Discovery of Novel Naphthoquinone-Chalcone Hybrids as Potent FGFR1 Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Molecular Modeling.

This work presents a flexible synthesis of 10 novel naphthoquinone-chalcone derivatives (1-10) by nucleophilic substitution of readily accessible aminochalcones and 2,3-dichloro-1,4-naphthoquinone. All compounds displayed broad-spectrum cytotoxic activities against all the tested cancer cell lines (i.e., HuCCA-1, HepG2, A549, MOLT-3, T47D, and MDA-MB-231) with IC50 values in the range of 0.81-62.06 µM, especially the four most potent compounds 1, 3, 8, and 9. The in vitro investigation on the fibroblast growth factor receptor 1 (FGFR1) inhibitory effect indicated that eight derivatives (1-2, 4-5, and 7-10) were active FGFR1 inhibitors (IC50 = 0.33-3.13 nM) with more potency than that of the known FGFR1 inhibitor, AZD4547 (IC50 = 12.17 nM). Promisingly, compounds 5 (IC50 = 0.33 ± 0.01 nM), 9 (IC50 = 0.50 ± 0.04 nM), and 7 (IC50 = 0.85 ± 0.08 nM) were the three most potent FGFR1 inhibitors. Molecular docking, molecular dynamics simulations, and MM/GBSA-based free energy calculation revealed that the key amino acid residues involved in the binding of the compounds 5, 7, and 9 and the target FGFR1 protein were similar with those of the AZD4547 (i.e., Val492, Lys514, Ile545, Val561, Ala640, and Asp641). These findings revealed that the newly synthesized naphthoquinone-chalcone scaffold is a promising structural feature for an efficient inhibition of FGFR1.

Molecular Docking Studies and Synthesis of Amino-oxy-diarylquinoline Derivatives as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors.

In this study, amino-oxy-diarylquinolines were designed using structure-guided molecular hybridization strategy and fusing of the pharmacophore templates of nevirapine (NVP), efavirenz (EFV), etravirine (ETV, TMC125) and rilpivirine (RPV, TMC278). The anti-HIV-1 reverse transcriptase (RT) activity was evaluated using standard ELISA method, and the cytotoxic activity was performed using MTT and XTT assays. The primary bioassay results indicated that 2-amino-4-oxy-diarylquinolines possess moderate inhibitory properties against HIV-1 RT. Molecular docking results showed that 2-amino-4-oxy-diarylquinolines 8(A-D): interacted with the Lys101 and His235 residue though hydrogen bonding and interacted with Tyr318 residue though π-π stacking in HIV-1 RT. Furthermore, 8A: and 8D: were the most potent anti-HIV agents among the designed and synthesized compounds, and their inhibition rates were 34.0% and 39.7% at 1 µM concentration. Interestingly, 8A: was highly cytotoxicity against MOLT-3 (acute lymphoblastic leukemia), with an IC50 of 4.63±0.62 µg/mL, which was similar with that in EFV and TMC278 (IC50 7.76±0.37 and 1.57±0.20 µg/ml, respectively). Therefore, these analogs of the synthesized compounds can serve as excellent bases for the development of new anti-HIV-1 agents in the near future.

New bioactive cyclopeptide alkaloids with rare terminal unit from the root bark of Ziziphus cambodiana.

Six new 14-membered ring cyclopeptide alkaloids, cambodines A-F (1-6), and two known compounds, frangufoline (7) and lotusanine B (8), were isolated from the root bark extract of Ziziphus cambodiana Pierre. Their structures and configurations were established based on 1D and 2D NMR, HRMS, ECD, and X-ray crystallographic data. Compounds 1 and 3 are rare 5(14)-type cyclopeptide alkaloids that possess an imidazolidin-4-one ring in the terminal unit. The cyclopeptides were tested for their in vitro antiplasmodial, antitubercular, and cytotoxic effects against three cancer cell lines. Compound 3 showed significant antiplasmodial activity against the malarial parasite Plasmodium falciparum, with an IC50 value of 6.09 µM.