ABSTRACT
Regarding the structural analysis of variable effective CDK-9 suppressors, we record the design and synthesis of two new sets of sulfaguanidine-based azopyrazolidine-3,5-diones and 3,5-diaminoazopyrazoles with expected anticancer and CDK-9 inhibiting activity. In the designed molecules, the pyrazole ring and sulphaguanidine fragment were linked together for the first time through diazo linkers as they are expected to enhance the anticancer activity and CDK degrading interaction. All derivatives have been estimated regarding their cytotoxic activity toward three tumor cells where CDK overexpression has been reported (HePG2, HCT-116, and MCF-7). Among these, four derivatives VII, VIII, X, and XIII exerted potent cytotoxicity against the chosen tumor cells presenting IC50 range equal to 2.86-25.89 µM. As well cytotoxicity on non-cancer cells and CDK-9 inhibition assay have been also assessed for these candidates to evaluate their selectivity indices and enzyme inhibition. The 3,5-diaminopyrazole-1-carboxamide derivative XIII showed a superior combined profile as cytotoxic with high selectivity toward cancer cells (HePG2: IC50 = 6.57 µM, SI = 13.31; HCT-116: IC50 = 9.54 µM, SI = 9.16; MCF-7: IC50 = 7.97 µM, SI = 10.97). Accordingly, it has been chosen to evaluate its probable mechanistic effect both in vitro (via enzyme assay, apoptosis induction, and cell cycle study) as well as in silico (through molecular docking). Overall, this work introduces the 3,5-diaminopyrazole-1-carboxamide derivative XIII as a potent CDK-9 inhibitor candidate (IC50 = 0.16 µM) that merits further investigations for the management of breast, colorectal, and hepatic malignancies.
Subject(s)
Antineoplastic Agents , Cyclin-Dependent Kinase 9 , Pyrazoles , Sulfaguanidine , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation , Dose-Response Relationship, Drug , Drug Design , Drug Screening Assays, Antitumor , Molecular Docking Simulation , Molecular Structure , Structure-Activity Relationship , Sulfaguanidine/analogs & derivatives , Sulfaguanidine/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Cyclin-Dependent Kinase 9/antagonists & inhibitorsABSTRACT
The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure-activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.
