Synthesis and biological evaluation of novel N,N′-bis-methylenedioxybenzyl-alkylenediamines as bivalent anti-Alzheimer disease ligands

A novel series of N,N′-bis-methylenedioxybenzyl-alkylenediamines 5a–5g have been designed, synthesized and evaluated as bivalent anti-Alzheimer’s disease ligands. The enzyme inhibition assay results indicated that compounds 5e–5g inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the micromolar range (IC₅₀, 2.76–4.24 µM for AChE and 3.02–5.14 µM for BuChE), which was in the same potential as the reference compound rivastigmine (IC₅₀, 5.50 µM for AChE and 1.60 µM for BuChE). It was found that compounds could bind simultaneously to the peripheral and catalytic sites of AChE. β-Amyloid (Aβ) aggregation inhibition assay results showed that compound 5e exhibited highest self-mediated Aβ fibril aggregation inhibition activity (40.3%) with a similar potential as curcumin (41.6%). It was also found that 5e–5g did not affect neuroblastoma cell viability at the concentration of 50 μM.     

Design,synthesis, and pharmacological evaluation of 2-amino-5-nitrothiazole derived semicarbazones as dual inhibitors of monoamine oxidase and cholinesterase: effect of the size of aryl binding site

A series of 2-amino-5-nitrothiazole derived semicarbazones were designed, synthesised and investigated for MAO and ChE inhibition properties. Most of the compounds showed preferential inhibition towards MAO-B. Compound 4, (1-(1-(4-Bromophenyl)ethylidene)-4-(5-nitrothiazol-2-yl)semicarbazide) emerged as lead candidate (IC₅₀?=?0.212?µM, SI?=?331.04) against MAO-B; whereas compounds 21 1-(5-Bromo-2-oxoindolin-3-ylidene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC₅₀?=?0.264?µM) and 17 1-((4-Chlorophenyl) (phenyl)methylene)-4-(5-nitrothiazol-2-yl)semicarbazide (IC₅₀?=?0.024?µM) emerged as lead AChE and BuChE inhibitors respectively; with activity of compound 21 almost equivalent to tacrine. Kinetic studies indicated that compound 4 exhibited competitive and reversible MAO-B inhibition while compounds 21 and 17 showed mixed-type of AChE and BuChE inhibition respectively. Docking studies revealed that these compounds were well-accommodated within MAO-B and ChE active sites through stable hydrogen bonding and/or hydrophobic interactions. This study revealed the requirement of small heteroaryl ring at amino terminal of semicarbazone template for preferential inhibition and selectivity towards MAO-B. Our results suggest that 5-nitrothiazole derived semicarbazones could be further exploited for its multi-targeted role in development of anti-neurodegenerative agents.

A library of 2-amino-5-nitrothiazole derived semicarbazones (4–21) was designed, synthesised and evaluated for in vitro MAO and ChE inhibitory activity. Compounds 4, 21 and 17 (shown) have emerged as lead MAO-B (IC₅₀:0.212?µM, competitive and reversible), AChE (IC₅₀:0.264?µM, mixed and reversible) and BuChE (IC₅₀:0.024?µM, mixed and reversible) inhibitor respectively. SAR studies disclosed several structural aspects significant for potency and selectivity and indicated the role of size of aryl binding site in potency and selectivity towards MAO-B. Antioxidant activity and neurotoxicity screening results further suggested their multifunctional potential for the therapy of neurodegenerative diseases.     

Synthesis and Antiviral Activities of New Pyrazolo[4,3‐c]quinolin‐3‐ones and Their Ribonucleoside Derivatives

Several new pyrazolo[4,3‐c]quinolin‐3‐one ribonucleosides (5a–g) and their corresponding heterocycle moieties (3a–g) were synthesized and evaluated against vaccinia virus (VV) and herpes simplex virus type 1 (HSV‐1). The derivatives 3c and 3d showed modest inhibitory activity against vaccinia virus reaching 70% at a concentration of 100 µM. All heterocyclic compounds (3a–f) showed a modest inhibition against HSV‐1, reaching the maximal inhibitory effect around 20–30%. The antiviral effects of most of the pyrazolo[4,3‐c]quinolin‐3‐one ribonucleosides (5a–f) on VV and HSV were not impressive.     

Synthesis,antitumour and antioxidant activities of novel α,β-unsaturated ketones and related heterocyclic analogues: EGFR inhibition and molecular modelling study

New α,β-unsaturated ketones 4a,b; 5a–c; and 6a,b; as well as 4-H pyran 7; pyrazoline 8a,b; isoxazoline 9; pyridine 10–11; and quinoline-4-carboxylic acid 12a,b derivatives were synthesized and evaluated for in vitro antitumour activity against HepG2, MCF-7, HeLa, and PC-3 cancer cell lines. Antioxidant activity was investigated by the ability of these compounds to scavenge the 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) radical cation (ABTS^?+). Compounds 6a, 6b, 7, and 8b exhibited potent antitumour activities against all tested cell lines with [IC₅₀] ?5.5–18.1 µΜ), in addition to significantly high ABTS^?+ scavenging activities. In vitro EGFR kinase assay for 6a, 6b, 7, and 8b as the most potent antitumour compounds showed that; compounds 6b, and 7 exhibited worthy EGFR inhibition activity with IC₅₀ values of 0.56 and 1.6?µM, respectively, while compounds 6a and 8b showed good inhibition activity with IC₅₀ values of 4.66 and 2.16?µM, respectively, compared with sorafenib reference drug (IC₅₀?=?1.28?µM). Molecular modelling studies for compounds 6b, 7, and 8b were conducted to exhibit the binding mode towards EGFR kinase, which showed similar interaction with erlotinib.     

Novel coumarin-6-sulfonamides as apoptotic anti-proliferative agents: synthesis,in vitro biological evaluation,and QSAR studies

Herein, we report the synthesis of different novel sets of coumarin-6-sulfonamide derivatives bearing different functionalities (4a, b, 8a–d, 11a–d, 13a, b, and 15a–c), and in vitro evaluation of their growth inhibitory activity towards the proliferation of three cancer cell lines; HepG2 (hepatocellular carcinoma), MCF-7 (breast cancer), and Caco-2 (colon cancer). HepG2 cells were the most sensitive cells to the influence of the target coumarins. Compounds 13a and 15a emerged as the most active members against HepG2 cells (IC₅₀?=?3.48?±?0.28 and 5.03?±?0.39?µM, respectively). Compounds 13a and 15a were able to induce apoptosis in HepG2 cells, as assured by the upregulation of the Bax and downregulation of the Bcl-2, besides boosting caspase-3 levels. Besides, compound 13a induced a significant increase in the percentage of cells at Pre-G1 by 6.4-folds, with concurrent significant arrest in the G2-M phase by 5.4-folds compared to control. Also, 13a displayed significant increase in the percentage of annexin V-FITC positive apoptotic cells from 1.75–13.76%. Moreover, QSAR models were established to explore the structural requirements controlling the anti-proliferative activities.     

Molecular modelling insights into a physiologically favourable approach to eicosanoid biosynthesis inhibition through novel thieno[2,3-b]pyridine derivatives

In this research, we exploited derivatives of thieno[2,3-b]pyridine as dual inhibitors of the key enzymes in eicosanoid biosynthesis, cyclooxygenase (COX, subtypes 1 and 2) and 5-lipoxygensase (5-LOX). Testing these compounds in a rat paw oedema model revealed potency higher than ibuprofen. The most active compounds 7a, 7b, 8b, and 8c were screened against COX-1/2 and 5-LOX enzymes. Compound 7a was the most powerful inhibitor of 5-LOX with IC₅₀?=?0.15?µM, while its p-chloro analogue 7b was more active against COX-2 (IC₅₀?=?7.5?µM). The less desirable target COX-1 was inhibited more potently by 8c with IC₅₀?=?7.7?µM. Surflex docking programme predicted that the more stable anti- conformer of compound (7a) formed a favourable complex with the active site of 5-LOX but not COX-1. This is in contrast to the binding mode of 8c, which resembles the syn-conformer of series 7 and binds favourably to COX-1.     

Synthesis and in vitro anti-proliferative activity of some novel isatins conjugated with quinazoline/phthalazine hydrazines against triple-negative breast cancer MDA-MB-231 cells as apoptosis-inducing agents

Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a–h, 10a–h and 13a–c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC₅₀?=?12.35?±?0.12 and 12.00?±?0.13?μM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC₅₀?=?29.38?±?1.24?μM). Compounds 5e and 10g induced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore, 10g showed significant increase in the percent of annexin V-FITC positive apoptotic cells from 3.88 to 31.21% (8.4 folds compared to control).     

VEGFR-2 inhibitors and apoptosis inducers: synthesis and molecular design of new benzo[g]quinazolin bearing benzenesulfonamide moiety

Two series of novel 4-(2-(2-(2-(substituted) hydrazinyl)-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 5–17 and 4-(2-(2-(substituted-1H-pyrazol-1-yl)-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 18–24 were synthesised from the starting material 4-(2-(2-hydrazinyl-2-oxoethylthio)-4-oxobenzo[g]quinazolin-3(4H)-yl) benzenesulfonamide 5, to be evaluated for their inhibitory activity towards VEGFR-2. The target compounds 5–24, were screened for their cytotoxic activity against MCF-7 breast cancer cell line and the percentage inhibition against VEGFR-2. Compounds 9, 20, 22 and 23, showed excellent VEGFR-2 inhibitory activity with IC₅₀ ranging from 0.64 to 1.04?µm. Being the most potent, compound 9 was evaluated for its apoptotic inducer effect by studying the effect on caspase-3, it was found to increase its level. Compound 9 boosted the level of Bax and reduced the level of BCl2, compared to the control. Cell cycle analysis was conducted, compound 9 showed cell cycle arrest at G2/M phase. Moreover, mild cytotoxic effect (IC₅₀?=?29.41?µm, respectively) in normal breast cells MCF-12?A, was observed when treated with the same compound. Finally, a molecular docking study was performed to investigate the possible binding interaction inside the active site of the VEGFR-2 enzyme.     

Synthesis of novel sulfonamide analogs containing sulfamerazine/sulfaguanidine and their biological activities

Sulfamerazine and sulfaguanidine are clenched with p-nitrobenzoyl chloride and the products obtained are reduced to Na_xS in ethanol–water. Novel sulfonamides (6a–g and 9a–g) were synthesized by the reaction of these reduced products (4 and 8) with various sulfonyl chlorides (5a–g). The structures of these compounds were characterized using spectroscopic analysis (IR, ¹H-NMR, ¹³C-NMR and HRMS) technique. Antimicrobial activity of sulfonamides (3, 4, 7, 8, 6a–g and 9a–g) was evaluated by the agar diffusion method. These compounds showed antimicrobial activity against tested microorganism strains (Gram-positive bacteria, clinic isolate and yeast and mold). Compounds 9d, 9e, 9a, 6d and 6e showed particularly antimicrobial activity against tested Gram-positive (Bacillus cereus and B. subtilis) and Gram-negative (Enterobacter aerogenes) bacteria.     

Synthesis and antimycobacterial evaluation of various 6-substituted pyrazolo[3,4-d]pyrimidine derivatives

Various pyrazolo[3,4-d]pyrimidines carrying a variety of substituents in the 6-position have been synthesised and their ability to inhibit growth of Mycobacterium tuberculosis in vitro has been determined. Compounds 5a, 5b, 6c, 7a, 7b, 8d, 8e and 8f demonstrated a minimum inhibitory concentration (MIC) of <6.25?µg/mL and were found to be active against Mycobacterium tuberculosis strain H₃₇RV. Compound 8d was found to be the most active compound in vitro with a MIC of <6.25?µg/mL and inhibitory concentration IC₉₀ of 1.53?µg/mL.     

Design,synthesis and preliminary structure–activity relationship investigation of nitrogen-containing chalcone derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors: a further study based on Flavokawain B Mannich base derivatives

In order to study the structure–activity relationship of Flavokawain B Mannich-based derivatives as acetylcholinesterase (AChE) inhibitors in our recent investigation, 20 new nitrogen-containing chalcone derivatives (4?a–8d) were designed, synthesized, and evaluated for AChE inhibitory activity in vitro. The results suggested that amino alkyl side chain of chalcone dramatically influenced the inhibitory activity against AChE. Among them, compound 6c revealed the strongest AChE inhibitory activity (IC₅₀ value: 0.85?μmol/L) and the highest selectivity against AChE over BuChE (ratio: 35.79). Enzyme kinetic study showed that the inhibition mechanism of compound 6c against AChE was a mixed-type inhibition. The molecular docking assay showed that this compound can both bind with the catalytic site and the peripheral site of AChE.     

Novel 5,6-disubstituted pyrrolo[2,3-d]pyrimidine derivatives as broad spectrum antiproliferative agents: Synthesis,cell based assays,kinase profile and molecular docking study

Two new series of 5-subtituted and 5,6-disubstituted pyrrolo[2,3-d]pyrimidine octamides (4a–o and 6a–g) and their corresponding free amines 5a–m and 7a–g have been synthesized and biologically evaluated for their antiproliferative activity against three human cancer cell lines. The 5,6-disubstituted octamides 6d–g as well as the amine derivative 7b have shown the best anticancer activity with single digit micromolar GI₅₀ values over the tested cancer cells, and low cytotoxic effects (GI₅₀?>?10.0?µM) against HFF-1 normal cell. A structure activity relationship (SAR) study has been established and disclosed that terminal octamide moiety at C2 as well as disubstitution with fluorobenzyl piperazines at C5 and C6 of pyrrolo[2,3-d]pyrimidine are the key structural features prerequisite for best antiproliferative activity. Moreover, the most active member 6f was tested for its antiproliferative activity over a panel of 60 cancer cell lines at NCI, and exhibited distinct broad spectrum anticancer activity with submicromolar GI₅₀ and TGI values over multiple cancer cells. Kinase profile of compound 6f over 53 oncogenic kinases at 10?µM concentration showed its highly selective inhibitory activity towards FGFR4, Tie2 and TrkA kinases. The observed activity of 6f against TrkA (IC₅₀?=?2.25?µM), FGFR4 (IC₅₀?=?6.71?µM) and Tie2 (IC₅₀?=?6.84?µM) was explained by molecular docking study, which also proposed that 6f may be a type III kinase inhibitor, binding to an allosteric site rather than kinase hinge region. Overall, compound 6f may serve as a promising anticancer lead compound that could be further optimized for development of potent anticancer agents.     

Synthesis and biological evaluation of some thiazole derivatives as new cholinesterase inhibitors

In the present study, some thiazole derivatives were synthesized via the ring closure reaction of 1-[2-(2-oxobenzo[d]thiazol-3(2H)-yl)acetyl]thiosemicarbazide with various phenacyl bromides. The chemical structures of the compounds were elucidated by ¹H NMR, ¹³C NMR and mass spectral data and elemental analyses. Each derivative was evaluated for its ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) using a modification of Ellman’s spectrophotometric method. The compounds were also investigated for their cytotoxic properties using MTT assay. The most potent AChE inhibitor was found as compound 4e (IC₅₀?=?25.5?±?2.12 µg/mL) followed by compounds 4i (IC₅₀?=?38.50?±?2.12 µg/mL), 4c (IC₅₀?=?58.42?±?3.14 µg/mL) and 4g (IC₅₀?=?68?±?2.12 µg/mL) when compared with eserine (IC₅₀?=?0.025?±?0.01 µg/mL). Effective compounds on AChE exhibited weak inhibition on BuChE (IC₅₀ > 80 µg/mL). MTT assay indicated that the cytotoxic dose (IC₅₀?=?71.67?±?7.63 µg/mL) of compound 4e was higher than its effective dose.     

Synthesis of new isoxazoline derivatives from harmine and evaluation of their anti-Alzheimer,anti-cancer and anti-inflammatory activities

Abstract

In our study, a series of new harmine derivatives has been prepared by cycloaddition reaction using various arylnitrile oxides and evaluated in vitro against acetylcholinesterase and 5-lipoxygenase enzymes, MCF7 and HCT116 cancer cell lines. Some of these molecules have been shown to be potent inhibitors of acetylcholinesterase and MCF7 cell line. The greatest activity against acetylcholinesterase (IC₅₀?=?10.4?µM) was obtained for harmine 1 and cytotoxic activities (IC₅₀?=?0.2?µM) for compound 3a. Two derivatives 3e and 3f with the thiophene and furan systems, respectively, showed good activity against 5- lipoxygenase enzyme (IC₅₀?=?29.2 and 55.5?µM, respectively).     

Synthesis,characterization, antiamoebic activity and cytotoxicity of new pyrazolo[3, 4-d]pyrimidine-6-one derivatives

A new series of pyrazolo[3,4-d]pyrimidine-6-one derivatives (2a–2j) were prepared by using the Biginelli multicomponent cyclocondensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (1a), different aromatic aldehydes, and urea with a catalytic amount of HCl at reflux temperature. These compounds were characterized by IR, ¹H NMR, ¹³C NMR, and Mass spectral data. In vitro antiamoebic activity was performed against HM1:IMSS strain of Entamoeba histolytica. The results showed that the compounds 2b, 2i, and 2j with IC₅₀ values of 0.37 µM, 0.04 µM, and 0.06 µM, respectively, exhibited better antiamoebic activity than the standard drug metronidazole (IC₅₀?=?1.33 µM). The toxicological studies of these compounds on human breast cancer MCF-7 cell line showed that the compounds 2b, 2i, and 2j exhibited >80% viability at the concentration range of 1.56–50 µM.     

Synthesis and biological activity of pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one derivatives: in silico approach

Xanthine oxidase (XO) is responsible for the pathological condition called gout. Inhibition of XO activity by various pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidine-4-one derivatives was assessed and compared with the standard inhibitor allopurinol. Out of 10 synthesized compounds, two compounds, viz. 3-amino-6-(2-hydroxyphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one (3b) and 3-amino-6-(4-chloro-2-hydroxy-5-methylphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2-a]pyrimidin-4-one (3g) were found to have promising XO inhibitory activity of the same order as allopurinol. Both compounds and allopurinol inhibited competitively with comparable Ki (3b: 3.56?µg, 3g: 2.337?µg, allopurinol: 1.816?µg) and IC₅₀ (3b: 4.228?µg, 3g: 3.1?µg, allopurinol: 2.9?µg) values. The enzyme–ligand interaction was studied by molecular docking using Autodock in BioMed Cache V. 6.1 software. The results revealed a significant dock score for 3b (?84.976?kcal/mol) and 3g (?90.921?kcal/mol) compared with allopurinol (?55.01?kcal/mol). The physiochemical properties and toxicity of the compounds were determined in silico using online computational tools. Overall, in vitro and in silico study revealed 3-amino-6-(4-chloro-2-hydroxy-5-methylphenyl)-1H-pyrazolo[3,4-d]thiazolo[3,2–a]pyrimidin-4-one (3g) as a potential lead compound for the design and development of XO inhibitors.     

Synthesis and biological evaluation of novel benzo[c][1,2,5]thiadiazol-5-yl and thieno[3,2-c]- pyridin-2-yl imidazole derivatives as ALK5 inhibitors

Transforming growth factor (TGF-β), a key mediator of tumor growth and metastasis, has been recognized as an important cancer drug target. A series of benzo[c][1,2,5]thiadiazol-5-yl imidazoles (14a–g) and thieno[3,2-c]-pyridin-2-yl imidazoles (20a–g) were designed, synthesized, and evaluated for their activin receptor-like kinase 5 (ALK5) activities. Among these compounds, 14c showed the highest activity (IC₅₀ = 0.008 μM) against ALK5 kinase, which was 16.1-fold and 1.8-fold higher than those of positive control compounds LY-2157299 (IC₅₀ = 0.129 μM) and EW-7197 (IC₅₀ = 0.014 μM), respectively. Compound 14g (350) showed the highest selectivity index of ALK5 against p38α MAP kinase, which was significantly higher than that of positive control compounds LY-2157299 (4) and EW-7197 (211). The inhibitory effects of compound 14c on TGF-β-induced Smad signaling and cell motility were studied in SPC-A1, HepG2 and HUVEC cells using western blot analysis and wound healing assay. ADMET prediction analysis showed that compounds 14c and 14g had good pharmacokinetics and drug-likeness behaviors.     

Novel 1-acyl-4-substituted semicarbazide derivatives of primaquine − synthesis,cytostatic, antiviral and antioxidative studies

A series of novel 1,4-substituted semicarbazides 5a–g with a primaquine moiety bridged by a carbonyl group at position 1 and a cycloalkyl, aryl, benzyloxy or hydroxy substituent at position 4 were prepared and biologically evaluated. The synthetic pathways applied for preparation of the title compounds involved benzotriazole as synthetic auxiliary. Primaquine semicarbazides 5a–g and their synthetic precursors benzotriazolecarbonyl semicarbazides 4 were evaluated for cytostatic, antiviral and antioxidative activities. All compounds of the series 5 showed high selectivity towards MCF-7 cells (breast carcinoma) with IC₅₀ values in the low micromolar range and the most active was benzyl derivative 5c (IC₅₀ 1?±?0.2 µM). The benzhydryl derivative 5e showed significant cytostatic activities towards all the tested cell lines (IC₅₀ 4–18 µM). The same compound was the strongest lipoxygenase inhibitor as well (51%). The highest antioxidant activity was demonstrated for the hydroxy derivative 5g and benzotriazolecarbonyl semicarbazides 4b,c (61.2–68.5%). No antiviral activity was observed against a wide variety of DNA and RNA viruses.     

Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies

The potential antitumor activities of a series of 7-(4-substituted piperazin-1-yl)fluoroquinolone derivatives (1–14a,b) using ciprofloxacin and norfloxacin as scaffolds are described. These compounds exhibit potent and broad spectrum antitumor activities using 60 human cell lines in addition to the inherent antibacterial activity. Compounds 1a, 2a, 3b, 6b and 7a were found to be the most potent, while 2b, 5b, and 6a were found to have an average activity. The results of this study demonstrated that compounds 1a, 2a, 3b, 6b and 7a (mean GI₅₀; 2.63–3.09?µM) are nearly 7-fold more potent compared with the positive control 5-fluorouracil (mean GI₅₀; 22.60?µM). More interestingly, compounds 1a, 2a, 3b, 6b and 7a have an almost antitumor activity similar to gefitinib (mean GI₅₀; 3.24?µM) and are nearly 2-fold more potent compared to erlotinib (mean GI₅₀; 7.29?µM). In silico study and ADME-Tox prediction methodology were used to study the antitumor activity of the most active compounds and to identify the structural features required for antitumor activity.     

Synthesis and biological evaluation of 2-styrylquinolines as antitumour agents and EGFR kinase inhibitors: molecular docking study

A new series of 4,6-disubstituted 2-(4-(dimethylamino)styryl)quinoline 4a,b–9a,b was synthesized by the reaction of 2-(4-(dimethylamino)styryl)-6-substituted quinoline-4-carboxylic acids 3a,b with thiosemicarbazide, p-hydroxybenzaldehyde, ethylcyanoacetate, and 2,4-pentandione. In addition, the antitumour activity of all synthesized compounds 3a,b–9a,b was studied via MTT assay against two cancer cell lines (HepG2 and HCT116). Furthermore, epidermal growth factor receptor (EGFR) inhibition, using the most potent antitumour compounds, 3a, 3b, 4a, 4b, and 8a, was evaluated. The interpretation of the results showed clearly that the derivatives 3a, 4a, and 4b exhibited the highest antitumour activities against the tested cell lines HepG2 and HCT116 with IC₅₀ range of 7.7–14.2?µg/ml, in comparison with the reference drugs 5-fluorouracil (IC₅₀?=?7.9 and 5.3?µg/ml, respectively) and afatinib (IC₅₀?=?5.4 and 11.4?µg/ml, respectively). In vitro EGFR screening showed that compounds 3a, 3b, 4a, 4b, and 8a exhibited moderate inhibition towards EGFR with IC₅₀ values at micromolar levels (IC₅₀ range of 16.01–1.11?µM) compared with the reference drugs sorafenib (IC₅₀ =?1.14?µM) and erlotinib (IC₅₀ =?0.1?µM). Molecular docking was performed to study the mode of interaction of compounds 3a and 4b with EGFR kinase.