1-Methyl-1H-pyrazole-5-carboxamide Derivatives Exhibit Unexpected Acute Mammalian Toxicity.

A series of 1-methyl-1H-pyrazole-5-carboxamides were synthesized as potent inhibitors of the parasitic nematode of sheep, Haemonchus contortus. These compounds did not show overt cytotoxicity to a range of mammalian cell lines under standard in vitro culture conditions, had high selectivity indices, and were progressed to an acute toxicity study in a rodent model. Strikingly, acute toxicity was observed in mice. Experiments measuring cellular respiration showed a dose-dependent inhibition of mitochondrial respiration. Under these conditions, potent cytotoxicity was observed for these compounds in rat hepatocytes suggesting that the potent acute mammalian toxicity of this chemotype is most likely associated with respiratory inhibition. In contrast, parasite toxicity was not correlated to acute toxicity or cytotoxicity in respiring cells. This paper highlights the importance of identifying an appropriate in vitro predictor of in vivo toxicity early on in the drug discovery pipeline, in particular assessment for in vitro mitochondrial toxicity.

Novel 1-Methyl-1 H-pyrazole-5-carboxamide Derivatives with Potent Anthelmintic Activity.

A phenotypic screen of two different libraries of small molecules against the motility and development of the parasitic nematode Haemonchus contortus led to the identification of two 1-methyl-1 H-pyrazole-5-carboxamide derivatives. Medicinal chemistry optimization targeted modifications of the left-hand side, middle section, and right-hand side of the hybrid structure of these two hits to elucidate the structure-activity relationship (SAR). Initial SAR around these hits allowed for the iterative and directed assembly of a focused set of 30 analogues of their hybrid structure. Compounds 10, 17, 20, and 22 were identified as the most potent compounds, inhibiting the development of the fourth larval (L4) stage of H. contortus at sub-nanomolar potencies while displaying strong selectivity toward the parasite when tested in vitro against the human MCF10A cell line. In addition, compounds 9 and 27 showed promising activity against a panel of other parasitic nematodes, including hookworms and whipworms.

Structure-Activity Relationship Studies of Tolfenpyrad Reveal Subnanomolar Inhibitors of Haemonchus contortus Development.

Recently, we have discovered that the registered pesticide, tolfenpyrad, unexpectedly and potently inhibits the development of the L4 larval stage of the parasitic nematode Haemonchus contortus with an IC50 value of 0.03 µM while displaying good selectivity, with an IC50 of 37.9 µM for cytotoxicity. As a promising molecular template for medicinal chemistry optimization, we undertook anthelmintic structure-activity relationships for this chemical. Modifications of the left-hand side (LHS), right-hand side (RHS), and middle section of the scaffold were explored to produce a set of 57 analogues. Analogues 25, 29, and 33 were shown to be the most potent compounds of the series, with IC50 values at a subnanomolar level of potency against the chemotherapeutically relevant fourth larval (L4) stage of H. contortus. Selected compounds from the series also showed promising activity against a panel of other different parasitic nematodes, such as hookworms and whipworms.

Optimization of Novel 1-Methyl-1 H-Pyrazole-5-carboxamides Leads to High Potency Larval Development Inhibitors of the Barber's Pole Worm.

A phenotypic screen of a diverse library of small molecules for inhibition of the development of larvae of the parasitic nematode Haemonchus contortus led to the identification of a 1-methyl-1 H-pyrazole-5-carboxamide derivative with an IC50 of 0.29 µM. Medicinal chemistry optimization targeted modifications on the left-hand side (LHS), middle section, and right-hand side (RHS) of the scaffold in order to elucidate the structure-activity relationship (SAR). Strong SAR allowed for the iterative and directed assembly of a focus set of 64 analogues, from which compound 60 was identified as the most potent compound, inhibiting the development of the fourth larval (L4) stage with an IC50 of 0.01 µM. In contrast, only 18% inhibition of the mammary epithelial cell line MCF10A viability was observed, even at concentrations as high as 50 µM.

Antimalarial Inhibitors Targeting Serine Hydroxymethyltransferase (SHMT) with in Vivo Efficacy and Analysis of their Binding Mode Based on X-ray Cocrystal Structures.

Target-based approaches toward new antimalarial treatments are highly valuable to prevent resistance development. We report several series of pyrazolopyran-based inhibitors targeting the enzyme serine hydroxymethyltransferase (SHMT), designed to improve microsomal metabolic stability and to identify suitable candidates for in vivo efficacy evaluation. The best ligands inhibited Plasmodium falciparum (Pf) and Arabidopsis thaliana (At) SHMT in target assays and PfNF54 strains in cell-based assays with values in the low nanomolar range (3.2-55 nM). A set of carboxylate derivatives demonstrated markedly improved in vitro metabolic stability (t1/2 > 2 h). A selected ligand showed significant in vivo efficacy with 73% of parasitemia reduction in a mouse model. Five new cocrystal structures with PvSHMT were solved at 2.3-2.6 Å resolution, revealing a unique water-mediated interaction with Tyr63 at the end of the para-aminobenzoate channel. They also displayed the high degree of conformational flexibility of the Cys364-loop lining this channel.

Non-resolving pneumonia: A rare presentation of progressive disseminated histoplasmosis.

Histoplasmosis, a fungal disease caused by Histoplasma capsulatum, is endemic in North and South America. Except few scattered cases, the disease is considered to be a non-entity in India. Furthermore, disseminated histoplasmosis is rare in the immunocompetent individuals. We report an adolescent boy presenting as middle lobe consolidation which did not respond to antibiotics. His condition deteriorated with the development of mediastinal lymphadenopathy, pleural effusion and hepatosplenomegaly. A diagnosis of progressive disseminated histoplasmosis was established by his clinical findings as well as bronchoscopic biopsy, transbronchial needle aspiration cytology and bronchoalveolar lavage culture demonstrating Histoplasma capsulatum. The case represents a unique example of progressive disseminated histoplasmosis in an immunocompetent individual in India.

Role of common investigations in aetiological evaluation of exudative pleural effusions.

BACKGROUND: Pleural effusion is a common problem encountered in daily practice. To Establish aetiology of exudative effusions is a diagnostic challenge to general practitioners and even to pulmonologists especially in resource poor government hospitals with lack of investigations like thoracoscopy. Some recent studies had shown that around 2% of patients remained undiagnosed even after these investigations. AIMS AND OBJECTIVE: To evaluate the role of the commonly available investigations such as pleural fluid study, blind pleural biopsy, sputum examination, CT scan thorax, bronchoscopy in the aetiological evaluation of exudative effusions and to ascertain the proportion of cases which remain undiagnosed after all the above investigations. MATERIAL AND METHODS: This was a prospective single-centred cross-sectional study carried out at the NRS Medical College, Kolkata, India from February 2008 to February 2013 which included 568 patients of exudative pleural effusions. We performed commonly available procedures like pleural fluid study, blind pleural biopsy, sputum examination, CT scan thorax, bronchoscopic procedures to the diagnosis. RESULTS: Total number of patients studied were 568. Tuberculosis was the most common cause (54.57%) followed by malignancy (28.17%), empyema (10.56%), parapneumonic effusion (5.28%) and others. Carcinoma of the lung was the commonest cause of malignant effusions and bronchoscopic biopsy was given the highest yield of histological diagnosis (84.6%) followed by CT guided FNAC (77.6%) and pleural fluid cytology (55%). Highest yield to diagnose tubercular effusion was found in lymph node FNAC (81.5%) followed by pleural biopsy (62%). Sputum smear for AFB was positive in only 27.4% cases. Bleeding followed by pneumothorax were the most common complications. Complications are very less (1.3% and 0.9% respectively). 2 patients (0.34%) remained undiagnosed even after these all above said investigations. CONCLUSION: Above mentioned commonly available investigations can ascertain diagnosis in most of the cases in the aetiological evaluation of exudative effusions and they are relatively safe procedures.

Cascade synthesis of (E)-2-alkylidenecyclobutanols.

A facile, one-pot reaction cascade condenses 1,1,1-trichloroalkanes with alpha,beta-unsaturated ketones to unexpectedly furnish moderate to good yields of (E)-2-alkylidenecyclobutanols.

Ring expansion/homologation--aldehyde condensation cascade using tert-trihalomethylcarbinols.

Treatment of cyclic tert-trihalomethylcarbinols with CrCl(2) in THF/HMPA in the presence of aryl or aliphatic aldehydes initiates a cascade sequence of one carbon ring expansion-olefination affording conjugated exocyclic ketones. Acyclic tert-trihalomethylcarbinols undergo a comparable cascade of one carbon homologation-olefination.

The general anesthetic propofol increases brain N-arachidonylethanolamine (anandamide) content and inhibits fatty acid amide hydrolase.

1. Propofol (2,6-diisopropylphenol) is widely used as a general anesthetic and for the maintenance of long-term sedation. We have tested the hypothesis that propofol alters endocannabinoid brain content and that this effect contributes to its sedative properties. 2. A sedating dose of propofol in mice produced a significant increase in the whole-brain content of the endocannabinoid, N-arachidonylethanolamine (anandamide), when administered intraperitoneally in either Intralipid or emulphor-ethanol vehicles. 3. In vitro, propofol is a competitive inhibitor (IC(50) 52 micro M; 95% confidence interval 31, 87) of fatty acid amide hydrolase (FAAH), which catalyzes the degradation of anandamide. Within a series of propofol analogs, the critical structural determinants of FAAH inhibition and sedation were found to overlap. Other intravenous general anesthetics, including midazolam, ketamine, etomidate, and thiopental, do not affect FAAH activity at sedative-relevant concentrations. Thiopental, however, is a noncompetitive inhibitor of FAAH at a concentration of 2 mM. 4. Pretreatment of mice with the CB(1) receptor antagonist SR141716 (1 mg kg(-1), i.p.) significantly reduced the number of mice that lost their righting reflex in response to propofol. Pretreatment of mice with the CB(1) receptor agonist, Win 55212-2 (1 mg kg(-1), i.p.), significantly potentiated the loss of righting reflex produced by propofol. These data indicate that CB(1) receptor activity contributes to the sedative properties of propofol. 5. These data suggest that propofol activation of the endocannabinoid system, possibly via inhibition of anandamide catabolism, contributes to the sedative properties of propofol and that FAAH could be a novel target for anesthetic development.

(Z)-alpha-haloacrylates: an exceptionally stereoselective preparation via Cr(II)-mediated olefination of aldehydes with trihaloacetates.

(Z)-alpha-Fluoro-, (Z)-alpha-chloro-, and (Z)-alpha-bromoacrylates were obtained with unprecedented yield and stereocontrol (>99%) via addition of the corresponding commercial trihaloacetates to aldehydes at room temperature using stoichiometric Cr(II) salts or catalytic Cr(II) with a regeneration system. The intermediate 2,2-dihalo-3-hydroxy adducts could be isolated in good yields under conditions of limited reagent at 0 degrees C.

A convenient preparation of 3-substituted furans: synthesis of perillene and dendrolasin.

A variety of 3-substituted furans, including the natural products perillene and dendrolasin, are obtained in good yield via reductive annulation of 1,1,1-trichloroethyl propargyl ethers using catalytic Cr(II) regenerated by Mn/TMSCl. [reaction: see text]