Therefore, there is a clear need for the discovery and development of new compounds that can compete and replace these drugs that have been controlling parasitic infections over the last decades. However, this approach is highly resource- intensive, expensive and time-consuming. Accordingly, a drug repositioning strategy of the existing drugs or drug-like molecules with known pharmacokinetics and safety profiles is alternatively being used as a fast approach towards the identification of new treatments. The artemisinins, mefloquine, tribendimidine, oxantel pamoate and doxycycline for the treatment of helminths, and posaconazole and hydroxymethylnitrofurazone for the treatment of protozoa are promising candidates. Therefore, traditional antiprotozoal drugs, which were developed in some cases decades ago, are a valid solution. Herein, we review the current status of traditional anti-helminthic and antiprotozoal drugs in terms of drug targets, mode of action, doses, adverse effects, and parasite resistance to define their suitability for repurposing strategies. Current antiparasitic drugs are not only still viable for the treatment of helminth and protozoan infections but are also important candidates for new pharmacological treatments.

Use of GC\u2013MS based metabolic fingerprinting for fast exploration of fungicide modes of action

BackgroundThe widespread occurrence of fungicide resistance in fungal plant pathogens requires the development of new compounds with different mode(s) of action (MOA) to avoid cross resistance. This will require a rapid method to identify MOAs.ResultsHere, gas chromatography–mass spectrometry (GC–MS) based metabolic fingerprinting was used to elucidate the MOAs of fungicides. Botrytis cinerea, an important pathogen of vegetables and flowers, can be inhibited by a wide range of chemical fungicides with different MOAs. A sensitive strain of B. cinerea was exposed to EC50 concentrations of 13 fungicides with different known MOAs and one with unknown MOA. The mycelial extracts were analyzed for their “metabolic fingerprint” using GC–MS. A comparison among the GC–MS vector’ profiles of cultures treated with fungicides were performeded. A model based on hierarchical clustering was established which allowed these antifungal compounds to be distinguished and classified coinciding with their MOAs. Thus, metabolic fingerprinting represents a rapid, convenient, and information-rich method for classifying the MOAs of antifungal substances. The biomarkers of fungicide MOAs were also established by an analysis of variance and included succinate for succinate dehydrogenase inhibitors and cystathionine for methionine synthesis inhibitors. Using the metabolic model and the common perturbation of metabolites, the new fungicide SYP-14288 was identified as having the same MOA as fluazinam.ConclusionThis study provides a comprehensive database of the metabolic perturbations of B. cinerea induced by diverse MOA inhibitors and highlights the utility of metabolic fingerprinting for defining MOAs, which will assist in the development and optimization of new fungicides.