Diabetes, a multifactorial metabolic disorder, demands the discovery of multi-targeting drugs with minimal side effects. This study investigated the multi-targeting antidiabetic potential of quercetin and kaempferol. The druggability and binding affinities of both compounds towards multiple antidiabetic targets were explored using pharmacokinetic and docking software (AutoDock Vina 1.1.2). Our findings showed that quercetin and kaempferol obey Lipinski’s rule of five and exhibit desirable ADMET (absorption, distribution, metabolism excretion, and toxicity) profiles. Both compounds showed higher binding affinities towards C-reactive protein (CRP), interleukin-1 (IL-1), dipeptidyl peptidase-4 (DPP-IV), peroxisome proliferator-activated receptor gamma (PPARG), protein tyrosine phosphatase (PTP), and sodium–glucose co-transporter-1 (SGLT-1) compared to metformin (the positive control). Both quercetin and kaempferol inhibited α-amylase activity (in vitro) up to 20.30 ± 0.49 and 37.43 ± 0.42%, respectively. Their oral supplementation significantly reduced blood glucose levels (p < 0.001), improved lipid profile (p < 0.001), and enhanced total antioxidant status (p < 0.01) in streptozotocin–nicotinamide (STZ-NA)-induced diabetic mice. Additionally, both compounds significantly inhibited the proliferation of Huh-7 and HepG2 (cancer cells) (p < 0.0001) with no effect on the viability of Vero cell line (non-cancer). In conclusion, quercetin and kaempferol demonstrated higher binding affinities towards multiple targets than metformin. In vitro and in vivo antidiabetic potential along with the anticancer activities of both compounds suggest promise for further development in diabetes management. The combination of both drugs did not show a synergistic effect, possibly due to their same target on the receptors.

MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds 2, 7, and 20, showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound 2 (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound 2 was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.

Cyclin-dependent kinases (CDKs) are promising targets in chemotherapy. In this study, we report a series of 2-anilinopyrimidine derivatives with CDK inhibitory activity. Twenty-one compounds were synthesized and their CDK inhibitory and cytotoxic activities were evaluated. The representative compounds demonstrate potent antiproliferative activities toward different solid cancer cell lines and provide a promising strategy for the treatment of malignant tumors. Compound 5f was the most potent CDK7 inhibitor (IC₅₀ = 0.479 µM), compound 5d was the most potent CDK8 inhibitor (IC₅₀ = 0.716 µM), and compound 5b was the most potent CDK9 inhibitor (IC₅₀ = 0.059 µM). All the compounds satisfied the Lipinski’s rule of five (molecular weight < 500 Da, number of hydrogen bond acceptors <10, and octanol–water partition coefficient and hydrogen bond donor values below 5). Compound 5j is a good candidate for lead optimization because it has a non-hydrogen atom (N) of 23, an acceptable ligand efficiency value of 0.38673, and an acceptable ligand lipophilic efficiency value of 5.5526. The synthesized anilinopyrimidine derivatives have potential as anticancer agents.

Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcriptional elongation, through which short-lived antiapoptotic proteins are overexpressed and make cancer cells resistant to apoptosis. Therefore, CDK9 inhibition depletes antiapoptotic proteins, which in turn leads to the reinstatement of apoptosis in cancer cells. Twenty-seven compounds were synthesized, and their CDK9 inhibitory and cytotoxic activities were evaluated. Compounds 7, 9, and 25 were the most potent CDK9 inhibitors, with IC₅₀ values of 0.115, 0.131, and 0.142 μM, respectively. The binding modes of these molecules were studied via molecular docking, which shows that they occupy the adenosine triphosphate binding site of CDK9. Of these three molecules, compound 25 shows good drug-like properties, as it does not violate Lipinski’s rule of five. In addition, this molecule shows promising ligand and lipophilic efficiency values and is an ideal candidate for further optimization.