الفهرس 
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Abstract
The current work illustrates the synthesis of 2-cyano-N’-(4- (piperidin-1-yl)benzylidene)acetohydrazide, 3 as a scaffold via using eco- friendly method; ultrasonic waves to synthesize novel arylidenes, heteroarylidenes and different heterocyclic compounds. These compounds were evaluated for their antitumor activity. The chemical and physicochemical properties of the biochemical arrangements can be predicted using different computational performances by studying the stability of newly synthesized compounds and investigating the results of their biological evaluation by optimizing theoretical modeling with DFT/B3LYP/6-31G (d) density functional theory.
The work was divided into two main parts:-
I. Ultrasonic-Induced Synthesis of Novel Diverse Arylidenes via Knoevenagel Condensation Reaction. Antitumor, QSAR, Docking and DFT Assessment.
II. Ultrasonic-induced synthesis and antitumor evaluation of novel piperidine-based heterocycles, Docking and DFT Assessment.
Part I
Ultrasonic-Induced Synthesis of Novel Diverse Arylidenes via Knoevenagel Condensation Reaction. Antitumor, QSAR, Docking and
DFT Assessment
Initially, we documented the synthesis of 2-cyano-N’-(4- (piperidin-1-yl)benzylidene)acetohydrazide 3 via the forthright condensation of 4-(piperidin-1-yl)benzaldehyde 1 with the indispensable cyanoacetohydrazide 2 in absolute ethanol under both conventional and ultrasonic conditions. (Scheme I)
Afterwards, a series of arylidenes derivatives 4 and 5a-d was synthesized through reaction of cyanoacetohydrazide derivative 3 with different aldehydes such as isonicotinaldehyde, 1H-pyrrole-2- carbaldehyde, 1H-indole-3-carbaldehyde and anthracene-9-carbaldehyde, beside 4-chloroacetophenone as a ketone, respectively. Additionally, reaction of cyanoacetohydrazide derivative 3 with 4-nitrobenzene diazonium chloride gave the hydrazone derivative 6. (Scheme I) Cytotoxicity and antitumor evaluation:
In-vitro cytotoxicity of the newly synthesized compounds 3-6 against four different human cancer cell lines (HEPG-2, MCF-7, HCT- 116, and PC-3) was investigated. For comparison, doxorubicin (Dox) was utilized as a standard anticancer drug.
According to our initial screening results, compounds 5d and 6 had the highest cytotoxic activity, while compounds 3, 4, 5a, and 5b showed intermediate cytotoxic activity. The cytotoxicity of compound 5c was minimal.
Computational Studies:
The MLR technique was used to create the QSAR model using five molecular descriptors (AATS6p, AATS7p, AATS8p, AATS0i, and SpMax4_Bhv). The examination of the constructed QSAR model equations revealed that the selected descriptors influence the tested compound’s anti-proliferative activity. The descriptors identified in this work by QSAR models can be utilized to predict the anticancer activity levels of novel arylidenes derivatives. This will allow for significant cost savings in the drug development process and synthesis at pharmaceutical chemistry laboratories.
According to the physicochemical properties, the results revealed that all of these compounds comply with Lipinski’s Rule of Five, indicating that they may have high permeability across biological membranes and reveal drug-relevant properties.
The Swiss Target Prediction webtool was used to assess the probable cellular mechanism for the promising candidate compounds (5d and 6), and the results revealed that adenosine A1 receptor (ADORA1) was a common target for both compounds. ADORA1 is involved in the regulation of cell metabolism and gene transcription. ADORA1 overexpression has been linked to a variety of cancers, including colon cancer, breast cancer, leukemia, and melanoma. The docking study of tested compounds 5d and 6 revealed that their binding scores to ADORA1 are more favorable than those of its co-crystalized ligand (DU172, selective ADORA1 antagonist) and adenosine (ADORA1 endogenous agonist), implying that they may hold great promise as an anti-cancer therapy. Density functional theory (DFT) with a (B3LYP) /6- 31G (d, p) basis set was used to calculate the physicochemical parameters of these compounds. The theoretical data from the DFT computation was found to be in good agreement with the experimental values.
Part II
Ultrasonic-induced synthesis and antitumor evaluation of novel piperidine-based heterocycles.
Sonication of 3 with phenyl isothiocyanate and elemental sulfur in ethanol containing triethylamine (TEA) gave 3-mercapto-3-phenylamino acrylohydrazide derivative 7 instead of the thiazole derivative 8, but the later was softly obtained under the conventional reflux methodology. Also, compound 7 was obtained via reaction of compound 3 with phenyl
isothiocyanate without elemental sulfur at ambient temperature under ultrasonic radiation. Similarly, reaction a mixture of 3, phenyl isocyanate and elemental sulfur under the same ultrasonic conditions also gave 2- cyano-3-hydroxy-3-(phenylamino)-N’-(4-(piperidin-1- yl)benzylidene)acrylohydrazide (9). (Scheme II)
Treatment of compound 3 with malononitrile and elemental sulfur in ethanol in the presence of morpholine achieved the thiophene ring containing β-enaminonitrile moiety11. (Scheme II)
Meanwhile, treatment of compound 3 with o-salicylaldehyde in ethanolic solution containing piperidine under ultrasonic conditions furnished the coumarin derivative 12. (Scheme II)
In another point of view, the proclivity of the doubly nucleophilic centers of hydrazide-hydrazone derivative 3; both the active methylene and NH centers was investigated with doubly electrophilic reagents such as acetylacetone, malononitrile and arylidenes afforded pyridone derivatives 14,15, 17 and 18. (Scheme III)
Then, we examined the nucleophilicity of the active methylene of cyanoacetohydrazide derivative 3 with phenyl isothiocyanate. Therefore, when compound 3 was subjected to react with phenyl isothiocyanate in dry dimethylformamide as an aprotic solvent containing KOH as a catalyst at ambient temperature under ultrasonic conditions gave potassium sulfide salt as the nonisolable intermediate A, followed by acidification with dilute HCl gave compound 7. Otherwise, treatment of the nonisolable intermediate A in situ with different reagents such as dimethyl sulfate and ethyl iodide delivered the S-alkylated product 19 and
20. (Scheme IV)
Eventually, assessment of the reactivity of the target compound 3 with nitrogen nucleophiles such as hydrazine monohydrate, phenyl hydrazine and hydroxylamine hydrochloride afforded 21, 23 and 25 respectively. (Scheme V)
Cytotoxicity and antitumor evaluation:
In-vitro cytotoxicity of the newly synthesized compounds 7-19 against four different human cancer cell lines (HEPG-2, MCF-7, HCT- 116, and PC-3) was investigated. For comparison, doxorubicin (Dox) was utilized as a standard anticancer drug.
According to our initial screening results, compounds 14 and 19 had the highest cytotoxic activity, while compounds 7, 11, 15 and 18 showed intermediate cytotoxic activity. The cytotoxicity of compound 8, 12 and 17 was minimal.
Computational Studies:
Molecular docking studies were conducted for the most promising candidate compounds (14 and 19) to reveal the probable mechanism for their anticancer potency.
The Swiss Target Prediction webtool was used to assess the probable cellular mechanism for the promising candidate compounds (14 and 19). These results were confirmed via DFT and the experimental result was compatible with the theoretical studies.