DBU mediated one-pot synthesis of triazolo triazines via Dimroth type rearrangement.

Herein we report an efficient one-pot synthesis of [1,2,4]triazolo[1,5 a][1,3,5]triazines from commercially available substituted aryl/heteroaryl aldehydes and substituted 2-hydrazinyl-1,3,5-triazines via N-bromosuccinimide (NBS) mediated oxidative C-N bond formation. Isomerisation of [1,2,4]triazolo[4,3-a][1,3,5]triazines to [1,2,4]triazolo[1,5-a][1,3,5]triazines is driven by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) affording both isomers with good to excellent yields (70-96%).

Development of a DHA-Losartan hybrid as a potent inhibitor of multiple pathway-induced platelet aggregation.

Despite the scientific progression in the prevention and treatment of cardiovascular diseases (CVDs) they remain the leading cause of mortality and disability worldwide. The classic treatment involves the simultaneous dosing of two antiplatelet drugs, aspirin and clopidogrel/prasugrel. However, besides drug resistance, severe side effects have been also manifested including acute bleeding and toxicity. Thus, new therapeutic agents with enhanced efficacy and diminished side effects are of importance. Towards this end, omega-3 (ω-3) fatty acids have demonstrated potent efficacy against CVDs through inhibiting platelet aggregation that bears a pivotal role in atherothrombosis. Another factor that displays a critical role in the pathogenesis of cardiovascular diseases is the renin-angiotensin system (RAS), and especially the AT1R blocker losartan that has been reported to exert antiplatelet activity mediated by this receptor. Along these lines, we envisaged developing a molecular hybrid consisted of docosahexaenoic acid (ω-3 fatty acid) and losartan, that could exert a notable antiplatelet effect against CVDs. The design and synthesis of the new DHA-losartan hybrid, designated DHA-L, bestowed with the additive properties of the parent compounds, is reported. In silico studies were first exploited to validate the potential of DHA-L to retain losartan's ability to bind AT1R. The antiplatelet activity of DHA-L was evaluated against in vitro platelet aggregation induced by several platelet agonists. Notably, the hybrid illustrated a pleiotropic antiplatelet profile inhibiting platelet aggregation through multiple platelet activation pathways including P2Y12, PAR-1 (Protease-Activated Receptor-1), PAF (Platelet Activating Factor), COX-1 (cyclooxygenase-1) and collagen receptors. The stability of DHA-L in human plasma and in a wide range of pH values was also evaluated over time using an HPLC protocol. The hybridization approach described herein could pave the way for the development of novel potent multitargeted therapeutics with enhanced antiplatelet profile.Communicated by Ramaswamy H. Sarma.

Development of niosomes for encapsulating captopril-quercetin prodrug to combat hypertension.

Novel and effective anti-hypertensive agents are required to manage hypertension; therefore, we synthesised a novel antihypertensive drug from captopril and quercetin (cap-que) and explored its antihypertensive potential in a niosomal formulation via molecular hybridisation. The cap-que hybrid was synthesised, and its structure was characterised via NMR, FTIR, and HRMS. Niosomes were then loaded with cap-que using the thin-film hydration method. The particle size, polydispersity index, surface charge and drug entrapment efficiency (EE%) of the formulation were 418.8 ± 4.21 nm, 0.393 ± 0.063, 16.25 ± 0.21 mV, and 87.74 ± 2.82%, respectively. The drug release profile showed a sustained release of the active compound (43 ± 0.09%) from the niosomal formulation, compared to the parent drug (80.7 ± 4.68%), over 24 h. The cell viability study confirmed the biosafety of the formulation. The in vivo study in a rat model showed enhanced antihypertensive activity of the hybrid molecule and niosomal formulation which reduced systolic and diastolic pressure when compared to the individual, bare drugs. The findings of this study concluded that the antihypertensive potential of captopril can be enhanced by its hybridisation with quercetin, followed by niosomal nano drug delivery.

Development of novel GnRH and Tat48-60 based luminescent probes with enhanced cellular uptake and bioimaging profile.

There is a clear need to develop photostable chromophores for bioimaging with respect to the classically utilized green fluorescent dye fluorescein. Along these lines, we utilized a phosphorescent carboxy-substituted ruthenium(ii) polypyridyl [Ru(bipy)2(mcb)]2+ (bipy = 2,2'-bipyridyl and mcb = 4-carboxy-4'-methyl-2,2'-bipyridyl) complex. We developed two luminescent peptide conjugates of the cell-penetrating peptide Tat48-60 consisting of either [Ru(bipy)2(mcb)]2+ or 5(6)-carboxyfluorescein (5(6)-FAM) tethered on the Lys50 of the peptide through amide bond. We confirmed the efficient cellular uptake of both bioconjugates in HeLa cells by confocal microscopy and flow cytometry and proved that the ruthenium-based chromophore possesses enhanced photostability compared to a 5(6)-FAM-based peptide, after continuous laser scanning. Furthermore, we designed and developed a luminescent agent with high photostability, based on the ruthenium core, that could be selectively localized in cancer cells overexpressing the GnRH receptor (GnRH-R). To achieve this, we took advantage of the tumor-homing character of d-Lys6-GnRH which selectively recognizes the GnRH-R. The [Ru(bipy)2(mcb)]2+-d-Lys6-GnRH peptide conjugate was synthesized, and its cellular uptake was evaluated through flow cytometric analysis and live-cell imaging in HeLa and T24 bladder cancer cells as negative and positive controls of GnRH-R, respectively. Besides the selective targeting that the specific conjugate could offer, we also recorded high internalization levels in T24 bladder cancer cells. The ruthenium(ii) polypyridyl peptide-based conjugates we developed is an intriguing approach that offers targeted cell imaging in the Near Infrared region, and simultaneously paves the way for further advancements in the dynamic studies on cellular imaging.