Acrylamide Moiety , a Valuable Fragment in Medicinal Chemistry : Insight into Synthetic Methodologies , Chemical Reactivity and Spectrum of Biological Activities of Acrylamide Derivatives

Acrylamide moiety is a pronounced Michael acceptor that has drawn much interest in a wide array of drugs designed for various therapeutic purposes. Herein we outline different synthetic pathways, scientific bases for its chemical reactivity and how it is functionalized for design of new therapeutic entities, in addition to a brief insight into spectrum of reported biological activities of acrylamide containing compounds up to date.


INTRODUCTION
Acrylamide moiety has been proved to be a valuable tool for design of novel therapeutic entities.Evidence for that is observed through the wide range of biological activities exhibited by acrylamide derivatives including antitumor activity 1 , epidermal growth factor receptor (EGFR) kinase inhibitor activity 2 , antiviral activity 3 , anti-inflammatory activity 4 , antiplatelet activity 5 , antidiabetic activity 6 , tubulin polymerization inhibitor activity 7 , antibacterial activity 8 , vasodilator activity 9 , antifungal activity 10 , angiotensin II receptor antagonist activity 11 and histone deacetylase HDAC inhibitor activity 12 .A considerable number of approved drugs incorporate acrylamide moiety in their structures, for example: Entacapone a catechol Omethyl transferase (COMT) inhibitor used for treatment of Parkinson disease.In addition, Panobinostat a HDAC inhibitor approved in February 2015 for the treatment of multiple myeloma.In the same context Belinostat HDAC inhibitor approved in July 2014 for treatment of peripheral T-cell lymphoma.Additionally, Ibrutinib, a Bruton's tyrosine kinase BTK inhibitor approved 2013 for treatment of various myeloid tumors.Rifampicin, a well-known antibiotic approved for treatment of mycobacterial infections as tuberculosis and leprosy.Anthramycin an antibiotic and antineoplastic drug.Afatinib EGFR kinase approved for treatment of non-small cell lung cancer (NSCLC), Carnetinib and Dacomitinib EGFR kinase inhibitors phase II clinical trials drugs for treatment of NSCLC Figure 1.

Synthetic pathways 1.Knovenagel condensation
Knovenagel originally reported the condensation of aldehydes with diethyl malonate in basic medium to yield alkylidene malonic acid diesters 13 , Scheme 1. Dobner reported the modification of Knovenagel condensation by carrying out the reaction between aldehydes and malonic acid in refluxing pyridine which promoted what is known as "pyridine-induced decarboxylation" to yield 3substituted acrylic acid derivatives.The produced acrylic acid derivatives can be further reacted with primary amines to yield 3-substituted acrylamide derivatives 7,14,15 Scheme 2.

Scheme 1. Knovenagel reaction Scheme 2. Knovenagel-Dobner reaction (pyridine induced decarboxylation)
Another applied modification of Knovenagel condensation for synthesis of substituted acrylamides is the reaction of aldehydes with acetamides substituted with an electron withdrawing group at position no. 2 under basic conditions to yield 2,3-disubstituted acrylamide derivatives.The most common is the reaction of the desired aldehyde with N-substituted 2cyanoacetamide derivatives to yield various desired 2cyanoacrylamide derivatives 1,[16][17][18] , Scheme 3.

Scheme 3. Knovenagel condensation between aldehydes and N-substituted 2-cyanoacetamide derivatives to yield 2-cyanoacrylamide derivatives
Augustine 19 et al. reported the synthesis of a series of 3-substituted acrylic acid derivatives with excellent yields using a modification of knovenageldobner reaction in which germinal dibromomethylarenes were used as alternatives for noncommercially available aldehydes, the obtained acrylic acid derivatives can be easily converted to the corresponding desired acrylamide derivative via reaction with appropriate primary amine, Scheme 4. Scheme 4. Modified Knovenagel Dobner reaction using germinal dibromomethylarenes as alternative for aldehydes

Via Horner-Wadsworth-Emmons (HWE) reaction
Applying the principle of HWE reaction 20,21 , (E) 3-substituted acrylamide derivatives can be obtained where desired aldehydes or ketones are reacted with acetate esters bearing a phosphonate ester derivative at alpha carbon (2-(phosphonate ester)-acetate ester derivatives) that were previously activated using strong bases as sodium hydride to yield (E) 3-substituted acrylate esters.The formed (E) 3-substituted acrylate esters undergo either alkaline hydrolysis of ester to give the free acrylic acid followed by reaction with various primary amines to yield the desired 3-substituted acrylamide or direct refluxing the formed 3-substituted acrylate esters with desired primary amine to yield the 3-substituted acrylamide 9,22 , scheme 5.

Via Mizoroki-Heck coupling reaction:
The principle of Mizoroki-Heck coupling reaction 23,24 is also applied for synthesis of the 3substituted acrylamide derivatives.It involves Palladium catalyzed reaction of aryl or aryl halides with acrylic acid esters yielding 3-substituted acrylate esters.The formed 3-substituted acrylate esters undergo both alkaline hydrolysis and reaction of the formed free acid with various primary amines or directly refluxing the formed 3-substituted acrylate esters with desired primary amine to yield the desired 3-substituted acrylamide 25,26 , Scheme 6.

Via reaction between 2-cyanoacetamides and aryl isothiocyanates
Another widely applied synthetic methodology is via the reaction between 2-cyanoacetamide derivatives and aryl isothiocyanates under basic conditions to yield a thiolate intermediate which is alkylated using methyl iodide or dimethyl sulfate to yield 3-aryl, 2-cyano, 3-methylthio acrylamide derivatives 27,28 , Scheme 7.

Acrylamide reactivity and its functionalization for design of new therapeutic entities
The reactivity of acrylamide moiety has been extensively investigated; it depends mainly on being Michael acceptor.This results from the presence of α, β-unsaturated carbonyl where the α, β-unsaturated moiety represents the electrophilic center required for Michael addition reaction of various nucleophiles as illustrated in Figure 2.This unique property is especially helpful for design of new therapeutic entities where acrylamide moiety can be functionalized for efficient targeting of different proteins which possess nucleophilic residues as cysteine and serine at active drug binding site [31][32][33][34] .

Advantage of additional nitrile substitution at the alpha carbon
An additional nitrile group at the alpha carbon of acrylamide (2-cyanoacrylamide) can increase the efficiency of acrylamide moiety as a tool for designing successful drugs addressing protein targets rich in nucleophilic residues and H-bond donor residues.This additional group forms "nitrile trap" which traps both nucleophilic residues and H-bond donor residues, for nucleophilic residues it undergoes nucleophilic addition at the electrophilic carbon of nitrile whereas for H-bond donor residues it serves as H-bond acceptor via the lone pair on the nitrogen of nitrile group.The advantage of nitrile moiety as a tool for designing various molecules addressing various therapeutic targets was highlighted by many researchers [35][36][37][38][39][40] .

Acrylamides a tool for design of targeted
covalent inhibitors TCI's TCI's are small molecules bearing specific functional groups capable of covalent binding with specific residues at target proteins leading to silencing and inhibition of the protein action.Design of TCI's is a successful strategy for developing new drugs [40][41][42][43] , a fact empathized through the well appreciated record of successful drugs belonging to this class of compounds..The added value of acrylamide was confirmed by Solca 49 et al via x-ray crystallography of Michael addition product of Afatinib an EGFR kinase inhibitor bearing acrylamide moiety and cysteine 797 residue of both wild-type EGFR and mutated EGFR L858R/T790M .They also provided experiment based proof that loss of acrylamide moiety leads to loss of activity using an analog lacking the acrylamide moiety.The Michael addition adduct obtained for Afatinib with both the wild EGFR and mutated EGFR L858R/T790M 49 is illustrated in Figure 3 and   and evaluated them for their angiotensin II receptor antagonist activity.A structure activity relationship study was generated revealing that substitution of imidazole at the 4-position with the N-methyl, 3, 3dimethylacrylamide group resulted in enhanced activity.Compound 1 was superior to the reference drug in vitro but with poor in vivo activity after oral administration.To overcome this problem prodrug esters were synthesized and evaluated; among which compound 2 (the -[(ethoxycarbonyl)oxy]ethyl ester) exhibited highest in vivo activity after oral administration.
Keenan 50 et al reported synthesis of a set of substituted (E) -acrylic acid derivatives for evaluation of their activity as angiotensin II receptor.They were guided by a developed pharmacophore model which suggests that the addition of acid chain and an aryl side chain to imidazole mimicking the C-terminal phenylalanine region of native ligand would lead to increased activity.A SAR study was developed which revealed that electron-rich hetero aryl rings improved the activity.Compound 3 was the most potent orally bioavailable candidate.

Transient receptor potential vanilloid 1 TRPV1 receptor antagonist
Gavva 52 et al. reported the evaluation of compound 7 coded as AMG 9810 for vanilloid receptor 1(VR1) -also known as transient receptor potential vanilloid 1 TRPV1-antagonist activity.VR1 is a cation channel receptor bound to the membrane of peripheral sensory neurons.Antagonism of VR1 produces antihyperalgesic effect in neuropathic and inflammatory pain animal models 53 .AMG9810 blocked TRPV1 activation in all models of TRPV1 activation at nanomolar concentrations (IC50 range 15.8-294 nM for different models).

Antidiabetic activity
Li 54 et al reported discovery of set of 3-phenyl acrylamide derivatives developed at GlaxoSmithKline GSK as novel potent human liver glycogen phosphorylase a (HLGPa) inhibitors via highthroughput screening.The discovered compounds possess an extreme advantage of being glucosesensitive where they exhibited activity at high blood glucose levels and no or minimal activity when blood glucose level decreases.The most active compounds were compound 8 (IC50 0.94 μM) and compound 9 (IC50 0.17 μM).
Onda 6 et al reported synthesis of a series of 3-(3,4-dichlorophenyl)acrylamide derivatives and their evaluation for human liver glycogen phosphorylase A (HLGPa) inhibitory activity.Compound 10 was most active (IC50 0.023 μM).X-ray crystallography study of the enzyme complexed with compound 10 revealed that compound 10 exhibited hydrophobic interaction with the enzyme via the 3,4-dichlorophenyl moiety.

Prostaglandin E2 receptor-3 EP3 antagonist activity
3-Acrylsulfonamide-4-aryloxy indole series was synthesized and evaluated for prostaglandin E2 receptor-3 EP3 antagonist activity by Zhou 5 et al.EP3 is associated with prostaglandin E2 induced platelet aggregation 55 , thus EP3 antagonism would produce antiplatelet activity without inhibiting PGE2 production which is a main drawback of conventional treatments.Synthesized derivatives were evaluated for IC50 of human EP3 receptor binding among which compounds 11, 12 and 13 showed highest potency with IC50 of 2.6 nM, 3.5 nM and 4.6 nM; respectively.

Antiviral activity against hepatitis B virus HBV
Dong 56 et al. reported the design, synthesis of a novel series of acrylamide derivatives bearing 1,2,3thiadiazole heterocycle and their evaluation for their in vitro antiviral activity against HBV.The IC50 values for the inhibition of HBV DNA replication exhibited by most potent compounds 14 and 15 were 3.59 μg/mL and 10.4 μg /mL respectively.These results are very promising taking into consideration that the IC50 exhibited by the positive control lamivudine was14.8mg/mL.

Diacyl glycerol transferase DGAT inhibitor activity
Hepatic DGAT represents a potential target for treatment of obesity and fatty liver disorders 57 .lee 58 et al reported synthesis of series of indolyl acrylamides and evaluation for their DGAT inhibitory activity.Compound 17 exhibited highest potency with IC50 of 2.5μM inhibiting synthesis of triglyceride in dose dependent manner.The study revealed the selectivity of indolyl acrylamides against DGAT-2.

Soluble guanylyl cyclase sGC activator activity
sGC is an enzyme responsible for cellular conversion of guanosine triphosphate (GTP) into cyclic guanosine mono phosphate cGMP.It serves as a receptor for nitric oxide (NO) and cellular transduction pathway for physiological NO induced vasodilator effects.sGC activators are identified as targets for novel vasodilator drugs.Zhang 9 et al reported the synthesis of set of O-substituted 3-aryl acrylamides.Synthesized compounds exhibited EC50 ranging (2.9-100 μM) compound 18 was the most active with EC50 2.9 μM.

COX II inhibitor activity
Yao 59 et al reported the synthesis of series of novel resveratrol amides including acrylamide derivatives and evaluation of their cyclooxygenase-2 (COX-2) inhibitory activity.Among various amides acrylamide derivatives showed the highest activity.Compounds 19 and 20 exhibited the most potent COX-2 inhibitory activity with the IC50 values of 1.02 and 1.98 μM, respectively.Molecular docking studies were carried out for 20 and 21 into COX-2 active site revealing the interaction via strong hydrophobic interactions and hydrogen bonding.

NLRP3 inflammasome inhibitor activity
NLRP3 inflammasome is an oligoprotein complex coded by NLRP3 gene, thus nominated after it.It is expressed mainly in myeloid tissue and macrophages as a part of innate immunity.It is involved in inflammatory response to different pathogens and inflammatory situations.Its role involves a caspase-1 activity for activation of chemokines as IL-1β and induction of chemotaxis, as well as roles in induction of necrosis and pyroptotic cell death 60 .Aberrations of NLRP3 inflammasome activity have been linked to number of diseases as neurological disorders 61 , Alzheimer's disease 62 , auto-immune disorders 63 and inflammatory disorders 64 .
Cocco 65 et al. reported synthesis of a set of acrylamide derivatives and evaluation for their activity as NLRP3 inflammasome inhibitors, including assay for inhibition of I IL-1β release from macrophages including mutant subtypes, then the most active compounds were further evaluated for NLRP3 ATPase

Chemokine receptor 3 CCR3 antagonist activity
CCR3 is a receptor for inflammatory chemokines as eaotaxin, MCP (monocyte chemoattractant protein) and RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted), it is expressed mainly on eosinophils 66 .It is involved in the chemotaxis of eosinophils in different inflammatory and allergic diseases thus represents potential target for addressing inflammatory and allergic diseases 67 .
Sato 4 et al. reported synthesis and characterization of acrylamide derivatives with potent CCR3 inhibitory activity and evaluation of in vitro metabolic stability in human liver microsomes expressed as clearance rate (CLint; mL/min/kg) of these compounds.A SAR study was generated for both CCR3 antagonism activity and CLint values .compound22 was among potent inhibitors (IC50 = 8.4 nM) with highest metabolic stability (Clint <64 mL/min/kg).

Antitumor activity:
Zhou et al. reported synthesis of a set of 3-aryl, 2cyanoacrylamide derivatives and evaluation of their anti-tumor activity against human nasopharyngeal carcinoma cell line KB, human gastric carcinoma cell line BGC-823 and human hepatoma cell line BEL-7402.23 was the most potent with IC50 values of 5.6 μg/mL for human gastric carcinoma cell line BGC-823, 13.1 μg/mL for human nasopharyngeal carcinoma cell line KB and 12.5 μg/mL for human hepatoma cell line BEL-7402.
Alafeefy 68 et al reported synthesis of a series of substituted quinazolin-4-(3H)-one-tyrophostin derivatives and evaluated their antitumor activity against selected tumor cell lines.Evaluation included human cervical cancer cell line (HeLa), human hepatocellular liver carcinoma cell line (HepG2) and human breast cancer cell line MCF-7.The design was based on combining the inherent antitumor activity of tyrophostin with selected quinazolines.Among evaluated compounds 10 of them exhibited considerable activity against the tested cell lines with the IC50 values range 0.008-0.015μM.Compound 24 was the most potent with IC50 of 0.008 μM against all tested cancer cell lines.
Resveratrol is a phytoalexin phenolic compound produced by several plants.It is reported to have biological activity as antimicrobial, antitumor, and inducer of apoptosis for tumor cells 69,70 .
Yao 59 et al reported synthesis of different series of novel resveratrol amide derivatives involving acrylamide derivatives and evaluated their anti-tumor activity against breast cancer MCF-7, non-small cell lung cancer cell line A549 and melanoma cancer cell line B16-F10.Compounds 25, 26 and 27 exhibited most potent anti-proliferative activity against selected cancer cell lines with IC50 values range of 1. 33-3.26  Ruan 71 et al reported synthesis of another series of 3-resveratrol, 2-cyno acrylamide derivatives and evaluated their activity against selected cancer cell lines including human hepatoma HuH-7, chronic myelocytic leukemia cell line K562, and lung carcinoma cell line A549.The most active compound against HuH-7 was compound 28 with IC50 of 4.5 µmol/L.the most active compound against K562 was compound 29 with IC50 of 2.9 µmol/L and the most active compound against A549 was compound 30 with IC50 of 3.8 µmol/L.Hu 72 et al reported synthesis of series of 4phenoxyquinoline derivatives incorporating 3-amino, 2cyano-acrylamide derivatives and their evaluation against five cancer cell lines which are: human colorectal adenocarcinoma HT-29, non-small cell lung cancer H460, pulmonary adenocarcinoma A549, gastric cancer cell line MKN-45 and glioma cell line U87MG.The tested compounds were compared to Foretinib as reference.A SAR study was generated indicating that the compounds with methyl groups at 4-position of the N-phenyl acrylamide are more effective.Compound 31 was most potent with IC50 of 0.04 μM/L, 0.09 μM/L, 0.67 μM/L, 0.39 μM/L and 1.10 μM/L against HT-29, H460, A549, MKN-45 and U87MG cell lines; respectively.

Tubulin polymerase inhibition activity
Tubulin polymerase enzyme is an essential enzyme for synthesis of microtubules a crucial cellular protein for mitotic division, thus it represents valuable target for development of antitumor agents.
Baytas 7 et al reported characterization of series of trans-indole-3-acrylamide derivatives as structural analogues to colchicine a well-known tubulin polymerase inhibitor 73 and evaluation of their antitumor activity against selected five human cancer cell lines (cervical cancer cell line HeLa, breast cancer cell line MCF7, breast cancer cell line MDA-MB-231, B-cell lymphoma cell line Raji and leukemia cell line HL-60).The results showed no significant effects on MDA-MB-231, MCF7 and HeLa.Compound 32 exerted inhibitory activities against Raji and HL-60 cell lines with IC50 values of 9.5 and 5.1 μM; respectively.It also exhibited moderate inhibitory activity on tubulin polymerization (IC50 value 17 μM in tubulin polymerase inhibitory assay).Cell cycle analysis showed arrest of cells at G2/M phase in HL-60.Moreover, compound 32 induced apoptotic cell death through the activation of caspase-3.Molecular modeling simulation study suggested that compound 32 binds to the colchicine site of tubulin.
Borrel 74 et al. reported synthesis of series of derivatives of combretastatin A4 a well-defined tubulin polymerase inhibitor 75 .The new derivatives included acrylamide derivatives and evaluated their cytotoxic effects against IGROV, KB-3-1 and MCF-7cancer cell lines.Tubulin polymerization inhibitory activity was also evaluated.Potent inhibitory activity was observed for acrylamide derivatives.Compound 33 the most potent cytotoxic agent exhibited activity against tubulin polymerase with an IC50 1.5 fold IC50 of colchicine.

HDAC inhibitor activity
Histones are the nuclear proteins responsible for packing DNA into nucleosome complex.The regulation of almost all cellular activities starts by activation of specific nucleosomes via acetylation and deacetylation of the lysine residue of histone.The process of acetylation and deacetylation is catalyzed by family of enzymes known as histone deacetylases.Through its acetylation and deacetylation activity HDAC regulates various cellular activities 76 , aberrations of HDAC have been linked to number of diseases including various types of cancer 77 .
Li 15 et al. reported the design and synthesis of series N-phenyl acrylamide derivatives and evaluated their cytotoxic activity against colon cancer cell line HCT 116 and HDAC-1 inhibitory activity.Compound 34 was the most active with IC50 of 0.62 μM against HCT116 colon cancer cell line and IC50 of 0.42 μM for HDAC-1 inhibitory activity.
Li 78 et al. reported synthesis of novel acrylamide analogues for Entinostat MS-275 an established HDAC-1 inhibitor 79 applying principles of non-classical isosterism.All synthesized compounds were evaluated for HDAC inhibitory activity and cytotoxic activity against colon cancer cell line HCT 116, breast cancer cell line MCF-7 and pulmonary adenocarcinoma cell line A549.All compounds exhibited superior antitumor effect.Compound 34 was most potent with IC50 of 0.118 µM, 1.258 µM, 2.871 µM and 0.723 µM for HDAC-1 inhibitory assay; cytotoxicity assay for HCT-116, MCF-7 and A549 cancer cell lines; respectively.Assay of pharmacokinetic profile was conducted for compound 35 which showed bioavailability of 76% in rat model.

Protein kinase inhibitor activity
Protein kinases represent a huge family of cellular enzymes which are pivotal in signal transduction pathways that control numerous cellular functions, including proliferation, differentiation, migration, apoptosis, and angiogenesis 80 .protein kinase enzymes represent a potential target for TCI's as a result of the high density of nucleophilic residues at active sites of protein kinases.As formerly mentioned numerous approved drugs with protein kinase inhibitory activity incorporate acrylamide moiety.In continuation for this promising activity several research papers reported the activity of different acrylamide derivatives against different kinases.

EGFR kinase inhibitory activity
EGFR is a transmembrane receptor tyrosine kinase which plays central role in cell adhesion, migration proliferation and differentiation via different signal transduction pathways 81 .Up-regulated EGFR signaling has been linked to a variety of tumor progression to metastasis and invasion; thus EGFR is a potential target for treatment of cancer 82 .Mutations in EGRF has been reported to be linked to resistance to conventional 1 st generation EGFR kinase inhibitors as gefitinib causing serious relapse of therapy.For instance exon 19 deletion mutation (labeled EGFR Del ), substitution mutation L858R (labeled as EGFR L858R ), substitution mutation T790M (labeled as EGFR T790M ), mutation including both double exon 19 deletion and T790M (labeled as EGFR T790M/Del ) and mutations involving both L858R and T790M (labeled as EGFR L858R/T790M ) arouse which required development of more potent generations 83 .

BTK inhibitor activity
BTK is a non-receptor tyrosine kinase expressed in hematopoietic B cells.BTK controls various signal transduction pathways of B cells.Dysregulation of BTK was linked to number of B cell malignancies 80 .Ibrutinib a purine analogue bearing a terminal acrylamide moiety was the 1st BTK inhibitor approved by FDA in 2013 for treatment of mantle cell lymphoma.
Wang 85 et al reported the synthesis of a series of N,9-diphenyl-9H-purin-2-amine derivatives and evaluated their BTK inhibitor activity as well as cytotoxic activity against Ramos and Raji B cell leukemia cell lines both of which is characterized by high expression of BTK.

Janus kinase III JAK 3 inhibitor
Janus kinases (JAKs) are cytoplasmic tyrosine kinases that play central role regarding cytokines signaling in immune cells.Considering these facts JAKs arise as potential targets for development of new anti-inflammatory or immunosuppressant drugs 86 .
Forster 87 et al reported the synthesis of series of novel 2-cyanoacrylamide derivatives and their evaluation as selective JAK3 inhibitors.X-ray crystallography was performed which provided precise data regarding identification of the binding pocket and types of interaction.Among synthesized compounds compound 39 and 40 were the most potent JAK3 inhibitors with nanomolar IC50 values of 9 nM and 17 nM for 39 and 40; respectively.Moreover, the x-ray crystallography for JAK3 bound to both 39 (PDB ID 5LWM) and 40 (PDB ID 5LWN) revealed covalent modification of cysteine 909 residue and hydrogen bonding interaction of 2-cyano group with arginine 911 residue Figure 5.   88 .The non-mutated ABL gene codes for normal functioning membrane tyrosine kinase involved in mitotic pathway.Under physiologic conditions the function of ABL coded tyrosine kinase is regulated and controlled, whereas the mutated BCR-ABL kinase is unregulated and act in an always-on mode leading to uncontrolled cell division.BCR-ABL kinase mutation as associated with chronic myeloid leukemia 88 .
Applying principles of nonclassical electronic isosteres Li 25 et al. reported synthesis of series of acrylamide derivatives as analogues for Imatinib and Nilotinib and evaluation of their cytotoxic activity on K562 leukemia cancer cells in vitro as well as inhibitory effect on BCR-ABL kinase.Results revealed that compounds with trifluoromethyl substitution were the active.Compound 41 was the most promising exhibiting IC50 of 20.6 nM for BCR-ABL kinase inhibition assay lower by 10.5 fold than that for imatinib and IC50 of 32.3 nM for cytotoxic activity which is 12 folds lower than that of imatinib.

Antimicrobial activity
Regarding antimicrobial activity several research papers reported the synthesis and evaluation of antimicrobial activity of various compounds incorporating acrylamide derivatives.
Bondok 18 et al reported synthesis of compound 42 a 2-cyanoacrylamide derivative incorporating benzothiazole moiety.It exhibited a good antimicrobial activity against tested strains with MIC of 25 μg/ml against Gram-negative E. coli, 50 μg/ml against Gram positive B. thuringiensis and 12.5 μg/ml against Botrytis fabae fungal strain Nasr 89 et al. reported the synthesis of compound 43 a 2-cyanoacrylamide derivative bearing sulfisoxazole moiety which exhibited good antimicrobial activity against tested strains with MIC of 7.81 μg/ml, 1.95 μg/ml and 3.9 μg/ml against Gram positive bacteria S. pneumoniae, B. subtilis and S. epidermidis; respectively and MIC of 1.95 μg/ml,7.81μg/ml and 0.49 μg/ml against Gram negative bacteria E. coli, P. vulgaris and K. pneumonia; respectively.Fu 8 et al. reported synthesis of a set of acrylamide derivatives and evaluation of their antimicrobial activity.Compound 44 was the most potent with MIC of 3.12 μg/ml against gram-positive bacteria Bacillus subtilis, 50 μg/ml against gramnegative bacteria P. fluorescens, and 42.8 μg/ml against fungal strain C. albicans.
Gouda 27 et al reported the synthesis of set of anthraquinone derivatives incorporating 2cyanoacrylamide derivatives and evaluation of their antimicrobial activity against selected strains using diameter of zone of inhibition in mm as indication for potency.Among synthesized compounds compound 45 was the most active with inhibition zone of 19 mm. for Gram positive S. epidermidis, 27 mm.for Gram negative P. aeruginosa, 18 mm.and 13 mm.for fungal strains A. solani and F. solani; respectively.

Anti-mycobacterial activity
Avalos 90 et al. reported synthesis of set of ,unsaturated amides and evaluation of their antimycobacterial activity against two Mycobacterium tuberculosis strains which are sensitive strain H37Rv and a resistant clinical isolate.Compounds 46 and 47 were the most potent acrylamide derivatives, they exhibited MIC of 2 μg/ml and 16 μg/ml against sensitive and resistant strains; respectively.

CONCLUSION
In this article we have provided an updated review describing the advances in medicinal chemistry applications of acrylamide derivatives highlighting the various synthetic pathways, the chemical reactivity of acrylamide derivatives, how it can be functionalized for design of new drugs and the spectrum of reported biological activities and applications.

Keenan 51
et al resumed their work for developing angiotensin II receptor antagonists where they introduced new modification to mimic the Tyr4 residue of angiotensin II via new para carboxylic group on the N-1-benzyl substitution.This led to evolution of some active compounds at nanomolar concentrations both in vitro and in vivo, compound 4 the main model for this study exhibited (in vitro IC50=1nM and in vivo ID50=0.08mg/kg),compound 5 (in vitro IC50=1.45nM and in vivo ID50=0.06mg/kg) and compound 6 (in vitro IC50=0.15nM and in vivo ID50=0.06mg/kg).

Dengue DEN and West Nile virus WNV protease inhibitory antiviral activity
Christoph 3 et al. reported the synthesis of a set of 86 analogues bearing 3-aryl, 2-cyanoacrylamide scaffold and their evaluation for serine proteases (NS2B-NS3) inhibitory activity for both DEN and WNV.Compound 16 which possess para hydroxy substitution at aryl ring was the most potent with a Ki value for Dengue virus protease of 35.7 μM and 44.6 μM for West Nile virus proteases respectively.The target selectivity for viral proteases versus thrombin was 2.8:1 for DEN protease and 2.3:1 for WNV protease.The mechanism of inhibition is via covalent irreversible inhibition by targeting the serine residue of target enzymes.

2357-0547 (Print) Review Article / JAPR ISSN: 2357-0539 (Online) Elgiushy et al., 2018, 2 (4), 221-237
et al. reported the design, synthesis and evaluation of novel EGFR kinase inhibitors targeting mutant types of EGFR kinase.The design was based on the scaffold of WZ4002 a third generation EGFR kinase inhibitor exhibiting high potency against Mutant EGFR kinases EGFR L858R and EGFR T790M 83 .Behenna 84 et al reported the structure based design, synthesis and biological evaluation of the purine derivative (PF-06747775) which exhibited high selectivity and affinity towards four types of mutant EGFR kinases over wild type EGFR including EGFR exon 19 deletion mutation EGFR Del , substitution mutation EGFR L858R , double mutation EGFR T790M/L858R ISSN: Compound 38 was the most potent among the designed analogues.It was almost equipotent to the control Ibrutinib.It exhibited IC50 values of 0.4nM, 7.75μM, 12.6 μM for BTK inhibition, Ramos and Raji leukemia cancer cell lines; respectively.Whereas for Ibrutinib the IC50 values were 0.3 nM, 8.11 μM and 15.2 μM; respectively.