Synthesis and evaluation of novel S-benzyl- and S-alkylphthalimide- oxadiazole -benzenesulfonamide hybrids as inhibitors of dengue virus protease.

Direct acting antiviral drugs (DAADs) are becoming therapeutics of choice for the treatment of viral infections. Successful development of anti HIV and HCV drugs by targeting the viral proteases has provided impetus for discovering newer DAADs. Dengue virus (DENV) protease, which is composed of two nonstructural proteins, NS2B and NS3pro, can be likewise exploited for discovering new anti-dengue therapeutics. In this study, we have linked together two pharmaceutically interesting motifs, namely 1,3,4-oxadiazole and benzenesulfonamide in two alternative series to develop novel S-benzylated and S-alkylphthalimidated hybrids. For the first series of hybrids, 4-aminobenzoic acid (1) was reacted with substituted benzenesulfonyl chlorides via its amino group, whereas the carboxylic acid side was elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (6a/b) in three steps. At this stage, the intermediates 6a/b were bifurcated to either S-alkylphthalimidated (8a-j) or S-benzylated (9a-c) hybrids by reacting with corresponding halides. For the alternative series of hybrids, the carboxylic acid group of probenecid (10) was similarly elaborated to sulfonamido-1,3,4-oxadiazole-2-thiols (13), and diverged to S-alkylphthalimidated (14a-f) and S-benzylated hybrids (15a-e). Bioactivity assays demonstrated that 8g and 8h are the most potent inhibitors among the synthesized analogs, exhibiting the IC50 values of 13.9 µM and 15.1 µM, respectively. Computational assessment predicted the binding of the inhibitors at an allosteric site developed in the open conformation of DENV2 NS2B/NS3pro. Taken together these findings point out that the synthesized hybrid inhibitors possess a great potential for further antiviral drug development.

Phytochemistry of Daphne oleoides.

Genus Daphne belongs to the Thymelaeaceae family and consists of 70 species. Its various species exist in Europe, Philippine Islands, temperate and subtropical Asia, North Africa, Australia and Pacific. In Pakistan, Daphne is represented by three species. Our focused Daphne oleoides is widely found in diverse climatic conditions from northern cold to central hot regions which creates a rich diversity and novelty in biosynthetic levels of its chemical constituents and hence is a great opportunity. Daphne oeloides is a proven rich source of a variety of unique and interesting nature-made skeletons with a wide range of therapeutic properties. D. oleoides possesses effective therapeutic properties, therefore, has been used in herbal medicines and is still being used to treat various diseases. The modern research by various groups, including ourselves, has resulted in the isolation of a number of natural molecules including some novel tris- and bis- coumarins, daphnane diterpenoids and lignoids. Therefore, due to novelty and richness of the nature-made molecules, and their therapeutic potential combined with our significant work on D. oleoides, this report covers chemical constituents isolated from D. oleoides. The pharmacological activities of the isolated compounds and use of this species in folk medicine have also been reviewed.

Comparison of postoperative pain relief by intercostal block between pre-rib harvest and post-rib harvest groups.

OBJECTIVE: To compare intercostal nerve block before and after rib harvest in terms of mean postoperative pain score and mean postoperative tramadol usage. STUDY DESIGN: Randomized controlled trial. PLACE AND DURATION OF STUDY: Department of Plastic Surgery, Mayo Hospital, KEMU, Lahore, from January 2011 to July 2012. METHODOLOGY: Patients (n = 120) of either gender with ASA class-I and II requiring autogenous costal cartilage graft were inducted. Patients having history of local anaesthetic hypersensitivity and age < 15 years or > 60 years were excluded. Subjects were randomly assigned to pre-rib harvest (group-1) and post-rib harvest (group-2). Local anaesthetic mixture was prepared by adding 10 milliliters 2% lidocaine to 10 milliliters 0.5% bupivacaine to obtain a total 20 ml solution. Group-1 received local anaesthetic infiltration along the proposed incision lines and intercostals block before the rib harvest. Group-2 received the infiltration and block after rib harvest. Postoperative consumption of tramadol and pain scores were measured at 6 and 12 hours postoperatively using VAS. RESULTS: Mean age was 31.43 ± 10.78 years. The mean pain scores at 6 hours postoperatively were 1.033 ± 0.609 and 2.4667 ± 0.812 in pre-rib harvest and post-rib harvest groups respectively (p < 0.0001). The mean pain scores at 12 hours postoperatively were 1.45 ± 0.565 and 3.65 ± 0.633 in pre-rib harvest and post-rib harvest groups respectively (p < 0.0001). The mean tramadol used postoperatively in first 24 hours was 169 ± 29.24 mg and 255 ± 17.70 mg in prerib harvest and post-rib harvest groups respectively (p < 0.0001). CONCLUSION: Intercostal block administered before rib harvest as preemptive strategy result in decreased postoperative pain scores and narcotic use.