Design, synthesis, graph theoretical analysis and molecular modelling studies of novel substituted quinoline analogues as promising anti-breast cancer agents.

The most promising class of heterocyclic compounds in medicinal chemistry are those with the quinolin-2-one nucleus. It is a versatile heterocyclic molecule that has been put together with numerous pharmaceutical substances and is crucial in the creation of anticancer medications. In this view, the present research work deals with design, synthesis, and characterization of various analogous of quinolin-2-one nucleus and evaluation of their anticancer activity against MCF-7 cells (adenoma breast cancer cell line). Fourteen new compounds have been synthesised using suitable synthetic route and are characterized by FTIR, 1H NMR, 13C NMR and Mass spectral data. Molecular docking studies of the title compounds were carried out using PyRx 0.8 tool in AutoDock Vina program. All the synthesised compounds were exhibited well conserved hydrogen bonding with one or more amino acid residues in the active pocket of EGFR tyrosine kinase (PDB ID: 1m17). The docking score of the derivatives ranged from - 6.7 to - 9.5 kcal mol-1, standard drug Imatinib with - 9.6 kcal mol-1 and standard active ligand 4-anilinoquinazoline with - 7.7 kcal mol-1. The designed compound IV-A1 showed least binding energy (- 9.5 kcal mol-1) against EGFR tyrosine kinase receptor. Further, top scored compound, IV-A1 found to be most significant against MCF-7 cells with IC50 value of 0.0870 µM mL-1, TGI of 0.0958 µM mL-1, GI50 of 0.00499 µM mL-1, LC50 of 1.670 µM mL-1.

Design, Synthesis, Characterisation, and Evaluation of Substituted Quinolin-2-one Derivatives as Possible Anti-lung Cancer Agents.

BACKGROUND: According to 2022, the estimated number of cancer cases in India was found to be 1,461,427. Lung cancers are the leading cause of death among Indian males. Research on cancer has been conducted to develop better treatments that are safe and effective and could be used to diagnose cancer at an early stage. It was found that quinolin-2-one possesses anticancer activity, which led us to synthesize substituted quinolin-2-one derivatives that can provide a longer future to cancer patients and decrease the risk of dying from cancer. OBJECTIVE: This study aimed to carry out the design, synthesis, characterisation, and evaluation of novel substituted quinolin-2-one analogues as possible anti-lung cancer agents. METHODS: Compound III a/III b on reaction with acids, sodium acetate and ethylchloroacetate, substituted benzaldehyde, phthalic anhydride, and 2N sodium hydroxide yielded compounds IV a/ IV b, V a/ V b, VI a/ VI b, VI c/ VI d, VI e/ VI f, VII a/ VII b, and VIII a/ VIII b, respectively. RESULT: Among all the synthesised derivatives, compound VII a was found to be most potent with a MolDock score of -132.78 as compared to standard drug imatinib (-114.37) and active ligand 4- anilinoquinazoline (-126.71). All the synthesized derivatives showed a good ADME profile, but compound VII a showed the best ADME data among all the synthesised derivatives. All the synthesised compounds were tested for their in vitro anticancer activity against the Hop-62 (human lung cancer) cell line, out of which compound VII a was found to be most potent, with a percent control growth of -51.7% at a concentration of 80 µg/ml, which was in comparable to the positive control, Adriamycin (-70.5%) and standard imatinib (-84.0%). CONCLUSION: Compound VII a showed the highest MolDock score and was most potent against human lung cancer cell line Hop-62.

Docking, Synthesis, and Evaluation of 4-hydroxy-1-phenyl-2(1H)-quinolone Derivatives as Anticancer Agents.

BACKGROUND: The estimated number of cancer cases in India for the year 2022 was found to be 14,61,427. The development of chemotherapeutic agents has reduced the mortality rate, however,they have high toxicity which is a disadvantage. Many researchers have found out that quinolin-2-one possesses anticancer activity, with this background we thought of synthesizing the quinolin-2-one derivatives. OBJECTIVE: This study aimed to carry out docking, synthesis, characterization, and evaluation of 2-(2-(4-Hydroxy-2-oxoquinolin-1(2H)-yl)phenyl/ substituted phenyl)-3-(phenylamino) thiazolidon-4-one derivatives (IVa-g) as an anticancer agent. METHOD: Diphenylamine and malonic acid treated with phosphoryl chloride gave compound I, which on formylation afforded compound II, which on reaction with various substituted aromatic phenylhydrazine derivatives gave compounds IIIa-g, which on further reaction with thioglycolic acid and anhydrous zinc chloride yielded the compounds IVa-g. RESULT: Among all the synthesized novel derivatives, compounds IV a-d showed 50% lysis in the IC50 range of 25-50µg for the A549 cell line, and compounds IVa, and IVb showed 50% lysis in the IC50 range of 25-50µg for the MDA-MB cell line. The compound, 3-((4-fluorophenyl)amino)-2-(2-(4-hydroxy-2-oxoquinolin-1(2H)-yl)phenyl)thiazolidin-4-one (IVg) was found to be the most active against both the cell line, A549 and MDA-MB with IC50 value of 0.0298µmol and 0.0338µmol respectively. The docking results revealed that the synthesized compounds exhibited well-conserved hydrogen bonding with one or more amino acid residues in the active pocket of EGFR tyrosine kinase domain with 4-anilinoquinazoline inhibitor erlotinib (PDB ID:1M17). Compound IVg showed the highest MolDock score of -137.813 compared to the standard drug Imatinib having a MolDock score of -119.354. CONCLUSION: Compound IVg showed the highest MolDock score and was also found to be most potent against both the cell line, A549, and MDA-MB.

Design, Docking, Characterisation, and Synthesis of Pyrimidine Derivatives for Antidepressant Activity.

BACKGROUND: According to the report, in 2022, the prevalence rate of depression in India was 4.50%, and the cases stood at 56,675,969. The development of antidepressant agents has reduced the number of depressant and suicidal cases. Many researchers have found that pyrimidine possesses antidepressant activity. With this background, we thought of synthesizing pyrimidine derivatives. OBJECTIVE: The objective of this study is to carry out molecular docking, synthesis, characterization, and evaluation of 2-((4,6-diphenylpyrimidin-2-yl)oxy)-N-phenylacetamide derivatives (17-26) as in vivo antidepressant agent. METHOD: The designed compounds were checked for their activity using Molegro virtual docker (MVD) and were further synthesized. Benzaldehyde reacted with acetophenone to give compound (3), which gave compound (4) upon reaction with urea. In another reaction, substituted anilines (5) were reacted with chloroacetyl chloride (6) to yield compounds (7-16), which upon further reaction with compound (4) yielded the final derivatives (17-26). The synthesized compounds were characterized by spectral analysis and checked for their antidepressant activity. RESULT: The MolDock scores of the derivatives ranged from -147.097 to -182.095, whereas of active ligand IXX_801 was -115.566. All the synthesized pyrimidine derivatives showed better affinity towards the Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine, and 15B8 Fab protein (PDB ID: 7LWD) as compared to standard drug clomipramine (-101.064). All the synthesized derivatives were screened for antidepressant activity at a 100mg/kg dose level compared to the standard clomipramine HCl at a dose level of 20mg/kg. Among all the synthesized derivatives, compound 24 showed the most potent antidepressant activity, and Compound 20 showed moderate antidepressant activity, which reduced the duration of immobility times to 35.42% and 31.97% at 100mg/kg dose level when compared to the control, respectively. CONCLUSION: Compound 24 showed the highest MolDock score as well as found to be the most potent antidepressant agent.