Syntheses of the thiazolo[4,5-d]pyrimidine system

This review is focused on the literature data about the preparation of the thiazolo[4,5-d]pyrimidine scaffold. The synthesis of this ring system has been accomplished by various methods. The synthesis can proceed via a pyrimidine onto which a thiazole ring can be annulated. The second approach involve annulation of a pyrimidine ring onto the preformed thiazole ring. Thiazolo[4,5-d]pyrimidines have been obtained by condensation of pyrimidine derivatives with thioamides [2], thionyl chloride [3], thiourea [4], bromomalononitrile [5], isothiocyanates [6] or under the influence of temperature [7]. However, most of the literature refers the methods of synthesis which begin with formation of the appropriately substituted thiazole ring. This synthetic route for preparation of fused derivatives utilizes orhtoesters [8, 9], acetic anhydride [9,10], formic acid derivatives [11, 12], carbon disulfide [13,14], appropriate isothiocyanates [15-18], urea and hydrazine derivatives [19–23], aromatic aldehydes and acid chlorides [24, 25] as key building blocks. Cyclization also occurs in high temperature or acidic reaction medium [26, 27]. The solid-phase synthesis was also described [28]

Biological activity of thiazolo[4,5-d]pyrimidine derivatives

Thiazolo[4,5-d]pyrimidine is one of the six structural isomers of the bicyclic ring system containing thiazole moiety fused with the pyrimidine. There are six structural isomers depending on the position of the nitrogen atoms. The isomer [4,5-d] does not contain the bridge-head nitrogen and can be considered as 7-thio analogue of the natural purine bases such as guanine and adenine. Due to the great of their biological potential the newly synthesized compounds are evaluated for various pharmacological activities. This review presents numerous thiazolo[4,5-d]pyrimidine derivatives reported for their interesting biological activity including antibacterial [2, 3, 5, 7, 8, 10, 19], antifungal [2–6, 9, 10], antiviral [11–13], analgesic [18, 19], antidepressant [17] and anticancer properties [23–26]. Some urea and thiourea derivatives exhibited significant antiparkinsonian activity [14–16]. Tumor necrosis factor (TNF) promotes an inflammatory response, which in turn causes many of the clinical problems associated with autoimmune disorders. Ethyl 4-(2-amino-5,7-dioxo-3,4,5,7-tetrahydro-thiazolo[4,5-d]pyrimidin- 6(2H)-yl)butanoate derivatives 29 (Fig. 24) as a TNFα inhibitors have a potential use in the treatment of diseases such as refractory asthma, psoriasis, rheumatoid arthritis, irritable bowel syndrome, and other [21]. Blocade of the CXCR2 receptor by thiazolo[4,5-d]pyrimidine-2(3H)-ones also represents an attractive strategy for treatment of inflammatory diseases [20]. Recently there have been developed CX3CR1 receptor antagonists for the treatment of multiple sclerosis [22]. Isatoribine, 5-amino-3-β-D-ribofuranosyl-3H-thiazolo[4,5-d]pyrimidin-2-one (20) (Fig. 15) is a small molecule toll-like receptor 7 (TLR7) agonist and an activator of innate immunity. Its orally bioavailable analogue ANA 975 (Fig. 16) has been reported for probable use in treating disease states associated with abnormal cell growth, such as cancer and has anti HCV activity [13]. Thiazolo[4,5-d]pyrimidines inhibit the growth of the weeds which implies that they have a potential as herbicides [27]

The comparative effectiveness of Core versus Core+Enhanced implementation strategies in a randomized controlled trial to improve substance use treatment receipt among justice-involved youth

Abstract Background Most justice-involved youth are supervised in community settings, where assessment and linkage to substance use (SU) treatment services are inconsistent and fragmented. Only 1/3 of youth with an identified SU need receive a treatment referral and even fewer initiate services. Thus, improving identification and linkage to treatment requires coordination across juvenile justice (JJ) and behavioral health (BH) agencies. The current study examines the comparative effectiveness of two bundled implementation intervention strategies for improving SU treatment initiation, engagement, and continuing care among justice-involved youth supervised in community settings. Exploration, Preparation, Implementation, Sustainment (EPIS) served as the conceptual framework for study design and selection/timing of implementation intervention components, and the BH Services Cascade served as the conceptual and measurement framework for identifying and addressing gaps in service receipt. Methods Part of a larger Juvenile-Justice Translational Research on Interventions for Adolescents in the Legal System (JJ-TRIALS) Cooperative, this study involved a multisite, cluster-randomized control trial where sites were paired then randomly assigned to receive Core (training teams on the BH Services Cascade and data-driven decision making; supporting goal selection) or Core+Enhanced (external facilitation of implementation teams) intervention components. Youth service records were collected from 20 JJ community supervision agencies (in five states) across five study phases (baseline, pre-randomization, early experiment, late experiment, maintenance). Implementation teams comprised of JJ and BH staff collaboratively identified goals along the BH Cascade and used data-driven decision-making to implement change. Results Results suggest that Core intervention components were effective at increasing service receipt over time relative to baseline, but differences between Core and Core+Enhanced conditions were non-significant. Time to service initiation was shorter among Core+Enhanced sites, and deeper Cascade penetration occurred when external facilitation (of implementation teams) was provided. Wide variation existed in the degree and nature of change across service systems. Conclusions Findings demonstrate the criticality of early EPIS phases, demonstrating that strategies provided during the formative exploration and preparation phases produced some improvement in service receipt, whereas implementation-focused activities produced incremental improvement in moving youth farther along the Cascade

Leadership and Workplace Innovation: An Investigation of Asian SMEs

Few studies have explored the relationship between leadership and workplace innovation in non-Western contexts. The purpose of this study was to examine this relationship in the context of two Asian countries. To this end, structural equation modelling (SEM) was implemented to analyze 696 usable questionnaires received from staff employed in small to medium enterprises (SMEs) in Thailand and Vietnam. The results revealed that design leadership has a significant effect on the four dimensions of workplace innovation, thus confirming an interactionist theory perspective which is under-researched in Thai and Vietnamese SME contexts. This study therefore extends the design leadership and innovation literatures