In silico Study and Solvent-free one-pot Synthesis of Tetrahydropyrimidine derivatives by Mechanochemistry Approach for Targeting Human Neutrophil Elastase against Lung Cancer.

BACKGROUND: Pyrimidine derivative has evinced its biological importance in targeting lung cancer by inhibiting neutrophil elastase. METHODS: All THPM derivatives were synthesized by the grindstone method at ambient temperature followed by molecular docking study for efficient binding interaction of THPM compounds by targeting human neutrophil elastase (HNE) (PDB ID: 5A0A) and In-silico ADMET study using PkCSM. Moreover, all synthesized compounds were characterized by spectroscopy techniques and screened for anti-cancer activity using in vitro HNE assay kit. RESULTS: We reported a one-pot solvent-free mechanochemical approach for synthesizing tetrahydropyrimidine (THPM) derivatives from various aromatic aldehydes, ethyl cyanoacetate, and urea followed by in silico study and evaluation against human neutrophil elastase (HNE) for treatment of lung cancer. We calibrated the best molecules that bound to specific targets more efficiently using a molecular docking approach and provided the desired efficacy. In-silico ADMET studies revealed that all best-scored compounds had drug-like characteristics for potential use as human neutrophil elastase inhibitors (HNE) in lung cancer treatment. Additionally, the in vitro studies revealed that compounds 1, 2, and 8 show potent HNE inhibitory activity for lung cancer treatment. CONCLUSION: In a nutshell, the tetrahydropyrimidine (THPM) scaffold and its derivatives may serve as potential HNE inhibitors for the development of a promising anti-cancer agent.

Virtual screening of curcumin and its analogs against the spike surface glycoprotein of SARS-CoV-2 and SARS-CoV.

COVID-19, a new pandemic caused by SARS-CoV-2, was first identified in 2019 in Wuhan, China. The novel corona virus SARS-CoV-2 and the 2002 SARS-CoV have 74% identity and use similar mechanisms to gain entry into the cell. Both the viruses enter the host cell by binding of the viral spike glycoprotein to the host receptor, angiotensin converting enzyme 2 (ACE2). Targeting entry of the virus has a better advantage than inhibiting the later stages of the viral life cycle. The crystal structure of the SARS-CoV (6CRV: full length S protein) and SARS-CoV-2 Spike proteins (6M0J: Receptor binding domain, RBD) was used to determine potential small molecule inhibitors. Curcumin, a naturally occurring phytochemical in Curcuma longa, is known to have broad pharmacological properties. In the present study, curcumin and its derivatives were docked, using Autodock 4.2, onto the 6CRV and 6M0J to study their capability to act as inhibitors of the spike protein and thereby, viral entry. The curcumin and its derivatives displayed binding energies, ΔG, ranging from -10.98 to -5.12 kcal/mol (6CRV) and -10.01 to -5.33 kcal/mol (6M0J). The least binding energy was seen in bis-demethoxycurcumin with: ΔG = -10.98 kcal/mol (6CRV) and -10.01 kcal/mol (6M0J). A good binding energy, drug likeness and efficient pharmacokinetic parameters suggest the potential of curcumin and few of its derivatives as SARS-CoV-2 spike protein inhibitors. However, further research is necessary to investigate the ability of these compounds as viral entry inhibitors.Communicated by Ramaswamy H. Sarma.

In silico analysis, synthesis and biological evaluation of DHFR inhibitors.

INTRODUCTION: Malaria is one of the varieties of fatal diseases caused by a protozoan parasite that is now considered to be the greatest global health challenge. A parasite of Plasmodium species triggers it transmitting the disease to humans by the bites of female Anopheles mosquitoes. AIM: To screen out designed molecules by molecular docking analysis and assess their pharmacokinetic properties using SwissADME. To synthesize the designed compounds. To characterize the synthesized compounds by TLC, melting point, IR spectroscopy, mass spectrometry, 1H NMR, and 13C NMR. To evaluate the synthesized compounds for antimalarial activity. MATERIALS AND METHODS: In silico analysis was performed with SWISSADME, and molecular docking was performed by AutoDock Vina version 4.2. In vitro antimalarial activity study was performed. RESULTS: In-vitro studies of synthesized molecules showed that compounds C2 (IC50 1.23), C6 (IC50 0.48), C10 (IC50 0.79), and C14 (IC50 0.19) possess good antimalarial activity. CONCLUSIONS: 7-chloroquinoline-piperazine derivatives exhibited potential antimalarial compounds for pf-DHFR inhibitors.