Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents.

Aromatic aldehydes and ethacrynic acid (ECA) exhibit antipolymerization properties that are beneficial for sickle cell disease therapy. Based on the ECA pharmacophore and its atomic interaction with hemoglobin, we designed and synthesized several compounds - designated as KAUS (imidazolylacryloyl derivatives) - that we hypothesized would bind covalently to ßCys93 of hemoglobin and inhibit sickling. The compounds surprisingly showed weak allosteric and antisickling properties. X-ray studies of hemoglobin in complex with representative KAUS compounds revealed an unanticipated mode of Michael addition between the ß-unsaturated carbon and the N-terminal αVal1 nitrogen at the α-cleft of hemoglobin, with no observable interaction with ßCys93. Interestingly, the compounds exhibited almost no reactivity with the free amino acids, L-Val, L-His and L-Lys, but showed some reactivity with both glutathione and L-Cys. Our findings provide a molecular level explanation for the compounds biological activities and an important framework for targeted modifications that would yield novel potent antisickling agents.

Reduction and internal fixation for acute midshaft clavicular fractures by mini-incision using cannulated screws.

UNLABELLED: Open reduction and internal fixation of fracture clavicle has typically been done by variable types of plates. Plates carry the disadvantages of longer incisions, prominence of the plates and wound complications. The purpose of this study is to present an alternative surgical technique for acute midshaft clavicular fracture using cannulated 6.5 screws with minimal incision over the fracture site. Twenty seven adult patients with acute midshaft clavicular fractures were surgically treated with mini open technique using 6.5mm cannulated screws. The modified shoulder rating scale by Chuang was used for outcome evaluation. Union occurred in a mean of 8.3 weeks range 6-12 weeks. Restoration of clavicular length was achieved in all cases. Twenty-four patients experienced no pain on all activity at latest follow-up. All patients expressed their willingness to have the surgery again should they have the same problem. One patient stated that she would not have the surgery again. CONCLUSION: reduction and internal fixation with a cannulated screw is an alternative economic technique for the treatment of acute midshaft clavicular fractures that is useful in selected cases where surgery is indicated.

Avoiding over diagnosis of shoulder dystocia.

In this study, we aimed to distinguish true shoulder dystocia from mere difficulty with delivery of the shoulder, by investigating the risk factors that lead to shoulder dystocia. Shoulder dystocia is a bony problem which occurs when either the anterior or, less commonly, the posterior fetal shoulder impacts on the maternal symphysis pubis or sacral promontory. Failure to apply the Royal College of Obstetricians and Gynaecologists (RCOG) clinical diagnostic criteria for shoulder dystocia has made it susceptible to over-diagnosis due to inclusion of all difficult shoulder deliveries, including those related to an inappropriate maternal position. This was a retrospective analysis of risk factors associated with 56 cases of shoulder dystocia which occurred in West Middlesex University Hospital between 2003 and 2004. The cases were analysed in two categories, good outcome and poor outcome, and compared with each other. The poor outcome had represented true shoulder dystocia. The incidence of shoulder dystocia increased from 0.94% in 2003 to 1.37% in 2004. However, the incidence of those with a poor outcome decreased from 45.4% of the whole shoulder dystocia group in 2003, to 17.6% in 2004 (p = 0.03). There were no clear diagnostic criteria documented in the notes for the condition other than the birth attendants' opinion and the turtle sign. This may either reflect over-diagnosis from increased awareness or possibly improvement in the outcome due to training and education. Interestingly, at least four risk factors were identified in each of the cases with poor outcome. A registrar conducting the delivery, forceps delivery for delayed second stage and the turtle sign were significantly common findings among the true shoulder dystocia group. Multiple risk factors can be a good predictor for the occurrence of shoulder dystocia. Applying the RCOG diagnostic criteria for shoulder dystocia may lead to improvement in diagnosis and therefore a better understanding of the risk factors and future management of shoulder dystocia.

Synthesis of some new benzothiazole derivatives as potential antimicrobial and antiparasitic agents.

Several thiazolidinonyl benzothiazoles 8a-b and thiazolinylbenzothiazoles 9a-j were synthesized by the reaction of 2-(N-substituted thiocarbamoyl hydrazino) benzothiazoles 7a-d with chloroacetic acid or phenacyl bromide respectively. The intermediate compounds 7a-d were prepared in a good yield by the reaction of 2-hydrazinobenzothiazole (6) with phenylisothiocyanates. Synthesis of hydrazones 10a-c were performed by the reaction of 6 with the corresponding aldehydes. Trials to cyclize the obtained hydrazones 10a-c into the corresponding triazolo derivatives 11a-c were unsuccessful. Addition of 4-morphylino carbonyl chloride to compound 6 yielded the corresponding 2-acid hydrazide derivative 12. Some of the prepared compounds were screened for their anti-parasitic activity. Most of them showed reasonable antinematodal or schistosomicidal activity. In addition, antimicrobial screening of all of the prepared new compounds was performed against Staphylococcus aeurus ATCC 6538, Escherichia coli ATCC 8735 and Candida albicans ATCC 10321 but non of them was active.

Synthesis and biological evaluation of certain alpha,beta-unsaturated ketones and their corresponding fused pyridines as antiviral and cytotoxic agents.

A new series of 3,5-bis(arylidene)-4-piperidones, as chalcone analogues carrying variety of aryl and heteroaryl groups, pyrazolo[4,3-c]pyridines, pyridolo[4,3-c]pyrimidines, and pyrido[4,3-c]-pyridines, carrying an arylidene moiety, and a series of pyrano[3,2-c]pyridines, as flavone and coumarin isosteres, were synthesized and screened for their in vitro antiviral and antitumor activities at the National Cancer Institute (NCI). Compounds 9 and 18 proved to be active against herpes simplex virus-1 (HSV-1), while compound 13 showed moderate activity against human immunodeficiency virus-1 (HIV-1). Compounds 14, 26, 28, 33, and 35 exhibited a broad spectrum antitumor activity. In addition, compounds 26, 33, and 35 proved to be of moderate selectivity toward leukemia cell lines. The pyrano[3,2-c]pyridines heterocyclic system proved to be the most active antitumors among the investigated heterocycles.

Quantitative structure-activity relationship of phenoxy and benzyloxy acid derivatives as antisickling agents.

Quantitative structure activity relationship of Hansch-type has been applied to develop correlation between the calculated physicochemical properties and the in vitro activities of phenoxy and benzyloxyacetic acid derivatives as antisickling agents. The antisickling effect of these compounds was first reported by Abraham et al., and is used as a database of this study. QSAR for these compounds was generated in order to provide more information about the structure requirements for the design of more active antisickling analogs. The solubility ratio A/Ao for 22 phenoxyacetic acids and 15 benzyloxyacetic acids were used to develop equations using hydrophobic (pi), electronic (sigma) and molar refraction (MR) parameters. Equations 1 and 2 with correlation coefficients of 0.872 and 0.894 respectively, were obtained for phenoxy and benzyloxy acetic. Potencies were correlated positively with pi values of ortho, meta and/or para substituents. Positive correlations were also obtained for sigma constants of para and/or meta substituents. Negative correlations, on the other hand, were obtained with the MR values of para substituents in the benzenic ring of the benzyloxy acid series. Using the generated correlation equation 2, three potent antigelling benzyloxyacetic acid derivatives were proposed and reported. These compounds are expected to be very promising antisickling agents having A/A. values of 1.016, 1.124 and 1.138.

Synthesis and biological evaluation of new cyclopenteno[b]thiophene derivatives as local anesthetic and antiarrhythmic agents.

A series of ethyl 2-substituted amino-cyclopenteno[b]thiophen-3-carboxylates was synthesized as a carticaine analogues and evaluated for their local anesthetic and antiarrhythmic activity. Compounds ethyl 2-[1-oxo-2-(ethylamino)ethylamino]-(4a), ethyl 2-[1-oxo-2-(n-propylamino)-ethylamino]-(4c), ethyl 2-[1-oxo-2-(4-methylpiperazino)ethylamino]-(4e), ethyl 2-[1-oxo-2-(ethylamino)propylamino]-(5a) and ethyl 2-[1-oxo-2-(n-propylamino)propylamino]cyclopenteno[b]thiophen++ +-3-carboxylate (5c) proved to possess local anesthetic and antiarrhythmic activity comparable to carticaine and lidocaine. The active compounds exert their antiarrhythmic potency via blocking Na+ channels as in case of 5c or blocking Ca+2 channels as in case of 4a, 4c and 5c. Compound 4e exhibited a dual mechanism by blocking both Na+ and Ca+2 channels.

Allosteric modifiers of hemoglobin. 1. Design, synthesis, testing, and structure-allosteric activity relationship of novel hemoglobin oxygen affinity decreasing agents.

Three isomeric series of 2-(aryloxy)-2-methylpropionic acids were prepared and studied for their ability to decrease the oxygen affinity of human hemoglobin A. The isomeric aryloxy groups included 4-[[(aryloyl)amino]methyl]phenoxy, 4-(arylacetamido)phenoxy, and 4-[[(arylamino)carbonyl]methyl]phenoxy. A total of 20 compounds were synthesized and tested. Structure-activity relationships are presented. Several of the new compounds were found to be strong allosteric effectors of hemoglobin. The two most active compounds are 2-[4-[[(3,5-dichloroanilino)carbonyl]-methyl]phenoxy]- 2-methylpropionic acid and the corresponding 3,5-dimethyl derivative. The latter two compounds have been compared to other known potent allosteric effectors in the same assay and show greater activity. Both compounds also exhibit a right shift in the oxygen equilibrium curve when incubated with whole blood. The new compounds may be of interest in clinical or biological areas that require or would benefit from a reversal of depleted oxygen supply (i.e., ischemia, stroke, tumor radiotherapy, blood storage, blood substitutes, etc.). They are also structurally related to several marketed antilipidemic agents.