Imidazopyridine-based kinase inhibitors as potential anticancer agents: A review.

Considering the fundamental role of protein kinases in the mechanism of protein phosphorylation in critical cellular processes, their dysregulation, especially in cancers, has underscored their therapeutic relevance. Imidazopyridines represent versatile scaffolds found in abundant bioactive compounds. Given their structural features, imidazopyridines have possessed pivotal potency to interact with different protein kinases, inspiring researchers to carry out numerous structural variations. In this comprehensive review, we encompass an extensive survey of the design and biological evaluations of imidazopyridine-based small molecules as potential agents targeting diverse kinases for anticancer applications. We describe the structural elements critical to inhibitory potency, elucidating their key structure-activity relationships (SAR) and mode of actions, where available. We classify these compounds into two groups: Serine/threonine and Tyrosine inhibitors. By highlighting the promising role of imidazopyridines in kinase inhibition, we aim to facilitate the design and development of more effective, targeted compounds for cancer treatment.

2-(Nitroaryl)-5-Substituted-1,3,4-Thiadiazole Derivatives with Antiprotozoal Activities: In Vitro and In Vivo Study.

Nitro-containing compounds are a well-known class of anti-infective agents, especially in the field of anti-parasitic drug discovery. HAT or sleeping sickness is a neglected tropical disease caused by a protozoan parasite, Trypanosoma brucei. Following the approval of fexinidazole as the first oral treatment for both stages of T. b. gambiense HAT, there is an increased interest in developing new nitro-containing compounds against parasitic diseases. In our previous projects, we synthesized several megazole derivatives that presented high activity against Leishmania major promastigotes. Here, we screened and evaluated their trypanocidal activity. Most of the compounds showed submicromolar IC50 against the BSF form of T. b. rhodesiense (STIB 900). To the best of our knowledge, compound 18c is one of the most potent nitro-containing agents reported against HAT in vitro. Compound 18g revealed an acceptable cure rate in the acute mouse model of HAT, accompanied with noteworthy in vitro activity against T. brucei, T. cruzi, and L. donovani. Taken together, these results suggest that these compounds are promising candidates to evaluate their pharmacokinetic and biological profiles in the future.

Quinazoline-based VEGFR-2 inhibitors as potential anti-angiogenic agents: A contemporary perspective of SAR and molecular docking studies.

Angiogenesis, the formation of new blood vessels from the existing vasculature, is pivotal in the migration, growth, and differentiation of endothelial cells in normal physiological conditions. In various types of tumour microenvironments, dysregulated angiogenesis plays a crucial role in supplying oxygen and nutrients to cancerous cells, leading to tumour size growth. VEGFR-2 tyrosine kinase has been extensively studied as a critical regulator of angiogenesis; thus, inhibition of VEGFR-2 has been widely used for cancer treatments in recent years. Quinazoline nucleus is a privileged and versatile scaffold with a broad range of pharmacological activity, especially in the field of tyrosine kinase inhibitors with more than twenty small molecule inhibitors approved by the US Food and Drug Administration in the last two decades. As of now, the U.S. FDA has approved eleven small chemical inhibitors of VEGFR-2 for various types of malignancies, with a prime example being vandetanib, a quinazoline derivative, which is a multi targeted kinase inhibitor used for the treatment of late-stage medullary thyroid cancer. Despite of prosperous discovery and development of VEGFR-2 down regulator drugs, there still exists limitations in clinical efficacy, adverse effects, a high rate of clinical discontinuation and drug resistance. Therefore, there is an urgent need for the design and synthesis of more selective and effective inhibitors to tackle these challenges. Through the gathering of this review, we have strived to broaden the extent of our view over the entire scope of quinazoline-based VEGFR-2 inhibitors. Herein, we give an overview of the importance and advancement status of reported structures, highlighting the SAR, biological evaluations and their binding modes.

Economic impact assessment indicators of circular economy in a decentralised circular water system - Case of eco-touristic facility.

The transition from a linear make-use-dispose model to a Circular Economy (CE) model has gained momentum in recent years. To date, substantive efforts have been put by researchers and practitioners on environmental assessment of circular water systems (CWS). Yet, the economic aspect of CWS has not received the same attention. This research is an attempt to bridge this gap by evaluating the economic viability of a decentralised hybrid rainwater- wastewater-greywater (HRWG) system. For this purpose, a framework of Shadow Pricing- Life Cycle Cost-Benefit (SLCCB) to analyse a CWS is proposed. Shadow pricing could compliment the established Life Cycle Costing (LCC) methods. The main parameters (costs and benefits) of the proposed SLCCB framework are divided into two types: Internal and External. The Internal pricing covers the capital expenditure (CAPEX) and operational expenditure (OPEX), while the External pricing covers the environmental and social costs-benefits of implementing CWS. The proposed SLCCB added to the classical Net Present Value (NPV) and Payback Period (PP) calculations could provide a more realistic evaluation of the economic performance of CWS. To demonstrate the efficacy of the new CE model, a new CWS in Greece was studied. A sensitivity analysis was conducted to assess the impact of the reclaimed water tariffs, internal costs, life span of the project, and the annual discount rate on the SLCCB. The results of the study reveal that the SLCCB of CWS is highly sensitive to these parameters. The economic feasibility of CWS boost with increasing discount rate and reclaimed water tariffs, as well as with decreasing project's life span and internal costs. The conclusion of this research demonstrates that investment in CWS is economically viable if External parameters are taken into consideration.

Economic assessment of nature-based solutions as enablers of circularity in water systems.

The transition from the current linear model of abstraction, use and discharge of water into recycle-reuse under the circular economy (CE) principles is momentous. An analysis of recent literature about the economic impact of linear to circular (L2C) transition is made. The review investigates the economic implications (i.e. cost-benefit) of deployment of enabling technologies, tools and methodologies within the circular water systems. The study is enhanced by presenting the results of our investigation into the policy impact (push-barriers) of L2C transition. As the vehicle for the L2C transition, nature-based solutions (NBS) and its economic and policy implications is discussed. A framework is proposed for the monetary assessment of the costs of investment in NBS technologies, infrastructure and education against the environmental and socio-economic benefits within the policy frameworks. This framework may build the early foundation for bridging the gap that exists for a systematic and objective economic impact (cost-benefit) analysis of L2C transition in the Water sector. This framework will lead to a generic multi-parametric cost model of NBS for Circularity Water Systems.

Midbrain area for differentiating Parkinson's disease from progressive supranuclear palsy.

OBJECTIVES: We aimed to investigate the values of midbrain area in diagnosing Parkinson's Disease (PD) and progressive supranuclear palsy (PSP) by using transcranial sonography (TCS). Disease duration effect on brain sonographic findings could decrease the accuracy of TCS in PD and PSP patients. We reduced the disease duration effect on sonographic differences found between PD and PSP patients by using multivariate analysis. PATIENTS AND METHODS: Patients with clinical diagnosis of PSP and PD were recruited. We used SonoSite Edge II Ultrasound system to measure midbrain area, diameter of third ventricle and substantia nigra echogenicity. Diagnostic value of each measured area in sonography was estimated regarding its power for diagnosing PD or PSP. Independent sample t-test, Regression analysis and receiver operating characteristic (ROC) curve were performed using SPSS software. RESULTS: Of 35 patients, 18 were PD and 17 PSP cases. The mean midbrain area was 4.86 ± 0.71cm2 in PD patients and 3.61 ± 0.85cm2 in those with PSP (P < 0.005). Regression for reducing the effect of disease duration on midbrain area variances between patients with PD and PSP revealed a significant P value (P < 0.005, Adjusted R2 = 0.36). The sensitivity and specificity of midbrain area in diagnosing PD were 83.3% and 70.6% respectively. The sensitivity of the third ventricle size in diagnosing PSP was 82% although its specificity was 62%. CONCLUSION: Midbrain area in patients with PD was wider than those with PSP that was not affected by disease duration. Midbrain area was the most accurate index for diagnosing PD by TCS although third ventricle size was the most sensitive one for diagnosing PSP.