Pyrazole, Pyrazoline, and Fused Pyrazole Derivatives: New Horizons in EGFR-Targeted Anticancer Agents.

Pyrazole and its derivatives remain popular heterocycles in drug design, and development. Pyrazole derivatives been extensively studied by the scientific community and as they possess a wide range of biological activity, especially anti-EGFR properies. Overexpression of EGFR signaling promotes tumor growth by inhibiting apoptosis. EGFR dysfunction has been described in several cancer. Therefore, EGFR represents a prospective target for cancer treatment. Several anti-EGFR drugs are thriving the market, notably dacomitinib, afatinib, erlotinib etc. However, almost all drugs have limited therapeutic effectiveness due to a lack of selectivity as well as substantial side effects.  To address this, innovative therapeutic anti-EGFR drugs with high effectiveness and low toxicity are needed. To combat therapeutic resistance to EGFR inhibitors, pyrazole, and pyrazole-based derivatives have been explored as a promising pharmacophore for developing novel compounds with higher potency, lower toxicity, and desirable pharmacokinetic profiles. The current review outlines the investigation of advancements towards anti- EGFR via pyrazole, pyrazoline, and fused pyrazole-based compounds and represents inclusive data on pyrazole-based marketed drugs as well as therapeutic candidates undergoing preclinical and clinical development. We have also summarised structure-activity relationship (SAR), mechanistic studies to afford ideas for the design and development of new anti-EGFR derivatives.

Ultra-sound assisted extraction, anti-oxidant, cytotoxic and anti-microbial studies of Moringa oleifera flowers.

The study was undertaken to determine antioxidant, anticancer and antimicrobial activities of Moringa oleifera flowers. We used three different solvents, hexane (MOF-H), ethyl acetate (MOF-EA) and methanol (MOF-M), to extract the flowers of M. oleifera using the ultrasound-assisted extraction (UAE) approach. Disc diffusion method was used to test for antimicrobial activity. In cytotoxicity research, cell lines derived from breast cancer (MCF-7) and ovarian cancer (ES-2) were used. IC50 values for DPPH, ABTS and Nitric oxide for MOF-EA are 33.54±1.13, 29.86±0.08 and 49.7±1.12µg/mL, respectively, making it the most effective antioxidant in terms of scavenging free radicals. The order of suppression of bacterial growth by the methanolic extract was E. coli>P. aeruginosa>S. aureus, making it the most effective antibacterial agent tested. MOF-H, MOF-EA and MOF-M had fungal inhibition zones of 5.6mm, 7mm and 10.7mm, respectively, compared to DMSO. It was found that MOF-EA had potent antioxidant, cytotoxic and antibacterial capabilities that could be employed as an alternate treatment therapy following clinical trials.

Molecular docking and dynamics studies of 4-anilino quinazolines for epidermal growth factor receptor tyrosine kinase to find potent inhibitor.

A series of novel 4-anilino quinazoline derivatives were taken based on the literature study and optimized with Autodock version 4.2 and molecular dynamics (MD) protocol to investigate the interaction between the target compounds and the amino acid residues of target protein epidermal growth factor receptor (EGFR) tyrosine kinase (PDB ID: 1M17). The free energies of binding and inhibition constants (Ki) of the docked ligands were calculated by the Lamarckian genetic algorithm (LGA). The docking results showed that the compounds SGQ4, DMUQ5, 6AUQ6, and PTQ8 had produced significant docking affinity for the protein tyrosine kinase with the binding energy of -7.46, -7.31, -6.85, and -6.74 kcal/mol, respectively, compared to the standard inhibitor Erlotinib (binding energy: -3.84 kcal/mol). Furthermore, molecular dynamics simulations (MDS) were performed using Gromacs to investigate the stability of a ligand-protein complex. The combined analysis of root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of 1M17 protein with docked ligands reveals that 1M17 protein has more stability when it interacts reacts with the inhibitor. Molecular descriptive properties and toxicity profile predicted by software. All the designed molecules passed Lipinski's rule of five successfully and they were found to be safe.

Pythagorean fuzzy transportation problem: New way of ranking for Pythagorean fuzzy sets and mean square approach.

The predominant domain for optimization in the current situation is the transportation problem (TP). In the majority of cases, accurate data have been employed, yet in reality, the values are vague and imprecise. In any decision-making process, imprecision is a significant issue. To deal with the ambiguous setting of collective decision-making, many tools and methods have been established. The Pythagorean fuzzy set is an extension of fuzzy sets that successfully handles ambiguity and fuzziness. To overcome the shortcomings of intuitionistic fuzzy context, Pythagorean fuzzy sets are considered to be the most recent tools. This study proposes a new method for addressing the uncertain Pythagorean transportation issue. In this study, we created a novel sorting technique for Pythagorean fuzzy sets that converts uncertain quantities into crisp numbers. We developed an innovative mean square strategy for obtaining the initial basic feasible solution (IBFS) for a Pythagorean Fuzzy Transit Issue (PyFTP) of three types (I, II, III) wherein the requirement, availability, and unit of transportation expenses are all in Pythagorean uncertainty. In addition, we used the MODI technique to find the best option. To demonstrate the suggested strategy, we used numerical problems of three distinct kinds. A comparison table with the results of the previous strategy and the suggested method is created to state the benefits of the ranking methodology with the proposed algorithm. The discussion of future research and conclusions is the final step.

Nitric oxide and reactive oxygen species: Clues to target oxidative damage repair defective breast cancers.

The identification of various biomolecules in cancer progression and therapy has led to the exploration of the roles of two cardinal players, namely Nitric Oxide (NO) and Reactive Oxygen Species (ROS) in cancer. Both ROS and NO display bimodal fashions of functional activity in a concentration dependent manner, by inducing either pro- or anti- tumorigenic signals. Researchers have identified the potential capability of NO and ROS in therapies owing to their role in eliciting pro-apoptotic signals at higher concentrations and their ability to sensitize cancer cells to one another as well as to other therapeutics. We review the prospects of NO and ROS in cancer progression and therapy, and analyze the role of a combinatorial therapy wherein an NO donor (SNAP) is used to sensitize the oxidative damage repair defective, triple negative breast cancer cells (HCC 1937) to a potent ROS inducer. Preliminary findings support the potential to employ various combinatorial regimes for anti-cancer therapies with regard to exploiting the chemo-sensitization property of NO donors.