Exploring cyclopropylamine containing cyanopyrimidines as LSD1 inhibitors: Design, synthesis, ADMET, MD analysis and anticancer activity profiling.

In this series we report the structure-based design, synthesis and anticancer activity evaluation of a series of eighteen cyclopropylamine containing cyanopyrimidine derivatives. The computational predictions of ADMET properties revealed appropriate aqueous solubility, high GI absorption, no BBB permeability, no Lipinski rule violations, medium total clearance and no mutagenic, tumorigenic, irritant and reproductive toxic risks for most of the compounds. Compounds VIIb, VIIi and VIIm emerged as the most potent anticancer agents among all compounds evaluated against 60 cancer cell lines through the one-dose (10 µM) sulforhodamine B assay. Further, the multiple dose cell viability studies against cancer cell lines MOLT-4, A549 and HCT-116 revealed results consistent with the one-dose assay, besides sparing normal cell line HEK-293. The three potent compounds also displayed potent LSD1 inhibitory activity with IC50 values of 2.25, 1.80 and 6.08 µM. The n-propyl-thio/isopropyl-thio group bonded to the pyrimidine ring and unsubstituted/ electron donating group (at the para- position) attached to the phenyl ring resulted in enhanced anticancer activity. However, against leukemia cancer, the electron donating isopropyl group remarkably enhanced anti-cancer activity. Our findings provide important leads, which merit further optimization to result in better cancer therapeutics.

Synthesis, in-Silico studies and biological evaluation of pyrimidine based thiazolidinedione derivatives as potential anti-diabetic agent.

Despite the advancements in the management of Diabetes mellitus, the design and synthesis of drug molecule which ameliorates the hyperglycemia and associated secondary complications in diabetic patients, still remains a challenge. Herein, we report the synthesis, characterization and anti-diabetic evaluation of pyrimidine-thiazolidinedione derivatives. The synthesized compounds were characterized by 1H NMR, 13C NMR, FTIR and Mass Spectroscopic analytical techniques. The in-silico ADME studies depicted that the compounds were within the permissible limits of the Lipinski's rule of five. The compounds 6e and 6m showing the best results in OGTT were evaluated for in-vivo anti-diabetic evaluation in STZ induced diabetic rats. Administration of 6e and 6m for four weeks decreased the blood glucose levels significantly. Compound 6e (4.5 mg/kg p.o.) was the most potent compound of the series. It reduced the level of blood glucose to 145.2 ± 1.35 compared to the standard Pioglitazone (150.2 ± 1.06). Moreover, the 6e and 6m treated group did not show increase in bodyweight. The biochemical estimations showed that the levels of ALT, ASP, ALP, urea, creatinine, blood urea nitrogen, total protein and LDH restored to normal in 6e and 6m treated groups as compared to STZ control group. The histopathological studies supported the results obtained in biochemical estimations. Both the compounds did not show any toxicity. Moreover, the histopathological studies of pancreas, liver, heart and kidney revealed that the structural integrity of these tissues restored to almost normal in 6e and 6m treated groups as compared to STZ control group. Based upon these findings it can be concluded that the pyrimidine-based thiazolidinedione derivatives represent novel anti-diabetic agents with least side effects.

Synthesis, biological evaluation and docking studies of methylene bearing cyanopyrimidine derivatives possessing a hydrazone moiety as potent Lysine specific demethylase-1 (LSD1) inhibitors: A promising anticancer agents.

A series of novel cyanopyrimidine-hydrazone hybrids were synthesized and characterized with various spectroscopic techniques. The synthesized compounds were tested at NCI, USA, on a 60-cell line panel and most of the compounds showed remarkable cytotoxic activity against different cancer cell lines. Compound 5a was found to be the most potent compound of the series and it was further selected for five dose assays wherein it exhibited GI50 value of 0.414 µM and 0.417 µM against HOP-62 and OVCAR-4 cell lines respectively. The in-silico mechanistic studies indicated that these compounds are acting through inhibition of lysine specific demethylase 1 (LSD1) as evident from in to vitro LSD1 inhibition activity of compounds. Among various synthesized derivatives, compound 5a was found to have IC50-value of 0.956 µM. In addition, absorption, distribution, metabolism, excretion and toxicity profile (ADMET) was assessed for these novel derivatives to get an insight on their pharmacokinetic/dynamic attributes which revealed that synthesized compounds showed acceptable metabolic stability in human liver microsomes with minimal inhibition of cytochrome P450s (CYPs). The results indicated that compound 5a could be a promising lead compound for further development as a therapeutic agent for anticancer activity.