Design and Synthesis of N-Substituted 3,4-Pyrroledicarboximides as Potential Anti-Inflammatory Agents.

In the present paper, we describe the biological activity of the newly designed and synthesized series N-substituted 3,4-pyrroledicarboximides 2a-2p. The compounds 2a-2p were obtained in good yields by one-pot, three-component condensation of pyrrolo[3,4-c]pyrrole scaffold (1a-c) with secondary amines and an excess of formaldehyde solution in C2H5OH. The structural properties of the compounds were characterized by 1H NMR, 13C NMR FT-IR, MS, and elemental analysis. Moreover, single crystal X-ray diffraction has been recorded for compound 2h. The colorimetric inhibitor screening assay was used to obtain their potencies to inhibit COX-1 and COX-2 enzymes. According to the results, all of the tested compounds inhibited the activity of COX-1 and COX-2. Theoretical modeling was also applied to describe the binding properties of compounds towards COX-1 and COX-2 cyclooxygenase isoform. The data were supported by QSAR study.

Design, Synthesis and Biological Evaluation of 5-amino-3-aryl-1-(6'-chloropyridazin-3'-yl)pyrazoles and their Derivatives as Analgesic Agents.

An efficient and environmental benign solvent-free synthesis of 5-amino-3-aryl-1-(6'-chloropyridazin-3'-yl)pyrazoles (4A-E): was accomplished by grinding 3-chloro-6-hydrazinopyridazine (2): and ß-ketonitriles (3A-E): in the presence of p-toulenesulfonic acid as a catalyst. Subsequently, 6'-chloro group in 4A-E: was replaced with cyclic 2° amine derivatives viz. pyrrolidine 5A: , piperidine 5B: and morpholine 5C: to obtain 6A-E: , 7A-E: , 8A-E: respectively. The newly synthesized compounds were characterized by using IR, NMR (1H and 13C), mass spectral studies, elemental analyses. All the synthesized compounds were studied for their docking interaction with target protein 6COX and screened for their in vivo analgesic mode of action against swiss albino mice (animal model) using acetic-acid induced writhing test. Consequently, docking simulations data justifies the potential of synthesized series as an analgesic and very well correlated with in vivo study. Preliminary results revealed that most of the synthesized compounds exhibited moderate to good analgesic activity as compared to reference/standard drug (s) sodium diclofenac and candidates 4D: and 7C: protrude out as a promising lead for further investigation.

QSAR Classification-Based Virtual Screening Followed by Molecular Docking Identification of Potential COX-2 Inhibitors in a Natural Product Library.

Developments of natural inhibitors to prevent the function of cyclooxygenase-2 (COX-2) protein, responsible for a variety of inflammations and cancers, are a major challenge in the scientific community. In this study, robust QSAR classification models for predicting COX-2 inhibitor were developed, by which the self-organizing feature map neural network and random forest (RF) were adopted to improve the prediction of classification model ability. The F-score-based criterion combined with RF was used for feature selection, and good performance for COX-2 inhibitor prediction in overall accuracy was demonstrated. We used this model as a virtual screening tool for identifying the potential COX-2 inhibitor from a natural product library and found potential hit compounds. This compound further screened by applying molecular docking simulation identified five potential hits such as osthole, kavain, vanillyl acetone, myristicin, and psoralen, having a comparable binding affinity to COX-2 protein. However, in cell experiment, three hit compounds revealed COX-2 inhibitory activity in mRNA and protein level such as osthole, kavain, and psoralen.