Investigating the Impact of Different Acrylamide (Electrophilic Warhead) on Osimertinib's Pharmacological Spectrum by Molecular Mechanic and Quantum Mechanic Approach.

BACKGROUND: Lung cancer has become the prominent cause of the cancer-related deaths globally. More than 80 % of all lung cancers have been diagnosed with Non- Small Cell Lung Cancer (NSCLC). The USFDA approved osimertinib to treat patients with metastatic T790M EGFR NSCLC on a regular basis in March 2017. Recently, C797S mutation to osimertinib has been reported, which indicates the need for structural modification to overcome the problem of mutation. METHODS: In this bioinformatics study, we have evaluated the impact of various acrylamide as an electrophilic warhead on the activity and selectivity of osimertinib. RESULT: Osimertinib analouge 48, 50, 60, 61, 67, 75, 80, 86, 89, 92, 93, 116 and 124 were the most active and selective compounds against T790M EGFR mutants compared to Osimertinib. CONCLUSION: These compounds also showed less inclination towards WT-EGFR.

Optimizing Bedaquiline for cardiotoxicity by structure based virtual screening, DFT analysis and molecular dynamic simulation studies to identify selective MDR-TB inhibitors.

Since the last 4 decades, Bedaquiline has been the first drug discovered as a new kind of anti-tubercular agent and received FDA approval in December 2012 to treat pulmonary multi-drug resistance tuberculosis (MDR-TB). It demonstrates excellent efficacy against MDR-TB by effectively inhibiting mycobacterial ATP synthase. In addition to these apparent assets of Bedaquiline, potential disadvantages of Bedaquiline include inhibition of the hERG (human Ether-à-go-related gene; KCNH2), potassium channel (concurrent risk of cardiac toxicity), and risk of phospholipidosis due to its more lipophilic nature. To assist the effective treatment of MDR-TB, highly active Bedaquiline analogs that display a better safety profile are urgently needed. A structure-based virtual screening approach was used to address the toxicity problems associated with Bedaquiline. Among the virtually screened compound, CID 15947587 had significant docking affinity (- 5.636 kcal/mol) and highest binding free energy (ΔG bind - 85.2703 kcal/mol) towards the Mycobacterial ATP synthase enzyme with insignificant cardiotoxicity and lipophilicity. During MD simulation studies (50 ns), the molecule optimizes its conformation to fit better the active receptor site justifying the binding affinity. The obtained results showed that CID15947587 could be a useful template for further optimizing the MDR-TB inhibitor. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00086-x.

Pyridine and nitro-phenyl linked 1,3,4-thiadiazoles as MDR-TB inhibitors.

In the present study, a series of substituted 1,3,4-thiadiazole derivatives 4(a-o), 5(a-m) and 6(a-j) were synthesized and characterized by IR, 1H NMR, 13C NMR and mass spectroscopic technique. The synthesized compounds were evaluated for their in vitro anti-mycobacterial activity against the Mycobacterium tuberculosis H37Rv and resistance MDR-TB strain. Among the compounds tested N-(5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)furan-2-carboxamide (4h) showed significant inhibitory activity with MIC of 9.87 µM (H37Rv strain) and 9.87 µM (MDR-TB strain) compared to isoniazide [MIC of 3.64 µM (H37Rv) and >200 µM (MDR-TB strain)] and rifampin [MIC of 0.152 µM (H37Rv) and 128 µM (MDR-TB strain)]. In addition, these compounds have also been assessed for their cyto-toxicity to a mammalian Vero cell line using the MTT assay. The result shows that these compounds exhibit anti-tubercular activity at non-cytototoxic concentrations.

Design and synthesis of novel 2,4-disubstituted aminopyrimidines: reversible non-covalent T790M EGFR inhibitors.

Cardiotoxicity is one amongst the adverse effect of Osimertinib delineate in clinical trials and related to escalating doses. To triumph over the drawbacks of Osimertinib, in this study, we tend to delineate the design, synthesis, in vitro biological analysis of a series of novel reversible selective T790M inhibitors with minimal cardiotoxicity. Amongst the virtually sorted compounds; compound 18 and 74 have been located to be the foremost active compounds of the series with IC50 value of 0.88, 0.92 µM in cellular assay and 0.56, 0.62 µM in enzymatic assay, against double mutant L858R/T790M EGFR. Additionally, they showed much less affinity toward wild-type (WT)-EGFR with minimal cardiotoxicity.