Search

Background: The neuropilin-like, Discoidin, CUB and LCCL domain containing 2 (DCBLD2) is a transmembrane protein with an unusually long signal sequence (SS) composed of N-terminal (N) and C-terminal (C) subdomains, separated by a transition (tra) subdomain. DCBLD2 interacts with VEGFR-2 and regulates VEGF-induced endothelial cell signaling, proliferation and migration, as well as angiogenesis. The exact mechanisms by which DCBLD2 interacts with VEGFR2 to modulate VEGF signaling remain unclear., Methods: Searching for VEGFR2 interacting DCBLD2 domains, we generated various constructs containing different DCBLD2 domain combinations and conducted co-immunoprecipitation and signaling studies in HEK 293T and endothelial cells. Several peptides were synthesized based on the identified domain, and their effect on VEGF signaling was assessed in vitro in cell culture and in vivo using matrigel plug and corneal micropocket assays. The effect of the lead peptide was further evaluated using a murine hindlimb ischemia model., Results: DCBLD2 SS interacted with VEGFR2 and promoted VEGF signaling. SS was not cleaved in the mature DCBLD2 and its hydrophobic transmembrane 'traC' segment, but not the 'N' subdomain, was involved in DCBLD2-VEGFR2 interaction. The smallest unit in DCBLD2 SS that interacts with VEGFR2 was the L5VL5 sequence. Even after the central valine was removed, the L10 sequence mimicked the DCBLD2 SS traC's effect on VEGF-signaling, while shorter or longer poly-leucine sequences were less effective. Finally, a synthetic traC peptide enhanced VEGF signaling in vitro, promoted VEGF-induced angiogenesis in vivo, and improved blood flow recovery following hindlimb ischemia., Conclusion: DCBLD2 SS along with its derivative peptides can promote VEGFR2 signaling and angiogenesis. Synthetic peptides based on DCBLD2 SS hold promise as therapeutic agents for regulating angiogenesis. Importantly these findings refine the traditional view of signal sequences as mere targeting elements, revealing a role in cellular signaling. This opens new avenues for research and therapeutic strategies.

The most common route for drug administration is the oral route due to the various advantages offered by this route, such as ease of administration, controlled and sustained drug delivery, convenience, and non-invasiveness. In spite of this, oral drug absorption faces challenges due to various issues related to its stability, permeability and solubility in the GI tract. Biologic drugs generally face problems when administered by oral route as they are readily degradable and thus required to be injected. To overcome these issues in oral absorption, different approaches like novel drug delivery systems and newer pharmaceutical technologies have been adopted. With a combined knowledge of drug delivery and pharmaceutical technology, robotic pills can be designed and used successfully to enhance the adhesion and permeation of drugs through the mucus membrane of the GI tract to achieve drug delivery at the target site. The potential application of robotic pills in diagnosis and drug dispensing is also discussed. The review highlights recent developments in robotic pill drug-device technology and discusses its potential applications to solve the problems and challenges in oral drug delivery., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Calcific aortic valve disease (CAVD) is a prevailing disease with increasing occurrence and no known medical therapy. Dcbld2 -/- mice have a high prevalence of bicuspid aortic valve (BAV), spontaneous aortic valve calcification, and aortic stenosis (AS). 18 F-NaF PET/CT can detect the aortic valve calcification process in humans. However, its feasibility in preclinical models of CAVD remains to be determined. Here, we sought to validate 18 F-NaF PET/CT for tracking murine aortic valve calcification and leveraged it to examine the development of calcification with aging and its interdependence with BAV and AS in Dcbld2 -/- mice. Methods: Dcbld2 -/- mice at 3-4 mo, 10-16 mo, and 18-24 mo underwent echocardiography, 18 F-NaF PET/CT ( n = 34, or autoradiography ( n = 45)), and tissue analysis. A subset of mice underwent both PET/CT and autoradiography ( n = 12). The aortic valve signal was quantified as SUV max on PET/CT and as percentage injected dose per square centimeter on autoradiography. The valve tissue sections were analyzed by microscopy to identify tricuspid and bicuspid aortic valves. Results: The aortic valve 18 F-NaF signal on PET/CT was significantly higher at 18-24 mo ( P < 0.0001) and 10-16 mo ( P < 0.05) than at 3-4 mo. Additionally, at 18-24 mo BAV had a higher 18 F-NaF signal than tricuspid aortic valves ( P < 0.05). These findings were confirmed by autoradiography, with BAV having significantly higher 18 F-NaF uptake in each age group. A significant correlation between PET and autoradiography data (Pearson r = 0.79, P < 0.01) established the accuracy of PET quantification. The rate of calcification with aging was significantly faster for BAV ( P < 0.05). Transaortic valve flow velocity was significantly higher in animals with BAV at all ages. Finally, there was a significant correlation between transaortic valve flow velocity and aortic valve calcification by both PET/CT ( r = 0.55, P < 0.001) and autoradiography ( r = 0.45, P < 0.01). Conclusion: 18 F-NaF PET/CT links valvular calcification to BAV and aging in Dcbld2 -/- mice and suggests that AS may promote calcification. In addition to addressing the pathobiology of valvular calcification, 18 F-NaF PET/CT may be a valuable tool for evaluation of emerging therapeutic interventions in CAVD., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Matrix metalloproteinase (MMP)-12 is highly expressed in abdominal aortic aneurysms and its elastolytic function has been implicated in the pathogenesis. This concept is challenged, however, by conflicting data. Here, we sought to revisit the role of MMP-12 in abdominal aortic aneurysm., Methods: Apoe -/- and Mmp12 -/- (factor H-immunoglobulin G), and macrophage-specific MMP-12 deficiency on adverse aortic remodeling and death from rupture in Ang II-infused mice were determined.Apoe -/- mice were infused with Ang II (angiotensin). Expression of neutrophil extracellular traps (NETs) markers and complement component 3 (C3) levels were evaluated by immunostaining in aortas of surviving animals. Plasma complement components were analyzed by immunoassay. The effects of a complement inhibitor, IgG-FH 1-5 (factor H-immunoglobulin G), and macrophage-specific MMP-12 deficiency on adverse aortic remodeling and death from rupture in Ang II-infused mice were determined., Results: Unexpectedly, death from aortic rupture was significantly higher in Mmp12 -/- / Apoe -/- mice. This associated with more neutrophils, citrullinated histone H3 and neutrophil elastase, markers of NETs, and C3 levels in Mmp12 -/- aortas. These findings were recapitulated in additional models of abdominal aortic aneurysm. MMP-12 deficiency also led to more pronounced elastic laminae degradation and reduced collagen integrity. Higher plasma C5a in Mmp12 -/- mice pointed to complement overactivation. Treatment with IgG-FH 1-5 decreased aortic wall NETosis and reduced adverse aortic remodeling and death from rupture in Ang II-infused Mmp12 -/- mice. Finally, macrophage-specific MMP-12 deficiency recapitulated the effects of global MMP-12 deficiency on complement deposition and NETosis, as well as adverse aortic remodeling and death from rupture in Ang II-infused mice., Conclusions: An MMP-12 deficiency/complement activation/NETosis pathway compromises aortic integrity, which predisposes to adverse vascular remodeling and abdominal aortic aneurysm rupture. Considering these new findings, the role of macrophage MMP-12 in vascular homeostasis demands re-evaluation of MMP-12 function in diverse settings.

Chronic kidney disease (CKD) is a debilitating progressive illness that affects more than 10% of the world's population. In this literature review, we discussed the roles of nutritional interventions, lifestyle modifications, hypertension (HTN) and diabetes mellitus (DM) control, and medications in delaying the progression of CKD. Walking, weight loss, low-protein diet (LPD), adherence to the alternate Mediterranean (aMed) diet, and Alternative Healthy Eating Index (AHEI)-2010 slow the progression of CKD. However, smoking and binge alcohol drinking increase the risk of CKD progression. In addition, hyperglycemia, altered lipid metabolism, low-grade inflammation, over-activation of the renin-angiotensin-aldosterone system (RAAS), and overhydration (OH) increase diabetic CKD progression. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend blood pressure (BP) control of <140/90 mmHg in patients without albuminuria and <130/80 mmHg in patients with albuminuria to prevent CKD progression. Medical therapies aim to target epigenetic alterations, fibrosis, and inflammation. Currently, RAAS blockade, sodium-glucose cotransporter-2 (SGLT2) inhibitors, pentoxifylline, and finerenone are approved for managing CKD. In addition, according to the completed Study of Diabetic Nephropathy with Atrasentan (SONAR), atrasentan, an endothelin receptor antagonist (ERA), decreased the risk of renal events in diabetic CKD patients. However, ongoing trials are studying the role of other agents in slowing the progression of CKD., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Alkhatib et al.)

Background: Matrix metalloproteinases (MMPs) play a key role in the pathogenesis of abdominal aortic aneurysm (AAA). Imaging aortic MMP activity, especially using positron emission tomography to access high sensitivity, quantitative data, could potentially improve AAA risk stratification. Here, we describe the design, synthesis, characterization, and evaluation in murine AAA and human aortic tissue of a first-in-class MMP-targeted positron emission tomography radioligand, 64 Cu-RYM2., Methods: The broad spectrum MMP inhibitor, RYM2 was synthetized, and its potency as an MMP inhibitor was evaluated by a competitive inhibition assay. Toxicology studies were performed. Tracer biodistribution was evaluated in a murine model of AAA induced by angiotensin II infusion in Apolipoprotein E-deficient mice. 64 Cu-RYM2 binding to normal and aneurysmal human aortic tissues was assessed by autoradiography., Results: RYM2 functioned as an MMP inhibitor with nanomolar affinities. Toxicology studies showed no adverse reaction in mice. Upon radiolabeling with Cu-64, the resulting tracer was stable in murine and human blood in vitro. Biodistribution and metabolite analysis in mice showed rapid renal clearance and acceptable in vivo stability. In vivo positron emission tomography/computed tomography in a murine model of AAA showed a specific aortic signal, which correlated with ex vivo measured MMP activity and Cd68 gene expression. 64 Cu-RYM2 specifically bound to normal and aneurysmal human aortic tissues in correlation with MMP activity., Conclusions: 64 Cu-RYM2 is a first-in-class MMP-targeted positron emission tomography tracer with favorable stability, biodistribution, performance in preclinical AAA, and importantly, specific binding to human tissues. These data set the stage for 64 Cu-RYM2-based translational imaging studies of vessel wall MMP activity, and indirectly, inflammation, in AAA.

Background: There are more than 5 million people with dementia in India. Multicentre studies looking at details of treatment for people with dementia In India are lacking. Clinical audit is a quality improvement process which aims to systematically assess, evaluate, and improve patient care. Evaluating current practice is the key to a clinical audit cycle., Aim: This study aimed to assess the diagnostic patterns and prescribing practices of psychiatrists for patients with dementia in India., Method: A retrospective case file study was conducted across several centers in India., Results: Information from the case records of 586 patients with dementia was obtained. Mean age of the patients was 71.14 years (standard deviation = 9.42). Three hundred twenty one (54.8%) were men. Alzheimer's disease (349; 59.6%) was the most frequent diagnosis followed by vascular dementia (117; 20%). Three hundred fifty five (60.6%) patients had medical disorders and 47.4% patients were taking medications for their medical conditions. Eighty one (69.2%) patients with vascular dementia had cardiovascular problems. Majority of the patients (524; 89.4%) were on medications for dementia. Most frequently prescribed treatment was Donepezil (230; 39.2%) followed by Donepezil-Memantine combination (225; 38.4%). Overall, 380 (64.8%) patients were on antipsychotics. Quetiapine (213, 36.3%) was the most frequently used antipsychotic. Overall, 113 (19.3%) patients were on antidepressants, 80 (13.7%) patients were on sedatives/hypnotics, and 16 (2.7%) patients were on mood stabilizers. Three hundred nineteen (55.4%) patients and caregivers of 374 (65%) patients were receiving psychosocial interventions., Conclusions: Diagnostic and prescription patterns in dementia which emerged from this study are comparable to other studies both nationally and internationally. Comparing current practices at individual and national levels against accepted guidelines, obtaining feedback, identifying gaps and instituting remedial measures help to improve the standard of care provided., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Indian Journal of Psychiatry.)

Expression of a neuropilin-like protein, DCBLD2, is reduced in human calcific aortic valve disease (CAVD). DCBLD2-deficient mice develop bicuspid aortic valve (BAV) and CAVD, which is more severe in BAV mice compared with tricuspid littermates. In vivo and in vitro studies link this observation to up-regulated bone morphogenic protein (BMP)2 expression in the presence of DCBLD2 down-regulation, and enhanced BMP2 signaling in BAV, indicating that a combination of genetics and BAV promotes aortic valve calcification and stenosis. This pathway may be a therapeutic target to prevent CAVD progression in BAV., Competing Interests: This work was supported by grants from the National Institutes of Health (NIH) grants R01AG065917 and R01HL138567. and Department of Veterans Affairs grant I0-BX004038. Dr Salarian was supported by National Institutes of Health training grant 5T32HL007950. The resources of the Yale Translational Research Imaging Center, funded in part by National Institutes of Health grant 1S10RR018039, were used for this study. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Inflammation plays a major role in the pathogenesis of several vascular pathologies, including abdominal aortic aneurysm (AAA). Evaluating the role of inflammation in AAA pathobiology and potentially outcome in vivo requires non-invasive tools for high-resolution imaging. We investigated the feasibility of X-ray computed tomography (CT) imaging of phagocytic activity using nanoparticle contrast agents to predict AAA outcome. Methods: Uptake of several nanoparticle CT contrast agents was evaluated in a macrophage cell line. The most promising agent, Exitron nano 12000, was further characterized in vitro and used for subsequent in vivo testing. AAA was induced in Apoe -/- mice through angiotensin II (Ang II) infusion for up to 4 weeks. Nanoparticle biodistribution and uptake in AAA were evaluated by CT imaging in Ang II-infused Apoe -/- mice. After imaging, the aortic tissue was harvested and used from morphometry, transmission electron microscopy and gene expression analysis. A group of Ang II-infused Apoe -/- mice underwent nanoparticle-enhanced CT imaging within the first week of Ang II infusion, and their survival and aortic external diameter were evaluated at 4 weeks to address the value of vessel wall CT enhancement in predicting AAA outcome. Results: Exitron nano 12000 showed specific uptake in macrophages in vitro . Nanoparticle accumulation was observed by CT imaging in tissues rich in mononuclear phagocytes. Aortic wall enhancement was detectable on delayed CT images following nanoparticle administration and correlated with vessel wall CD68 expression. Transmission electron microscopy ascertained the presence of nanoparticles in AAA adventitial macrophages. Nanoparticle-induced CT enhancement on images obtained within one week of AAA induction was predictive of AAA outcome at 4 weeks. Conclusions: By establishing the feasibility of CT-based molecular imaging of phagocytic activity in AAA, this study links the inflammatory signal on early time point images to AAA evolution. This readily available technology overcomes an important barrier to cross-sectional, longitudinal and outcome studies, not only in AAA, but also in other cardiovascular pathologies and facilitates the evaluation of modulatory interventions, and ultimately upon clinical translation, patient management., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Macrophage elastase [matrix metalloproteinase (MMP)-12] is the most upregulated MMP in abdominal aortic aneurysm (AAA) and, hence, MMP-12-targeted imaging may predict AAA progression and rupture risk. Here, we report the design, synthesis, and evaluation of three novel hydroxamate-based selective MMP-12 inhibitors (CGA, CGA-1, and AGA) and the methodology to obtain MMP-12 selectivity from hydroxamate-based panMMP inhibitors. Also, we report two 99m Tc-radiotracers, 99m Tc-AGA-1 and 99m Tc-AGA-2, derived from AGA. 99m Tc-AGA-2 displayed faster blood clearance in mice and better radiochemical stability compared to 99m Tc-AGA-1. Based on this, 99m Tc-AGA-2 was chosen as the lead tracer and tested in murine AAA. 99m Tc-AGA-2 uptake detected by autoradiography was significantly higher in AAA compared to normal aortic regions. Specific binding of the tracer to MMP-12 was demonstrated through ex vivo competition. Accordingly, this study introduces a novel family of selective MMP-12 inhibitors and tracers, paving the way for further development of these agents as therapeutic and imaging agents.

Rearrangements of the ALK gene are found in approximately 5% of non-small-cell lung cancer. It is of particular importance to test for this rearrangement in patients with metastatic lung adenocarcinoma because these tumors are highly sensitive to therapy with ALK-targeted inhibitors. Lorlatinib is a reversible potent third generation tyrosine kinase inhibitor that is highly selective and targets ALK and ROS1. It was developed to target resistant ALK mutants including the most common G1202R. Lorlatinib has excellent central nervous system (CNS) penetration and its efficacy has also been demonstrated even in patients with intracranial metastases after progression on second generation ALK inhibitors. Potential toxicities include neurocognitive effects and hyperlipidemia. "A User's Guide to Lorlatinib" reviews the mechanism of action, pharmacology and clinical trial data. Also covering the management of adverse events, this "guide" has been prepared to be a practical reference tool to both clinicians and basic researchers., Competing Interests: Declaration of Competing Interest The authors have not received any funding for this study and declare no direct conflict of interest. Dr. Nagasaka serves on the advisory board for AstraZeneca and has received study funding from Tempus. Dr. Sukari serves on the advisory board for Merck and Eisai. He has received study funding from Eisai. Dr. Ou declares the following including honorarium/speaker bureau: Pfizer, Astra Zeneca, Roche/Genentech, Takeda/ARIAD, Merck, honorarium/advisory: Pfizer, Astra Zeneca, Roche/Genentech, Takeda/ARIAD, stock ownership: Turning Point Therapeutics Inc and scientific Advisory Board (Former): Turning Point Therapeutics. All other authors have no potential conflict of interest to declare., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To describe the evidence regarding communication partner training (CPT) interventions for individuals with traumatic brain injury (TBI) and their conversation partners., Data Sources: Eleven key databases-PubMed, CINAHL, Cochrane Registry of Controlled Trials, Embase, Linguistic and Language Behavior Abstracts, ProQuest, Scopus, Web of Science, PsycBITE, SpeechBITE, and ERIC-were searched from inception through 2019., Study Selection: Selected articles had to be peer reviewed, written in English, experimental or quasiexperimental design, report on TBI communication partners, and describe interventions or strategies targeting communication partners., Data Extraction: Of 1088 articles identified, 12 studies were selected for data extraction, critical appraisal, and analysis with considerations of sex and gender. The Oxford Centre for Evidence-Based Medicine's guideline was used to critically appraise Levels of Evidence. Assessment of bias was conducted using the Cochrane Collaboration tools for randomized controlled trials and risk of bias in nonrandomized studies of interventions for nonrandomized controlled trials and the risk of bias in N-of-1 trials scale., Data Synthesis: A systematic review with a qualitative meta-analysis of themes and findings across the selected studies identified 3 major categories: (1) benefits of the training for those with TBI, (2) risks of CPT, and (3) suggestions to improve its efficacy., Conclusion: Most of the evidence comes from 1 research group, which may be viewed as a weakness in the current body of literature. However, although the evidence to date is modest, CPT may help to increase accessibility and reduce participation inequities in the community for individuals with TBI., (© 2019 The Authors.)

ABO hemolytic disease of the newborn occurs almost exclusively in infants of blood group A and B who are born to group O mothers. Positive Direct Antiglobulin Test (DAT) can identify those infants who are at risk of developing the ABO hemolytic disease. Earlier studies have suggested that BO incompatibility is associated with a positive DAT in black infants. In this study we sought to determine whether ABO incompatibility type could be associated with a higher rate of DAT positivity or clinical hemolytic disease. We reviewed the electronic medical records of all ABO-incompatible births over a 2-year period. There were 1537 ABO-incompatible births during the study period. DAT was more commonly positive among BO incompatible (21.5% in BO vs. 14.8% in AO, P=0.001) and black (18.8% in blacks vs. 10.8% in nonblacks, P=0.003) infants. DAT positivity was significantly associated with both severe hyperbilirubinemia (P=0.028) and hemolytic anemia (P<0.001). BO incompatibility was significantly associated with hemolytic anemia, but not severe hyperbilirubinemia, in the infants tested.

The intramolecular hydrogen bond formed between a protonated amine and a neighboring H-bond acceptor group in the side chain of amodiaquine and isoquine is thought to play an important role in their antimalarial activities. Here we describe isoquine-based compounds in which the intramolecular H-bond is mimicked by a methylene linker. The antimalarial activities of the resulting benzoxazines, their isosteric tetrahydroquinazoline derivatives, and febrifugine-based 1,3-quinazolin-4-ones were examined in vitro (against Plasmodium falciparum ) and in vivo (against Plasmodium berghei ). Compounds 6b,c caused modest inhibition of chloroquine transport via the parasite's "chloroquine resistance transporter" (PfCRT) in a Xenopus laevis oocyte expression system. In silico predictions and experimental evaluation of selected drug-like properties were also performed on compounds 6b,c. Compound 6c emerged from this work as the most promising analogue of the series; it possessed low toxicity and good antimalarial activity when administered orally to P. berghei -infected mice.

GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 μM)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5 g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; >100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; >100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Antimalarial agents structurally based on novel pharmacophores, synthesized by low-cost synthetic procedures and characterized by low potential for developing resistance are urgently needed. Recently, we developed an innovative class of antimalarials based on a polyaromatic pharmacophore. Hybridizing the 4-aminoquinoline or the 9-aminoacridine system of known antimalarials with the clotrimazole-like pharmacophore, characterized by a polyarylmethyl group, we describe herein the development of a unique class (4a-l and 5a-c) of antimalarials selectively interacting with free heme and interfering with Plasmodium falciparum (Pf) heme metabolism. Combination of the polyarylmethyl system, able to form and stabilize radical intermediates, with the iron-complexing and conjugation-mediated electron transfer properties of the 4(9)-aminoquinoline(acridine) system led to potent antimalarials in vitro against chloroquine sensitive and resistant Pf strains. Among the compounds synthesized, 4g was active in vivo against P. chabaudi and P. berghei after oral administration and, possessing promising pharmacokinetic properties, it is a candidate for further preclinical development.

We describe herein the design, synthesis, biological evaluation, and structure-activity relationship (SAR) studies of an innovative class of antimalarial agents based on a polyaromatic pharmacophore structurally related to clotrimazole and easy to synthesize by low-cost synthetic procedures. SAR studies delineated a number of structural features able to modulate the in vitro and in vivo antimalarial activity. A selected set of antimalarials was further biologically investigated and displayed low in vitro toxicity on a panel of human and murine cell lines. In vitro, the novel compounds proved to be selective for free heme, as demonstrated in the beta-hematin inhibitory activity assay, and did not show inhibitory activity against 14-alpha-lanosterol demethylase (a fungal P450 cytochrome). Compounds 2, 4e, and 4n exhibited in vivo activity against P. chabaudi after oral administration and thus represent promising antimalarial agents for further preclinical development.

Malaria is a major health problem in poverty-stricken regions where new antiparasitic drugs are urgently required at an affordable price. We report herein the design, synthesis, and biological investigation of novel antimalarial agents with low potential to develop resistance and structurally based on a highly conjugated scaffold. Starting from a new hit, the designed modifications were performed hypothesizing a specific interaction with free heme and generation of radical intermediates. This approach provided antimalarials with improved potency against chloroquine-resistant plasmodia over known drugs. A number of structure-activity relationship (SAR) trends were identified and among the analogues synthesized, the pyrrolidinylmethylarylidene and the imidazole derivatives 5r, 5t, and 8b were found as the most potent antimalarial agents of the new series. The mechanism of action of the novel compounds was investigated and their in vivo activity was assessed.

The design, synthesis, and antiplasmodial activity of antimalarial heterodimers based on the 1,4-bis(3-aminopropyl)piperazine linker is reported. In this series key structural elements derived from quinoline antimalarials were coupled to fragments capable of coordinating metal ions. Biological evaluation included determination of activity against chloroquine-sensitive and chloroquine-resistant Plasmodium falciparum strains. Some of the novel compounds presented high activity in vitro against chloroquine-resistant strains, more potent than chloroquine and clotrimazole. Computational studies revealed that the activity is likely due to the ability of the compounds to assume a multisite iron coordinating geometry.

Identification of new molecular scaffolds structurally unrelated to known antimalarials may represent a valid strategy to overcome resistance of P. falciparum (Pf) to currently available drugs. We describe herein the investigation of a new polycyclic pharmacophore, related to clotrimazole, to develop innovative antimalarial agents. This study allowed us to discover compounds characterized by a high in vitro potency, particularly against Pf CQ-resistant strains selectively targeting free heme, which are easy to synthesize by low-cost synthetic strategies.

A series of N1-arylidene-N2-quinolyl- and N2-acrydinylhydrazones were synthesized and tested for their antimalarial properties. These compounds showed remarkable anti-plasmodial activity in vitro especially against chloroquine-resistant strains. Their potent biological activity makes them promising lead structures for the development of new antimalarial drugs.

An unexpected synthesis of symmetrical hydroxybiphenylmethanes involving the reaction of 2-hydroxyphenyl benzyl ketones with ethoxymethyl chloride has been observed. Some new interesting observations of Labat test on colorimetric detection of bichalconyloxy, bichalconyl and biflavonylmethanes having oxygenated ortho positions are presented.

Hepatitis C virus (HCV) infection is an emerging global epidemic, and no effective cure is yet available. Interferon-alpha (INFalpha) and pegylated INFs, in combination or otherwise with ribavirin, have proven to be effective in no more than 50% of chronically infected patients. New and better therapeutic strategies are therefore needed. HCV nonstructural protein 3 (NS3) RNA helicase (h) is a promising target for developing new therapeutics. QU663 was discovered as a potent new selective inhibitor of the helicase reaction of HCV NS3 (K(i) = 0.75 microM), competing with the nucleic acid substrate without affecting ATPase function, even at high concentrations. QU663 is one of a new generation of small-molecule nucleotide-mimicking inhibitors which are potential anti-HCV agents. A thorough molecular modeling study was carried out to explain the molecular basis of NS3h inhibition by QU663. The resulting three-dimensional interaction model is discussed.

We have recently developed five novel pyrrolo-1,5-benzoxazepines as proapoptotic agents. Their JNK-dependent induction of apoptosis in tumor cells suggested their potential as novel anticancer agents. The core structure of the apoptotic agent 6 was investigated, and the SARs were expanded with the design and synthesis of several analogues. To define the apoptotic mechanism of the new compounds and the localization of their drug target, two analogues of 6 were designed and synthesized to delineate events leading to JNK activation. The cell-penetrating compound 16 induced apoptosis in tumor cells, while its nonpenetrating analogue, 17, was incapable of inducing apoptosis or activating JNK. Plasma membrane permeabilization of tumor cells resulted in 17-induced JNK activation, suggesting that the pyrrolo-1,5-benzoxazepine molecular target is intracellular. Interestingly, compound 6 displayed cytotoxic activity against a panel of human tumor cell lines but demonstrated negligible toxicity in vivo with no effect on the animals' hematology parameters.