Developing multitarget coumarin based anti-breast cancer agents: synthesis and molecular modeling study

Abstract A new series of 7-substituted coumarin scaffolds containing a methyl ester moiety at the C4-position were synthesized and tested for their in vitro anti-proliferative activity against MCF-7 and MDA-MB-231 breast cancer cell lines using Doxorubicin (DOX) as reference. Compounds 2 and 8 showed noticeable selectivity against MCF-7 with IC50 = 6.0 and 5.8 µM, respectively compared to DOX with IC50 = 5.6 µM. Compounds 10, 12, and 14 exhibited considerable selectivity against Estrogen Negative cells with IC50 = 2.3, 3.5, and 1.9 µM, respectively) compared to DOX with (IC50 = 7.3 µM). The most promising compounds were tested as epidermal growth factor receptor and aromatase (ARO) enzymes inhibitors using erlotinib and exemestane (EXM) as standards, respectively. Results proved that compound 8 elicited the highest inhibitory activity (94.73% of the potency of EXM), while compounds 10 and 12 displayed 97.67% and 81.92% of the potency of Erlotinib, respectively. Further investigation showed that the promising candidates 8, 10, and 12 caused cell cycle arrest at G0–G1 and S phases and induced apoptosis. The mechanistic pathway was confirmed by elevating caspases-9 and Bax/Bcl-2 ratio. A set of in silico methods was also performed including docking, bioavailability ADMET screening and QSAR stud

Rational repurposing, synthesis, in vitro and in silico studies of chromone-peptidyl hybrids as potential agents against Leishmania donovani

AbstractA chromone-peptidyl hybrids series was synthesised and rationally repurposed towards identification of potential antileishmanial hits against visceral leishmaniasis. Three hybrids 7c, 7n, and 7h showed potential IC50 values (9.8, 10, and 12 µM, respectively) which were comparable to erufosine IC50 (9.8 µM) but lower potency than miltefosine IC50 (3.5 µM). Preliminary assessment of cytotoxicity using human THP-1 cells presented chromone-peptidyl hybrids 7c and 7n as non-cytotoxic up to 100 µM while erufosine and miltefosine had CC50 of 19.4 µM and >40 µM, respectively. In silico studies pinpointed the N-p-methoxyphenethyl substituent at the peptidyl moiety together with the oxygen-based substituted functions of the phenyl ring of the chromone moiety as crucial players in binding to LdCALP. Together, these findings present chromone-peptidyl hybrids 7c and 7n as potential and anticipated non-cytotoxic antileishmanial hit compounds for possible development of potential antileishmanial agents against visceral leishmaniasis