A nicotinamide-based derivative was designed as an antiproliferative VEGFR-2 inhibitor with the key pharmacophoric features needed to interact with the VEGFR-2 catalytic pocket. The ability of the designed congener ((E)-N-(4-(1-(2-(4-benzamidobenzoyl)hydrazono)ethyl)phenyl)nicotinamide), compound 10, to bind with the VEGFR-2 enzyme was demonstrated by molecular docking studies. Furthermore, six various MD simulations studies established the excellent binding of compound 10 with VEGFR-2 over 100 ns, exhibiting optimum dynamics. MM-GBSA confirmed the proper binding with a total exact binding energy of −38.36 Kcal/Mol. MM-GBSA studies also revealed the crucial amino acids in the binding through the free binding energy decomposition and declared the interactions variation of compound 10 inside VEGFR-2 via the Protein–Ligand Interaction Profiler (PLIP). Being new, its molecular structure was optimized by DFT. The DFT studies also confirmed the binding mode of compound 10 with the VEGFR-2. ADMET (in silico) profiling indicated the examined compound’s acceptable range of drug-likeness. The designed compound was synthesized through the condensation of N-(4-(hydrazinecarbonyl)phenyl)benzamide with N-(4-acetylphenyl)nicotinamide, where the carbonyl group has been replaced by an imine group. The in-vitro studies were consonant with the obtained in silico results as compound 10 prohibited VEGFR-2 with an IC₅₀ value of 51 nM. Compound 10 also showed antiproliferative effects against MCF-7 and HCT 116 cancer cell lines with IC₅₀ values of 8.25 and 6.48 μM, revealing magnificent selectivity indexes of 12.89 and 16.41, respectively.

Four new nicotinamide-based derivatives were designed as antiangiogenic VEGFR-2 inhibitors. The congeners were synthesized possessing the pharmacophoric essential features to bind correctly with the VEGFR-2 active pocket. All members were evaluated for their cytotoxic and VEGFR-2 inhibitory potentialities. Compound 6 was the most potent showingIC₅₀ values of 9.3 ± 0.02 and 7.8 ± 0.025 µM against HCT-116 and HepG-2 cells, respectively, and IC₅₀ of 60.83 nM regarding VEGFR-2 enzyme inhibition. Compound 6 arrested the growth of HCT-116 cells at the pre-G1 and G2-M phases. Further, it induced both early and late apoptosis. Additionally, compound 6 caused a significant decrease in TNF-α and IL6 by 66.42% and 57.34%, respectively. The considered compounds had similar docking performances to that of sorafenib against the VEGFR-2 (PDB ID: 2OH4). The correct binding of compound 6 with VEGFR-2 was validated using MD simulations, and MM-GPSA calculations.

Corresponding to the reported features of anti-VEGFR-2-approved compounds, a new 1H-indole derivative (compound 7) was designed. The inhibitory potential of the designed compound was revealed via a molecular docking study that showed the appropriate binding. Then, MD simulation (six studies) over a period of 100 ns was performed to confirm the precise binding and optimum energy. Additionally, MM-GBSA reaffirmed the perfect binding, exhibiting a total precise energy of −40.38 Kcal/Mol. The MM-GBSA experiments named the essential amino acids in the protein–ligand interaction, employing the binding energy decomposition and revealing the diversity of interactions of compound 7 inside the VEGFR-2 enzyme. As compound 7 is new, DFT experiments were utilized for molecular structure optimization. Additionally, the DFT results validated the coherent interaction of compound 7 with the VEGFR-2 enzyme. A good value of drug-likeness of compound 7 was acknowledged via in silico ADMET studies. Interestingly, the experimental in vitro prohibitory potential of compound 7 was better than that of sorafenib, demonstrating an IC₅₀ value of 25 nM. Notably, the strong inhibitory effects of compound 10 against two cancer cell lines (MCF-7 and HCT 116) were established with IC₅₀ values of 12.93 and 11.52 μM, disclosing high selectivity indexes of 6.7 and 7.5, respectively.

Based on the pharmacophoric features of EGFR inhibitors, a new semisynthetic theobromine-derived compound was designed to interact with the catalytic pocket of EGFR. Molecular docking against wild (EGFR^WT; PDB: 4HJO) and mutant (EGFR^T790M; PDB: 3W2O) types of EGFR-TK indicated that the designed theobromine derivative had the potential to bind to that pocket as an antiangiogenic inhibitor. The MD and MM-GBSA experiments identified the exact binding with optimum energy and dynamics. Additionally, the DFT calculations studied electrostatic potential, stability, and total electron density of the designed theobromine derivative. Both in silico ADMET and toxicity analyses demonstrated its general likeness and safety. We synthesized the designed theobromine derivative (compound XI) which showed an IC₅₀ value of 17.23 nM for EGFR inhibition besides IC₅₀ values of 21.99 and 22.02 µM for its cytotoxicity against A549 and HCT-116 cell lines, respectively. Interestingly, compound XI expressed a weak cytotoxic potential against the healthy W138 cell line (IC₅₀ = 49.44 µM, 1.6 times safer than erlotinib), exhibiting the high selectivity index of 2.2. Compound XI arrested the growth of A549 at the G2/M stage and increased the incidence of apoptosis.

(E)-N-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide (compound 10) was designed as an antiangiogenic VEGFR-2 inhibitor with the essential pharmacophoric structural properties to interact with the catalytic pocket of VEGFR-2. The designed derivative was synthesized, and its structure was confirmed through Ms, elemental, ¹H, and ¹³C spectral data. The potentiality of the designed pyridine derivative to bind with and inhibit the vascular endothelial growth factor receptor-2 (VEGFR-2) enzyme was indicated by molecular docking assessments. In addition, six molecular dynamic (MD) experiments proved its correct binding with VEGFR-2 over 100 ns. Additionally, the molecular mechanics energies, combined with the generalized born and surface area (MM-GBSA) analysis, identified the precise binding with optimum energy. To explore the stability and reactivity of the designed pyridine derivative, density functional theory (DFT) calculations, including electrostatic potential maps and total electron density, were carried out. Additionally, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis demonstrated its general likeness and its safety. The designed compound was synthesized to evaluate its effects against VEGFR-2 protein, cancer, and normal cells. The in vitro results were concordant with the in silico results, because the new pyridine derivative (compound 10) displayed VEGFR-2 inhibition with an IC₅₀ value of 65 nM and displayed potent cytotoxic properties against hepatic (HepG2) and breast (MCF-7) cancer cell lines with IC₅₀ values of 21.00 and 26.10 μM, respectively; additionally, it exhibited high selectivity indices against the normal cell lines (W-38) of 1.55 and 1.25, respectively. The obtained results present compound 10 as a new lead VEGFR-2 inhibitor for further biological investigation and chemical modifications.

A new lead compound has been designed as an antiangiogenic EGFR inhibitor that has the pharmacophoric characteristics to bind with the catalytic pocket of EGFR protein. The designed lead compound is a (para-chloro)acetamide derivative of the alkaloid, theobromine, (T-1-PCPA). At first, we started with deep density functional theory (DFT) calculations for T-1-PCPA to confirm and optimize its 3D structure. Additionally, the DFT studies identified the electrostatic potential, global reactive indices and total density of states expecting a high level of reactivity for T-1-PCPA. Secondly, the affinity of T-1-PCPA to bind and inhibit the EGFR protein was studied and confirmed through detailed structure-based computational studies including the molecular docking against EGFR^WT and EGFR^T790M, Molecular dynamics (MD) over 100 ns, MM-GPSA and PLIP experiments. Before the preparation, the computational ADME and toxicity profiles of T-1-PCPA have been investigated and its safety and the general drug-likeness predicted. Accordingly, T-1-PCPA was semi-synthesized to scrutinize the proposed design and the obtained in silico results. Interestingly, T-1-PCPA inhibited in vitro EGFR^WT with an IC₅₀ value of 25.35 nM, comparing that of erlotinib (5.90 nM). Additionally, T-1-PCPA inhibited the growth of A549 and HCT-116 malignant cell lines with IC₅₀ values of 31.74 and 20.40 µM, respectively, comparing erlotinib that expressed IC₅₀ values of 6.73 and 16.35 µM, respectively.