In this study, an efficient multistep synthesis of novel aromatic tricyclic hybrids incorporating different biological active moieties, such as 1,3,4-thiadiazole and 1,2,4-triazole, was reported. These target scaffolds are characterized by having terminal lipophilic or hydrophilic parts, and their structures are confirmed by different spectroscopic methods. Further, the cytotoxic activities of the newly synthesized compounds were evaluated using in vitro MTT cytotoxicity screening assay against three different cell lines, including HepG-2, MCF-7, and HCT-116, compared with the reference drug Taxol. The results showed variable performance against cancer cell lines, exhibiting MCF-7 and HepG-2 selectivities by active analogs. Among these derivatives, 1,2,4-triazoles 11 and 13 and 1,3,4-thiadiazole 18 were found to be the most potent compounds against MCF-7 and HepG-2 cancer cells. Moreover, structure–activity relationship (SAR) studies led to the identification of some potent LSD1 inhibitors. The tested compounds showed good LSD1 inhibitory activities, with an IC₅₀ range of 0.04–1.5 μM. Compounds 27, 23, and 22 were found to be the most active analogs with IC₅₀ values of 0.046, 0.065, and 0.074 μM, respectively. In addition, they exhibited prominent selectivity against a MAO target with apparent cancer cell apoptosis, resulting in DNA fragmentation. This research provides some new aromatic-centered 1,2,4-triazole-3-thione and 1,3,4-thiadiazole analogs as highly effective anticancer agents with good LSD1 target selectivity.

Thiazolopyrimidines are well known to be designed to act as bio-isosteric analogues of purine nucleus. They proved to show a wide range of biological activities, such as anticancer, anti-inflammatory, antifungal, antiviral and antitubercular activity. In this study, a literature survey was thoroughly performed to elect the most active thiazolopyrimidine-containing scaffolds, acting as anticancer agents, to be subjected to extensive computational studies in order to explore the possible credible mode of their anticancer activity. First, drug-likeness was investigated for the most active derivatives, followed by molecular docking study against Cyclin-dependent kinases (CDK), Vascular endothelial growth factor receptor (VEGFR) and Phosphoinositide 3-kinases (PI3K) enzymes in order to assess their binding energy and propose the mode of action. Next, contact preference and surface mapping studies were carried out to explain the presence of remarkable affinity of certain analogues towards a specific enzyme, in addition to providing more information about their activity. Finally, physicochemical properties, Lipinski’s rule of five and ADMET prediction studies were applied to predict the best route of administration and to suggest the pharmacokinetics of the most promising candidates.