Identification of novel pyrazole acid antagonists for the EP1 receptor

The discovery, synthesis and structure-activity relationship (SAR) of a novel series of EP1 receptor antagonists is described. Pyrazole acid 4, identified from a chemical array, had desirable physicochemical properties, an excellent in vitro microsomal inhibition and cytochrome P450 (CYP450) profile and good exposure levels in blood. This compound had an ED50 of 1.3 mg/kg in a rat pain model. A range of more potent analogues in the in vitro assay was identified using efficient array chemistry. These EP1 antagonists have potential as agents in the treatment of PGE2 mediated pain.     

DNA gyrase (GyrB)/topoisomerase IV (ParE) inhibitors: Synthesis and antibacterial activity

The synthesis and antibacterial activities of three chemotypes of DNA supercoiling inhibitors based on imidazolo[1,2-a]pyridine and [1,2,4]triazolo[1,5-a]pyridine scaffolds that target the ATPase subunits of DNA gyrase and topoisomerase IV (GyrB/ParE) is reported. The most potent scaffold was selected for optimization leading to a series with potent Gram-positive antibacterial activity and a low resistance frequency.     

Synthesis and testing of 5-benzyl-2,4-diaminopyrimidines as potential inhibitors of leishmanial and trypanosomal dihydrofolate reductase

Dihydrofolate reductase is a drug target that has not been thoroughly investigated in leishmania and trypanosomes. Work has previously shown that 5-benzyl-2,4-diaminopyrimidines are selective inhibitors of the leishmanial and trypanosome enzymes. Modelling predicted that alkyl/aryl substitution on the 6-position of the pyrimidine ring should increase enzyme activity of 5-benzyl-2,4-diaminopyrimidines as inhibitors of leishmanial and trypanosomal dihydrofolate reductase. Various compounds were prepared and evaluated against both the recombinant enzymes and the intact organisms. The presence of a substituent had a small or negative effect on activity against the enzyme or intact parasites compared to unsubstituted compounds.     

Effect of osmolytes and chaperone-like action of P-protein on folding of nucleocapsid protein of Chandipura virus.

Amino acid sequences of nucleocapsid proteins are mostly conserved among different rhabdoviruses. The protein plays a common functional role in different RNA viruses by enwrapping the viral genomic RNA in an RNase-resistant form. Upon expression of the nucleocapsid protein alone in COS cells and in bacteria, it forms large insoluble aggregates. In this work, we have reported for the first time the full-length cloning of the N gene of Chandipura virus and its expression in Escherichia coli in a soluble monomeric form and purification using nonionic detergents. The biological activity of the soluble recombinant protein has been tested, and it was found to possess efficient RNA-binding ability. The state of aggregation of the recombinant protein was monitored using light scattering. In the absence of nonionic detergents, it formed large aggregates. Aggregation was significantly reduced in the presence of osmolytes such as d-sorbitol. Aggregate formation was suppressed in the presence of another viral product, phosphoprotein P, in a chaperone-like manner. Both the osmolyte and phosphoprotein P also suppressed aggregation to a great extent during refolding from a guanidine hydrochloride-denatured form. The function of the phosphoprotein and osmolyte appears to be synergistic to keep the N-protein in a soluble biologically competent form in virus-infected cells.     

Characteristics of users of traditional contraceptive methods in Bangladesh

Various national surveys suggest that the % of eligible couples in Bangladesh who are using traditional methods of contraception has been growing. This article presents detailed information on knowledge and use patterns of traditional methods and compares the use patterns of traditional and modern methods of contraception. The data are derived from the 1981 Contraceptive Prevalence Survey and information collected from a nationally representative sample of ever married women aged under 50, by way of field interviews using female interviewers. Quality of data was checked at different phases of the survey. Over 96% of the women reported that they knew at least 1 traditional method of contraception. The safe period was the most well known method (36.5%); about 30% reported knowledge of abstinence and 22% knew about withdrawal. Compared with modern methods, where knowledge declined with increased age, the knowledge of traditional methods shows no systematic pattern by age. Respondents with primary and higher education have higher knowledge of traditional methods than women who have never been to school. A similar pattern exists for employment status; non-Muslim women have consistently higher levels of knowledge than Muslim women. Data on patterns of use suggest that about 36% have used at least 1 contraceptive method, 15% having used traditional methods and 20.4% modern methods. The number of women who have used traditional methods increases from ages 20 to 44 and then declines. Use of traditional methods is relatively higher by the number of living children than by the number of children ever born. A similar pattern of association between background characteristics (education, employment and religion) and contraceptive knowledge is evident regarding level of use. Husband's level of education does not show any significant relationship with the use of traditional methods. The use rate of traditional methods was more than doubled among the women owning land compared to those having no land. The total current use rate of modern methods was higher among women aged 40-44 having relatively higher numbers of living children. As with current use, a positive relationship was observed between the socioeconomic variables and ever use. In general, it is concluded that socioeconomic variables played a dominant role in the decision of couples in choosing various methods of contraception. It is suggested that traditional methods still have an important role in family planning and that this should not be disregarded.