“…Melting points were measured in a Stuart Scientific apparatus. Synthesis of phthalazinones 11 – 12 and 4-bromomethyl phthalazinone 18 was performed as previously described [ 38 , 39 ]. Synthesis of 2-(2-bromoethyl) phthalazinones 15 – 17 , which was accomplished by adapting procedures previously reported, as detailed in the Supplementary Materials Section .…”
Nowadays, cancer disease seems to be the second most common cause of death worldwide. Molecular hybridization is a drug design strategy that has provided promising results against multifactorial diseases, including cancer. In this work, two series of phthalazinone-dithiocarbamate hybrids were described, compounds 6–8, which display the dithiocarbamate scaffold at N2, and the compounds 9, in which this moiety was placed at C4. The proposed compounds were successfully synthesized via the corresponding aminoalkyl phthalazinone derivatives and using a one-pot reaction with carbon disulfide, anhydrous H3PO4, and different benzyl or propargyl bromides. The antiproliferative effects of the titled compounds were explored against three human cancer cell lines (A2780, NCI-H460, and MCF-7). The preliminary results revealed significant differences in activity and selectivity depending on the dithiocarbamate moiety location. Thus, in general terms, compounds 6–8 displayed better activity against the A-2780 and MCF-7 cell lines, while most of the analogues of the 9 group were selective toward the NCI-H460 cell line. Compounds 6e, 8e, 6g, 9a–b, 9d, and 9g with IC50 values less than 10 µM were the most promising. The drug-likeness and toxicity properties of the novel phthalazinone-dithiocarbamate hybrids were predicted using Swiss-ADME and ProTox web servers, respectively.
“…Melting points were measured in a Stuart Scientific apparatus. Synthesis of phthalazinones 11 – 12 and 4-bromomethyl phthalazinone 18 was performed as previously described [ 38 , 39 ]. Synthesis of 2-(2-bromoethyl) phthalazinones 15 – 17 , which was accomplished by adapting procedures previously reported, as detailed in the Supplementary Materials Section .…”
Nowadays, cancer disease seems to be the second most common cause of death worldwide. Molecular hybridization is a drug design strategy that has provided promising results against multifactorial diseases, including cancer. In this work, two series of phthalazinone-dithiocarbamate hybrids were described, compounds 6–8, which display the dithiocarbamate scaffold at N2, and the compounds 9, in which this moiety was placed at C4. The proposed compounds were successfully synthesized via the corresponding aminoalkyl phthalazinone derivatives and using a one-pot reaction with carbon disulfide, anhydrous H3PO4, and different benzyl or propargyl bromides. The antiproliferative effects of the titled compounds were explored against three human cancer cell lines (A2780, NCI-H460, and MCF-7). The preliminary results revealed significant differences in activity and selectivity depending on the dithiocarbamate moiety location. Thus, in general terms, compounds 6–8 displayed better activity against the A-2780 and MCF-7 cell lines, while most of the analogues of the 9 group were selective toward the NCI-H460 cell line. Compounds 6e, 8e, 6g, 9a–b, 9d, and 9g with IC50 values less than 10 µM were the most promising. The drug-likeness and toxicity properties of the novel phthalazinone-dithiocarbamate hybrids were predicted using Swiss-ADME and ProTox web servers, respectively.
“…The Molecular Docking studies showed two different binding modes for the compounds i.e., the alkyl chain linking both scaffolds and the binding of the dithiocarbamate group in the proximity of the basic residues Phe168, Leu171, and Cys172. Finally, the predicted ADME descriptors showed that the novel pyridazinone/dithiocarbamate derivatives showed good drug-like properties for oral absorption and BBB permeation [ 100 ]. Fig.…”
Parkinson’s disease is a neurodegenerative disorder characterized by slow movement, tremors, and stiffness caused due to loss of dopaminergic neurons caused in the brain’s substantia nigra. The concentration of dopamine is decreased in the brain. Parkinson’s disease may be happened because of various genetic and environmental factors. Parkinson’s disease is related to the irregular expression of the monoamine oxidase (MAO) enzyme, precisely type B, which causes the oxidative deamination of biogenic amines such as dopamine. MAO-B inhibitors, available currently in the market, carry various adverse effects such as dizziness, nausea, vomiting, lightheadedness, fainting, etc. So, there is an urgent need to develop new MAO-B inhibitors with minimum side effects. In this review, we have included recently studied compounds (2018 onwards). Agrawal et al
.
reported MAO-B inhibitors with IC
50
0.0051 µM and showed good binding affinity. Enriquez et al
.
reported a compound with IC
50
144 nM and bind with some critical amino acid residue Tyr60, Ile198, and Ile199. This article also describes the structure–activity relationship of the compounds and clinical trial studies of related derivatives. These compounds may be used as lead compounds to develop potent compounds as MAO-B inhibitors.
Graphic Abstract
“…Pyridazine and its polycyclic structures have still played an interesting role in organic chemistry because of their remarkable properties in forming supramolecular assembly [ 15 , 16 , 17 , 18 ]. Pyridazine molecules are important heterocycle scaffolds that reveal diverse biological activities in medicine [ 19 , 20 , 21 , 22 , 23 , 24 , 25 ] and agriculture [ 26 ]. For example, Pyridazomycin is an antifungal and antibiotic compound, the first pyridazine derivative isolated from a natural source [ 27 ].…”
An efficient synthesis of a series of pyridazino[4,3-c:5,6-c′]diquinolines was achieved via the autoxidation of 4-hydrazinylquinolin-2(1H)-ones. IR, NMR (1H and 13C), mass spectral data, and elemental analysis were used to fit and elucidate the structures of the newly synthesized compounds. X-ray structure analysis and theoretical calculations unequivocally proved the formation of the structure. The possible mechanism for the reaction is also discussed.
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