Background: Camptothecin is a quinoline alkaloid, isolated from the Chinese tree Camptotheca acuminate which exhibits its cytotoxic activity by the inhibition of nuclear enzyme Topoisomerase I (topo I). Camptothecin and its analogues forms a covalent bond with DNA which can arrest the tumor growth by slowing the religation step of the enzyme and stabilize the covalent adduct between topo I and DNA. Besides its strong anticancer potential, the limited solubility as well as instability of the hydroxylactone ring (Ring E) limits the clinical application of Camptothecin. This study was undertaken to identify novel compounds having anticancer activity with mechanism of action similar to that of Camptothecin using scaffold perception technique. Materials and methods: We developed a common pharmacophore hypothesis using 32 camptothecin analogues, which was used for preliminary screening of large databases (ZINC “drug-like” database) to make sure, to include only compounds containing the key structural features needed to be Topoisomerase I inhibitors. In terms of a structure based approach, we systematically investigated various types of docking protocols to identify the most active compounds from the identified hit molecules. A post docking energy calculation was also carried out by MM/GBSA method. Results: From the selected series of camptothecin analogs, a 3D-QSAR pharmacophore model was developed. The model consists of one acceptor site, one donor site, one hydrophobic site and two aromatic functions (ADHRR). Then, the pharmacophore model was employed as 3D search query to screen compounds from ZINC database which followed by molecular docking study and MM/GBSA calculation identified 2 lead molecules which, however, were not biologically validated. In silico studies reveals that the identified lead molecules have a better binding affinity than the co crystallized ligand. Conclusion: The identified molecules were able to bind to the active site of Topo-I enzyme similar to that of Camptothecin and the ADME properties were within the acceptable range defined for human use. The new molecules identified by virtual screening as such or on further optimization can be used as potential leads in designing Topoisomerase I inhibitors.

Aim and Objective: For the development of new class of anticancer agents, a series of novel 2-amino-3-cyanopyridine derivatives were designed from virtual screening with Glide program by setting Topoisomerase II as the target. Materials and Methods: The top ranked ten molecules from the virtual screening were synthesized by microwave assisted technique and investigated for their cytotoxic activity against MCF-7 and A-549 cell lines by using sulforhodamine B assay method. Results: The most active compound 2-amino-4-(3,5-dibromo-4-hydroxyphenyl)-6-(2,4-dichlorophenyl) nicotinonitrile (CG-5) showed significant cytotoxic profile with (LC50 = 97.1, TGI = 29.9 and GI50 = <0.1 µM) in MCF-7 and (LC50= 93.0, TGI= 50.0 and GI50= <7 µM) in A-549 cell lines. A molecular docking study was performed to explore the binding interaction of CG-5with the active site of Topoisomerase II. Conclusion: It can be concluded that halogen substituent pyridine ring was benefit for cytotoxicity.

A small series of nitro group-bearing enamides was designed, synthesized (NEA1–NEA5), and evaluated for their inhibitory profiles of monoamine oxidases (MAOs) and β-site amyloid precursor protein cleaving enzyme 1 (β-secretase, BACE1). Compounds NEA3 and NEA1 exhibited a more potent MAO-B inhibition (IC₅₀ value = 0.0092 and 0.016 µM, respectively) than the standards (IC₅₀ value = 0.11 and 0.14 µM, respectively, for lazabemide and pargyline). Moreover, NEA3 and NEA1 showed greater selectivity index (SI) values toward MAO-B over MAO-A (SI of >1652.2 and >2500.0, respectively). The inhibition and kinetics studies suggested that NEA3 and NEA1 are reversible and competitive inhibitors with K_i values of 0.013 ± 0.005 and 0.0049 ± 0.0002 µM, respectively, for MAO-B. In addition, both NEA3 and NEA1 showed efficient BACE1 inhibitions with IC₅₀ values of 8.02 ± 0.13 and 8.21 ± 0.03 µM better than the standard quercetin value (13.40 ± 0.04 µM). The parallel artificial membrane permeability assay (PAMPA) method demonstrated that all the synthesized derivatives can cross the blood–brain barrier (BBB) successfully. Docking analyses were performed by employing an induced-fit docking approach in the GLIDE module of Schrodinger, and the results were in agreement with their in vitro inhibitory activities. The present study resulted in the discovery of potent dual inhibitors toward MAO-B and BACE1, and these lead compounds can be fruitfully explored for the generation of newer, clinically active agents for the treatment of neurodegenerative disorders.

The purpose is to synthesize a new class of furan-based chalcone compounds (KD1-KD14) and to investigate their monoamine oxidase (MAO)-A and -B inhibitory activities. The 14 chalcones were synthesized using an open mortar and pestle. Lead molecules were screened via inhibitory activity, BBB permeability, and computation studies. Most of the tested compounds showed promising activity for MAO-B over than MAO-A. Among the molecules, KD1 and KD9 revealed the significant inhibitory potentials toward MAO-B with IC₅₀ values of 0.023 ± 0.004 and 0.015 ± 0.001 µM, respectively, and with high selectivity indices of 723.04 and >2666.66, respectively, over MAO-A. Further, kinetics and reversibility test revealed that both KD1 and KD9 were competitive reversible MAO-B inhibitors with K_i values of 13.5 ± 4.95 and 6.15 ± 0.92 nM, respectively. Additionally, the PAMPA test showed that both KD1 and KD9 compounds permeated the central nervous system. Furthermore, molecular docking and dynamics simulations showed that both the chemicals formed pi-cation and hydrogen bonds with the MAO-B pocket and stabilized the MAO-B over the course of a 100 ns simulation. Our results revealed that KD1 and KD9 are potent selective, reversible, and competitive MAO-B inhibitors.