Design, in silico study, synthesis and in vitro evaluation of some N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives as potential pancreatic lipase inhibitors for anti-obesity activity.

OBJECTIVE: The aim of the study is to design N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives and evaluate its anti-obesity activity. MATERIALS AND METHODS: A few pyrazole-fused benzimidazole derivatives were designed as potential Pancreatic Lipase (PL) inhibitors. The designed N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine derivatives have been screened using the Lipinski rule of five, ADMET analysis, acute toxicity prediction, and molecular docking. Later on, the derivatives which possess the most drug-likeness properties and displayed the most potent inhibition of the enzyme in molecular docking were synthesized. Then, in vitro enzyme assay was performed. RESULTS: Orlistat used as the standard exhibited 91±1.68% inhibition of the enzyme, displayed binding affinity (BA) of only -4.5 kcal/mol with Pancreatic Lipase (PL), and made only one salt bridge attractive charge and carbon-hydrogen bond with ASP79 and TRP252, respectively. Compound 9 displayed the most potent activity (93±1.12% inhibition of P.L. and -9.5 kcal/mol BA). It has formed five conventional H- bonds with GLU253, ILE78, ASP79, PHE258, and one Pi-donor H- bond with ILE78. From the present investigation, we hereby reported (E)-N2-((naphthalene-1-yl)methylene)-N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine as most potent PL inhibitor for the treatment of obesity, which can be further optimized by undergoing more studies using in vivo and in vitro models. CONCLUSIONS: (E)-N2-((naphthalene-1-yl)methylene)-N5-(1H-pyrazol-3-yl)-3H-benzo[d]imidazole-2,5-diamine as most potent PL inhibitor for the treatment of obesity which can be further optimized better using more in vivo and in vitro models. PL plays a critical role in digesting dietary fat. Therefore, PL inhibitors are verified as a potential therapy for treating obesity.

Modulation of host epigenome by coronavirus infections and developing treatment modalities for COVID-19 beyond genetics.

The recent Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) outbreak has resulted in coronavirus disease 2019 (COVID-19) pandemic worldwide, affecting millions of lives. Although vaccines are presently made available, and vaccination drive is in progress to immunize a larger population; still the risk of SARS-CoV-2 infection and related mortality is persistent amid threats of the third wave of the ongoing pandemic. In the scenario of unavailability of robust and efficient treatment modalities, it becomes essential to understand the mechanism of action of the virus and deeply study the molecular mechanisms (both at the virus level and the host level) underlying the infection processes. Recent studies have shown that coronaviruses (CoVs) cause-specific epigenetic changes in the host cells to create a conducive microenvironment for replicating, assembling, and spreading. Epigenetic mechanisms can contribute to various aspects of the SARS-CoV-2 multiplication cycle, like expressing cytokine genes, viral receptor ACE2, and implicating different histone modifications. For SARS-CoV-2 infection, viral proteins are physically associated with various host proteins resulting in numerous interactions between epigenetic enzymes (i.e., histone deacetylases, bromodomain-containing proteins). The involvement of epigenetic mechanisms in the virus life cycle and the host immune responses to control infection result in epigenetic factors recognized as emerging prognostic COVID-19 biomarkers and epigenetic modulators as robust therapeutic targets to curb COVID-19. Therefore, this narrative review aimed to summarize and discuss the various epigenetic mechanisms that control gene expression and how these mechanisms are altered in the host cells during coronavirus infection. We also discuss the opportunities to exploit these epigenetic changes as therapeutic targets for SARS-CoV-2 infection. Epigenetic alterations and regulation play a pivotal role at various levels of coronavirus infection: entry, replication/transcription, and the process of maturation of viral proteins. Coronaviruses modulate the host epigenome to escape the host immune mechanisms. Therefore, host epigenetic alterations induced by CoVs can be considered to develop targeted therapies for COVID-19.

Melioidosis: Case reports of confirmed Burkholderia pseudomallei in Saudi Arabia.

Melioidosis is an infectious disease of tropical climates. The disease is caused by the bacterium Burkholderia pseudomallei. Most cases are diagnosed in southeast Asia and northern Australia. Some imported cases diagnosed in returning tourists, soldiers, and immigrants from endemic areas. It caught much attention since the Centers for Disease Control and Prevention (CDC) designated B. pseudomallei as an agent for biological warfare and terrorism. We describe two cases of a 26-year-old Saudi woman who had fulminant sepsis soon after returning from Thailand & a 48-year-old woman with a long history of fever. B. pseudomallei was isolated from both patients blood cultures, and they had different consequences. A confirmed case of melioidosis was not reported before in Saudi Arabia.

An investigation of the role acceptor side chains play in the processibility and efficiency of organic solar cells fabricated from small molecular donors featuring 3,4-ethylenedioxythiophene cores.

Organic photovoltaic devices fabricated from small molecular donors continue to receive significant interest due to their desirable properties such as convenient synthesis, purification and batch-to-batch reproducibility. In this study, we have synthesized two small molecules based on an alternating A-D-A structure, utilizing a central EDOT donor moiety and either 2-ethylhexyl cyanoacetate (SAM-72) or N-(2-ethylhexyl)cyanoacetamide (SAM-80) units as acceptor termini. The small molecules were incorporated into bulk heterojunction solar cells with PC71BM. Our investigations have shown that the side chains utilized for SAM-80 only allow for solution processing using volatile solvents, such as chloroform, which limits the reproducibility of device fabrication. However, SAM-72 displays better solubility and devices fabricated using a SAM-72:PC71BM active layer reached average power conversion efficiencies of 1.9%, with fill factors reaching 60%. Post-processing methods such as thermal and solvent vapor annealing were found to significantly increase the stability of devices, but were not able to improve overall device performance.

Evidence for multidimensional resilience in adult patients with transfusion-dependent thalassemias: Is it more common than we think?

BACKGROUND: Life expectancy of patients with transfusion-dependent thalassemias has increased with the development of improved treatment over the last few decades. However, ß-thalassemia disorder still has considerable lifetime treatment demands and heightened risk of frequent complications due to transfusion-transmitted infections and iron overload, which may affect thalassemic patients' functioning in different domains. OBJECTIVES: The vast majority of published studies on thalassemic patients have focused on children and adolescent functioning, and little research has examined adults. Hence, the current study was planned to examine the functioning and resilience of adult thalassemic patients in a comprehensive way. METHODS: We examined multidimensional resilience and functioning across different domains (psychological adjustment, treatment adherence, social functioning and occupational functioning). We also examined demographic and medical variables that may relate to resilience and functioning. Participants were adult patients [n = 38; age M = 31·63, standard deviation (SD) = 7·72; 72% female] with transfusion-dependent thalassemia in treatment in a hospital in the northeastern United States. RESULTS: The results suggest that most adult thalassemic patients tend to be resilient, demonstrating good functioning in four main domains: psychological adjustment, treatment adherence, social functioning and occupational functioning. CONCLUSION: Despite the considerable demands of their illness, adult thalassemic patients appeared to be adapting well, demonstrating evidence of multidimensional resilience.