New anti-inflammatory thiazolyl-carbonyl-thiosemicarbazides and thiazolyl-azoles with antioxidant properties as potential iNOS inhibitors

The varied reactions of the host to infection, inflammation, or trauma are collectively known as the acute-phase response and encompass a wide range of pathophysiological responses such as pyrexia, leukocytosis, hormone alterations, and muscle protein depletion combining to minimize tissue damage while enhancing the repair process. The mechanism for stimulation of hepatic production of acute-phase proteins is by proinflammatory cytokines. The functions of positive acute-phase proteins (APP) are regarded as important in optimization and trapping of microorganism and their products, in activating the complement system, in binding cellular remnants like nuclear fractions, in neutralizing enzymes, scavenging free hemoglobin and radicals, and in modulating the host’s immune response. APP can be used as diagnostic tool in many diseases like bovine respiratory syncytial virus, prostate cancer, bronchopneumonia, multiple myeloma, mastitis, Streptococcus suis infection, starvation, or lymphatic neoplasia. Thus, acute-phase proteins may provide an alternative means of monitoring animal health.

A novel series of potent specific HIV-1 inhibitory compounds is described. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 microM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 microM. The 50% cytotoxic dose in cell culture is > 380 microM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2-pyridyl)-thiourea (62; LY300046.HCl) as a candidate for clinical evaluation. LY300046.HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.

Production of NO from arginine and molecular oxygen is a complex chemical reaction unique to biology. Our understanding of the chemical and regulation mechanisms of the NO synthases has developed over the past two decades, uncovering some extraordinary features. This article reviews recent progress and highlights current issues and controversies. The structure of the enzyme has now been determined almost in entirety, although it is as a selection of fragments, which are difficult to assemble unambiguously. NO synthesis is driven by electron transfer through FAD and FMN cofactors, which is controlled by calmodulin binding in the constitutive mammalian enzymes. Many of the unique structural features involved have been characterised, but the mechanics of calmodulin-dependent activation are largely unresolved. Ultimately, NO is produced in the active site by the reaction of arginine with activated heme-bound oxygen in two distinct cycles. The unique role of the tetrahydrobiopterin cofactor as an electron donor in this process has now been established, but the subsequent chemical events are currently a matter of intense speculation and debate. Copyright (c) 2010 Elsevier Inc. All rights reserved.