COMBATTING CHALLENGING ASPECTS OF CANCER WITH THIOSEMICARBAZONES

Cancer claims the second largest number of deaths across the globe every year. With the new addition and discoveries in the therapeutic area, there are also some serious challenges which come into play. These include the emergence of resistance, malignancy, relapses and some life-threatening adverse effects. These challenges further intensify the need to discover better alternatives. Thiosemicarbazones have been explored extensively against many resistant and non-resistant forms of cancer in vitro as well as in vivo. Chelation of iron and copper has been attributed to their activity as anticancer agents, but recent studies have revealed few more complex mechanisms of their action. With different approaches to target different aspects of cancers, they have gained ample attention. Structural variations of these compounds were found to be highly selective in their action

Synthesis and Pharmacological Evaluation of Some Novel Imidazole Derivatives for Their Potential Anti-hypertensive Activity

Benzimidazole, which is a heterocyclic nucleus, plays an important role in various medicines. A number of therapeutic agents such as H1 antihistaminic agent clemizole, a potent opioid analgesic etonitazene, nonnucleoside antiviral compound enviroxime, for promotion of excretion of uric acid irtemazole, non sedating antihistaminic agent astemizole, anti ulcer drugs omeprazole and pentoprazole, antihelmintic thiabendazole, antinematodal nocodazole etc. are based on benzimidazole heterocyclic nucleus. The synthesis of various benzimidazole derivatives by the reaction of ortho phenylene diamine I with various organic acids to yield 2-substituted benzimidazole derivatives II which on further treatment with nitric acid and sulphuric acid yielded 5-nitro-2-substituted benzimdazoles III. Coupling of this compound with halogenated beta picoline V yielded the title compounds. The structures of synthesized compounds were elucidated mainly by spectral evidence. All the compounds were screened for their anti-hypertensive activity. The compounds exhibited moderate to signiicant activities

Cold Injury Prevention and Management in High Altitude Extreme Environments Pharmacological and Therapeutical Interventions

Cold injury refers to local or systemic body response that occurs due to massive loss of body heat when the body is exposed to extremely cold temperatures. The current modalities for the prevention and management of cold injury(ies) are very limited due to the paucity of availability of targeted therapeutics. Pathophysiological cascades in cold injury include: (a) desensitization of sensory neurons can be manifest as a result of altered pathophysiological functions viz., Ca2+ imaging, calcitonin gene-related peptide release, expressions of inflammatory mediators (PGE2: prostaglandin E2, NGF: nerve growth factors), (b) inflammatory markers viz.; interleukins (IL-1β, IL-6, and IL-10), tumor necrosis factor-alpha (TNF-α), and CD62E/endothelial-leukocyte adhesion molecule 1 (E-selectin); (c) oxidative stress markers associated with cold injury measured through serum level of protein carbonyl, 4-hydroxy-2-nonenal (4-HNE), superoxide dismutase (SODs), advanced oxidative protein products (AOPP) and nitrotyrosine; (d) endothelial damage: nitric oxide (NO), prostacyclin (PGI2), reactive oxygen species (ROS), Von-Willebrand factor (VWF), CD31/PECAM-1 (platelet/endothelial cell adhesion molecule 1), CD36/SR-B3 (scavenger receptor class B member 3) and tissue-type plasminogen activator (TTPA). In this review paper, we elaborate on the current state-of-the-art pharmacological interventions for cold injury that may be beneficial in developing novel and targeted therapeutics for the prevention, management, and treatment of cold injury

Physicochemical Characterisation of Commercially Available Prussian Blue Insoluble Samples and Its Comparison with Radiogardase Cs

The physicochemical properties of insoluble Prussian blue (PB) play an important role in its thallium binding ability. Therefore, the present study aimed to characterise various physicochemical parameters of PB available commercially and compare them with the USFDA-approved Radiogardase ® -Cs. In addition, PB was synthesised by indirect and direct methods. PB samples and Radiogardase®-Cs were analysed for various parameters like particle size, moisture content, and thermogravimetric analysis (TGA) and correlated with its Maximum Binding Capacity (MBC) for thallium. Radiogardase ® -Cs showed the highest MBC of 238 mg/g for thallium with D 90 of 785 μm and moisture content of 23.24 %. The MBC of other PB samples was found to be significantly lower than Radiogardase ® -Cs which was found to be directly proportional to the moisture content. However, other parameters like particle size, and iron content vary significantly but no correlation was observed with MBC for thallium. This finding suggests that moisture content and MBC are extremely important parameters for optimising the PB to achieve desirable pharmacological efficacy for removing thallium in vivo

BENZOXAZOLE: THE MOLECULE OF DIVERSE PHARMACOLOGICAL IMPORTANCE

Benzoxazole nucleus is one of the most important heterocyclic compounds exhibiting remarkable pharmacological activities. The present review provides a broad overview of the synthesis and pharmacological activities such as antimycobacterial, anticonvulsant, anti-inflammatory, anticancer, DNA topoisomerase inhibitor, cholesterol ester transfer protein inhibitor and miscellaneous activities.Â

Crystallographic mining driven computer-guided approach to identify the ASK1 inhibitor likely to perturb the catalytic region

The pathological levels of reactive oxygen species (ROS) and oxidative stress has been recognized as a critical driver for inflammatory disorders. Apoptosis signal-regulating kinase 1 (ASK1) has been reported to be activated by intracellular ROS and its inhibition leads to a down regulation of p38-and JNK-dependent signaling. ASK1 inhibitors are reported to have the potential to treat clinically important inflammatory pathologies including liver, pulmonary and renal disorders. In view of its biological and pathological significance, inhibition of ASK1 with small molecules has been pursued as an attractive strategy to combat human diseases such as non-alcoholic steatohepatitis (NASH). Despite several ASK1 inhibitors being developed, the failure in Phase 3 clinical trials of most advanced candidate selonsertib’s, underscores to discover therapeutic agents with diverse chemical moiety. Here, by using structural pharmacophore and enumeration strategy on mining co-crystals of ASK1, different scaffolds were generated to enhance the chemical diversity keeping the critical molecular interaction in the catalytic site intact. A total of 15,772 compounds were generated from diverse chemical scaffolds and were evaluated using a virtual screening pipeline. Based on docking and MM-GBSA scores, a lead candidate, S3C-1-D424 was identified from top hits. A comparative molecular dynamics simulations (MD) of APO, Selonsertib and shortlisted potential candidates combined with pharmacokinetics profiling and thermodynamic analysis, demonstrating their suitability as potential ASK1 inhibitors to explore further for establishment towards hit-to-lead campaign. Communicated by Ramaswamy H. Sarma</p