Bis(Benzofuran-1,3-N,N-heterocycle)s as Symmetric and Synthetic Drug Leads against Yellow Fever Virus.

The yellow fever virus (YFV) is an emerging RNA virus and has caused large outbreaks in Africa and Central and South America. The virus is often transmitted through infected mosquitoes and spreads from area to area because of international travel. Being an acute viral hemorrhagic disease, yellow fever can be prevented by an effective, safe, and reliable vaccine, but not be eliminated. Currently, there is no antiviral drug available for its cure. Thus, two series of novel bis(benzofuran−1,3-imidazolidin-4-one)s and bis(benzofuran−1,3-benzimidazole)s were designed and synthesized for the development of anti-YFV lead candidates. Among 23 new bis-conjugated compounds, 4 of them inhibited YFV strain 17D (Stamaril) on Huh-7 cells in the cytopathic effect reduction assays. These conjugates exhibited the most compelling efficacy and selectivity with an EC50 of <3.54 µM and SI of >15.3. The results are valuable for the development of novel antiviral drug leads against emerging diseases.

Computer-Aided Design and Synthesis of (Functionalized quinazoline)-(α-substituted coumarin)-arylsulfonate Conjugates against Chikungunya Virus.

Chikungunya virus (CHIKV) has repeatedly spread via the bite of an infected mosquito and affected more than 100 countries. The disease poses threats to public health and the economy in the infected locations. Many efforts have been devoted to identifying compounds that could inhibit CHIKV. Unfortunately, successful clinical candidates have not been found yet. Computations through the simulating recognition process were performed on complexation of the nsP3 protein of CHIKV with the structures of triply conjugated drug lead candidates. The outcomes provided the aid on rational design of functionalized quinazoline-(α-substituted coumarin)-arylsulfonate compounds to inhibit CHIKV in Vero cells. The molecular docking studies showed a void space around the ß carbon atom of coumarin when a substituent was attached at the α position. The formed vacancy offered a good chance for a Michael addition to take place owing to steric and electronic effects. The best conjugate containing a quinazolinone moiety exhibited potency with EC50 = 6.46 µM, low toxicity with CC50 = 59.7 µM, and the selective index (SI) = 9.24. Furthermore, the corresponding 4-anilinoquinazoline derivative improved the anti-CHIKV potency to EC50 = 3.84 µM, CC50 = 72.3 µM, and SI = 18.8. The conjugate with 4-anilinoquinazoline exhibited stronger binding affinity towards the macro domain than that with quinazolinone via hydrophobic and hydrogen bond interactions.

Synthesis and antiviral activities of quinazolinamine-coumarin conjugates toward chikungunya and hepatitis C viruses.

Development of new drugs with broad-spectrum to combat RNA viruses would be beneficial to mankind but faces a great challenge. We designed and efficiently synthesized a series of quinazolin-4-amine-SCH2-coumarin conjugated compounds. Our data of the virus-cell-based assay show five new conjugates inhibit chikungunya virus with EC50 values as potent as 1.96 µM and two conjugates inhibit hepatitis C virus with EC50 values as low as 16.6 µM. These conjugates possess a xylene substituent at the C-4 amino group of quinazoline and a t-butyl substituent at the C-6' position of coumarin.

Enterovirus Inhibition by Hinged Aromatic Compounds with Polynuclei.

The modern world has no available drugs for the treatment of enteroviruses (EV), which affect millions of people worldwide each year. The EV71 is a major causative disease for hand, foot, and mouth disease; sometimes it is associated with severe central nervous system diseases. Treatment for enteroviral infection is mainly supportive; treatment for aseptic meningitis caused by enteroviruses is also generally symptomatic. Upon the urgent request of new anti-enterovirus drugs, a series of hinged aromatic compounds with polynulei were synthesized through two different chemical pathways. Among these morpholine-furan/thiophene/pyrrole-benzene-pyrazole conjugates, three new agents exhibited inhibitory activity with EC50 = 2.29-6.16 µM toward EV71 strain BrCr in RD cells. Their selectivity index values were reached as high as 33.4. Their structure-activity relationship was deduced that a thiophene derivative with morpholine and trifluorobenzene rings showed the greatest antiviral activity, with EC50 = 2.29 µM.

Domino Reaction for the Synthesis of Polysubstituted Pyrroles and Lamellarin R.

A three-component annulation reaction was developed for the synthesis of pyrroles, a class of compounds with various properties valuable to biomedical and polymer industries. Treatment of α-silylaryl triflates, Schiff bases, and alkynes generated polysubstituted pyrroles in good yields (61-86%) with regioselectivity. This domino reaction involved completion of five sequential steps in a single flask, which comprised aryne formation through 1,2-elimination, their alkylation by Schiff bases through 1,2-addition, 1,4-intramolecular proton transfer, Hüisgen 1,3-dipolar cycloaddition, and dehydrogenative aromatization. It was then successfully applied as the key step in the synthesis of the natural product lamellarin R. This new reaction represents an efficient, sustainable process for the production of chemical materials.

Structure-Activity Relationship of NF023 Derivatives Binding to XIAP-BIR1.

Inhibitors of Apoptosis Proteins (IAPs) are conserved E3-ligases that ubiquitylate substrates to prevent apoptosis and activate the NF-kB survival pathway, often deregulated in cancer. IAPs-mediated regulation of NF-kB signaling is based on the formation of protein complexes by their type-I BIR domains. The XIAP-BIR1 domain dimerizes to bind two TAB1 monomers, leading to downstream NF-kB activation. Thus, impairment of XIAP-BIR1 dimerization could represent a novel strategy to hamper cell survival in cancer. To this aim, we previously reported NF023 as a potential inhibitor of XIAP-BIR1 dimerization. Here we present a thorough analysis of NF023 binding to XIAP-BIR1 through biochemical, biophysical and structural data. The results obtained indicate that XIAP-BIR1 dimerization interface is involved in NF023 binding, and that NF023 overall symmetry and the chemical features of its central moiety are essential for an efficient interaction with the protein. Such strategy provides original hints for the development of novel BIR1-specific compounds as pro-apoptotic agents.

Chikungunya virus inhibition by synthetic coumarin-guanosine conjugates.

Since its discovery in Tanganyika, Africa in 1952, chikungunya virus (CHIKV) outbreaks have occurred in Africa, Asia, Europe, and America. Till now chikungunya fever has spread in nearly 40 countries. Because of lack of effective vaccines and antiviral drugs to intervene this disease, 21 new conjugated compounds were designed and synthesized by coupling of 6,8-dithioguanosine at its C-6 position with 3-(chloromethyl)coumarins bearing an F, Cl, Br, Me, or -OMe substituent through the -SCH2- joint. Meanwhile, an organic "dummy" ligand (e.g., methyl, benzyl, and naphthylmethyl) or a coumarinyl moiety was attached at the C-8 position. By high through-put screening, three of these new conjugates were found to inhibit CHIKV in Vero cells with significant potency (EC50 = 9.9-13.9 µM) and showed low toxicity (CC50 = 96.5-212 µM). The selectivity index values were 9.37-21.7. Their structure-activity relationship was deduced, which indicates that the coumarin moiety is essential and the presence of a -OMe group enhances the antiviral activity.

Bis(benzofuran-thiazolidinone)s and bis(benzofuran-thiazinanone)s as inhibiting agents for chikungunya virus.

There are currently still no approved antiviral drugs to treat or prevent chikungunya virus (CHIKV) infections despite the fact that this arbovirus continues to cause outbreaks in Africa, Asia, and South- and Central-America. Thus 20 new conjugated compounds in the families of bis(benzofuran-1,3-thiazolidin-4-one)s and bis(benzofuran-1,3-thiazinan-4-one)s were designed based on the structural features of suramin. These new compounds were synthesized by chemical methods and their structures were confirmed spectroscopically. In CPE reduction assays, six of these new bis-conjugates inhibited CHIKV replication in Vero E6 cells with EC50 in the range of 1.9-2.7 µM and selectivity index values of ∼75 or higher. These results and compounds provide a starting point for further optimization, design, and synthesis of new antiviral agents for this (re)emerging disease.

Synthesis and Structure-Activity Relationships of Imidazole-Coumarin Conjugates against Hepatitis C Virus.

A series of new conjugated compounds with a -SCH2- linkage were synthesized by chemical methods from imidazole and coumarin derivatives. The experimental results indicate that of the twenty newly synthesized imidazole-coumarin conjugates, three of them exhibited appealing EC50 values (5.1-8.4 µM) and selective indices >20 against hepatitis C virus. Their potency and selectivity were increased substantially by modification of their structure with two factors: imidazole nucleus with a hydrogen atom at the N(1) position and coumarin nucleus with a substituent, such as Cl, F, Br, Me, and OMe. These guidelines provide valuable information for further development of conjugated compounds as anti-viral agents.

Coumarins hinged directly on benzimidazoles and their ribofuranosides to inhibit hepatitis C virus.

A new compound library that contained 20 hinged benzimidazole-coumarin hybrids and their ß-d-ribofuranosides was established. The anti-hepatitis C virus (HCV) activity of all novel coumarin derivatives, which were obtained by use of organic synthetic methods, was tested. Two of these hybrids exhibited appealing EC50 values of as low as 3.0 and 5.5 µM. The best selectivity index was 14. The incorporation of a d-ribofuranose into the hinged hybrids provided the corresponding nucleosides with the ß configuration, one of which inhibited HCV replication with an EC50 value of 20 µM. Additionally, the structure-activity relationship is elucidated on the basis of the functional groups that were attached to the nuclei of benzimidazole, coumarin, and ribofuranose of the hybrids.

Delayed hemopericardium with constrictive pericarditis after blunt trauma: a report of a surgical case.

Constrictive pericarditis (CP) following hemopericardium has been reported in the literature but its pathogenesis is open to question. Proposed mechanisms include trauma leading to damage of the mesothelial lining resulting in decreased fibrinolytic activity in the presence of blood. We present a patient who sustained blunt thoracoabdominal trauma in a car accident and subsequently developed delayed hemopericardium leading to constrictive pericarditis and impending cardiac tamponade. We performed a pericardiectomy to relieve the compression. Closely prolonged monitoring and emergent operation are suggested for such kinds of delayed complications.

Effectiveness of short-term antibiotic prophylaxis on postoperative recovery course after pulmonary lobectomies.

BACKGROUND: Postoperative pneumonia is a major cause of mortality and morbidity after lung surgery. The effectiveness of prophylactic antibiotics for preventing postoperative pneumonia and the recovery course after pulmonary lobectomy is still not clarified yet. We conducted this study to evaluate the effectiveness of prophylactic antibiotics on the post-operative recovery course after pulmonary lobectomies. METHODS: Forty-five cases undergoing pulmonary lobectomies between June 2002 and January 2003 were enrolled in this prospective study. Each patient received prophylactic antibiotics of cefuroxime and sisomicin. Sputum culture upon admission and swab culture from the bronchus cut-end during operation were obtained. The clinical vital signs including heart rates, respiratory rates and core body temperature in the postoperative recovery courses were analyzed. RESULTS: Four (8.9%) patients developed pneumonia after lobectomies, and pneumonia occurred only in patients who had positive culture results from bronchial cut-end. The organisms cultured from the sputum seemed to be controlled by prophylactic antibiotics. All the organisms cultured in the bronchus cut-end differed from those in the sputum; it denoted these pathogens were inoculated during anesthesia for surgical operation. The postoperative vital signs including tachycardia and fever improved gradually in the initial 3 days. Patients with pneumonia sustained significant higher fever than the non-pneumonic patients during postoperative course. CONCLUSIONS: The short-term combination of cefuroxime and sisomicin offers sufficient effectiveness in prophylaxis of pneumonia after pulmonary surgery. Positive bronchial cut-end cultures were related to the post-lobectomy pneumonia significantly. Body temperature was the most useful presenting vital sign for early detection of the postoperative pneumonia.

Retained rectal foreign bodies.

BACKGROUND: Retained rectal foreign bodies have been encountered more frequently and present a dilemma for management. Most of the reports on these cases were documented in the form of case report and from Western countries. The present study was a review on the authors' experiences in such cases. METHODS: Data from January 1979 to January 2000 were extracted from a computerized database of Taipei Veterans General Hospital. The clinical features, treatment strategies and outcomes were analyzed. RESULTS: Ten male patients (mean age: 57.0 years) with 12 presentations of retained rectal foreign bodies were collected. Glass bottles and vibrators were the most common objects encountered, while anal eroticism was reported as the reason for insertion in 50% of the cases. The majority of the objects were extracted by non-surgical methods through either anoscope (n = 4), rigid sigmoidoscope (n = 2) or colonoscope (n = 1). Obstetric forceps was utilized to remove an incarcerated bowling bottle. Emergent laparotomies were performed in cases with overt peritonitis (n = 2), pelvic sepsis (n = 1) and an impacted high-lying glass bottle. Minor complications, such as mucosal abrasion or superficial tear, were found in 62.5% of the non-surgically treated cases. Delayed bleeding was found in 2 of them. There was no mortality in our series. CONCLUSIONS: Despite its rarity, the retained rectal foreign body had varying clinical features. Most of the uncomplicated rectal foreign bodies could be simply extracted transanally under adequate anesthesia. Fiberoptic colonoscopic extraction provided an alternative choice. Open surgery should be reserved only for those patients with overt peritonitis or pelvic sepsis.