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A new series of hydrazone derivatives incorporating spirocyclic aminopyrimidine with aryl alkanesulfonates were synthesized. The targeted products were obtained in excellent yields via an acid catalyzed reaction of spirocyclic hydrazinopyrimidine with aryl aldehyde sulfonates. The structures of the synthesized hydrazones were studied by the different spectroscopic tools, in addition to the high resolution mass analysis. The antiproliferative activities of the compounds were tested in vitro against the National Cancer Institute (NCI) 60 cell panel by the Developmental Therapeutics Program. Amongst the tested hydrazone compounds, the methansulfonate derivatives showed the highest activities against lung, brain, kidney, and breast cancers. [ABSTRACT FROM AUTHOR]

2-[(4-Acetylphenyl)carbamoyl]phenyl acetate, C17H15NO4, has been synthesized and structurally characterized. In the structure, N--H⋯O hydrogen-bonding interactions form chains of molecules aligned along the [101] direction. The chains are linked by π-π and C--H⋯π interactions, forming a three dimensional network. The compound has been screened for in vitro anti-proliferative activity revealing considerable activity. [ABSTRACT FROM AUTHOR]

A new set of thiazolyl-pyrazolines 3a–l was prepared by cyclization of carbothioamides 2a–g with phenacyl bromide and/or 4-bromo phenacyl bromide. The new chemical entities were tested for their antimicrobial properties, while none of the tested samples showed promising activity. The derivatives 2a–c demonstrated moderate potency against Staphylococcus aureus having the potential to be optimized into promising antimicrobial candidates. In addition to elemental analyses, the structural elucidation of the new analogues was carried out via IR, 1H NMR, 13C NMR as well as mass spectral data. [ABSTRACT FROM AUTHOR]

A new set of pyridine-3-carbonitriles (3a–v) conjugated with various five-membered ring systems at pyridinyl C-6 were designed and synthesized as vasorelaxant active agents. The majority of the new target derivatives exhibited noteworthy vasodilation efficacy and compounds 3b, 3k, 3l, 3m, 3o, 3p, 3s, 3u and 3v were the most potent analogues with IC50 values = 220.7, 256.7, 164.1, 252.2, 229.8, 265.2, 247.9, 239.1 and 159.8 μM, respectively, which were superior to that of prazosin hydrochloride (IC50 = 272.8 μM). Moreover, 3b, 3l, 3o and 3v displayed significant α1-adrenergic receptor (α1-AR) blocking efficiency ranging from 65.38 to 87.86% compared with 89.34% for prazosin hydrochloride. Furthermore, a 2D-QSAR study and 3D-pharmacophore model were introduced to carry out compare-fit study for the designed molecules with the generated hypothesis and creating a statistically significant model. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • We designed and synthesized some new dispiropyrrolodinyl-oxindole -based alkaloids. • We evaluated the newly synthesized analogues as cholinesterase inhibitors. • Some of the new chemical entities showed promising BuChE inhibitors. • The bio-results were validated by 2D-QSAR study. • The achieved model can be adopted for optimizing hits of high potency. Abstract In this work, we describe the regioselective synthesis of some new dispiro[ indene -2,3′- pyrrolidine -2′,3″- indoline ]-1,2″(3H)-dione 4 - 29 attributable to the previously described methods. All the new chemical entities were assessed in-vitro as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes; while no significant inhibitory activity for the tested compounds were assigned on AChE, compounds 4 , 27 , 29 , 28 and 15 were the most active against BChE enzyme with IC 50 = 13.7 µM, 21.8 µM, 22.1 µM, 22.9 µM and 24.9 µM respectively compared to Donepezil (IC 50 = 0.72 µM). Compound 4 was found to have a mixed type mode of inhibition, the bioactivity of the new chemical entities (N = 26, n = 5, R 2 = 0.893, R 2 cvOO = 0.831, R 2 cvMO = 0.838, F = 33.32, s2 = 0.003) was elucidated via a statistically significant QSAR model utilizing CODESSA-Pro software that validated the observed results. [ABSTRACT FROM AUTHOR]

Four indole-based compounds have been synthesized and their crystal structures determined using high-resolution synchrotron powder X-ray diffraction. In vacuo density function theory (DFT) optimization has been used in building initial molecular models for structure solution with the help of the Cambridge structure database. All four compounds were found to crystallize in the monoclinic space group P21/c. Dispersion-corrected DFT (DFT-D) has been used for experimental crystal structure validation with acceptable agreement found between the DFT-optimized and final refined structures. Three of the compounds exhibit bronchodilation properties with potency comparable to the theophylline (standard reference). [ABSTRACT FROM AUTHOR]

A new series of 2-alkyloxy-pyridine-3-carbonitrile-benzofuran hybrids (4a-x) was synthesized. All the new derivatives were examined via the standard technique for their vasodilation activity. Some of the investigated compounds exhibited a remarkable activity, with compounds 4w, 4e, 4r, 4s, 4f and 4g believed to be the most active hits in this study with IC50 values 0.223, 0.253, 0.254, 0.268, 0.267 and 0.275 mM, respectively, compared with amiodarone hydrochloride, the reference standard used (IC50 = 0.300 mM). CODESSA PRO was employed to obtain a statistically significant 2-Dimensional Quantitative Structure Activity Relationship (2D-QSAR) model describing the bioactivity of the newly synthesized analogs (N = 24, n = 4, R² = 0.816, R² cvOO = 0.731, R² cvMO = 0.772, F = 21.103, s² = 6.191 x 10-8). [ABSTRACT FROM AUTHOR]

4-(1 H-benzo[d]imidazol-2-yl)thiazol-2-amine and its 1-methyl derivative ( 1) were reacted with different reagents such as acid anhydrides, malononitrile, chloroacetyl chloride, and aromatic aldehydes to produce the corresponding benzimidazole products 2, 3, 4, 5, 6, 7, 8, 9, respectively. Also, 2-chloro- N-(4-(1-methyl-1 H-benzo[d]imidazol-2-yl)thiazol-2-yl) acetamide ( 6) was reacted with diaminoethane, ortho-substituted aniline, thioglycolic acid, thiosemicarbazide derivatives, secondary amines, and potassium isothiocyanate to afford the corresponding derivatives 10, 11, 12, 13, 14, 15, 16, 17, respectively. The cytotoxic activity of some newly synthesized derivatives was studied against two different cell lines HepG2 and PC12. Compounds 9 and 15b showed promising anticancer activity against both types of the tested cancerous cell lines. [ABSTRACT FROM AUTHOR]

New functionalized thiazol-benzimidazole derivatives were designed, synthesized and evaluated for their in vitro EGFR inhibiting activities. In vitro anti-breast cancer activity of the promising derivatives was also evaluated. The pro-apoptotic activity of the analogue 4a was evaluated against caspase-3, p53, Bax/Bcl-2 expression levels, cell cycle analysis as well as PARP-1 inhibition. QSAR analysis and molecular modelling studies were carried out representing the binding modes of the promising compounds in the active pocket of EGFR. • New thiazol-benzimidazole derivatives 4a-q have been synthesized. • Utilizing EGFR as a putative target, the new compounds 4a-q were evaluated in vitro as EGFR inhibitors. • The promising compounds (4a, 4b, 4d, 4f, 4h, 4i, 4j, 4m, 4n) were examined as anticancer agents against MCF-7 cancer cells. • Compound 4a was selected to study its effect on cell cycle and apoptosis induction as well as its pro-apoptotic activity against caspase-3, p53, Bax/Bcl-2 and PARP-1 expression levels. • QSAR and molecular modelling of 4a , 4d , 4h , 4i and 4n were also performed to elucidate their binding modes with amino acid residues of EGFR. Heterocyclic rings such as thiazole and benzimidazole are considered as privileged structures, since they constitute several FDA-approved drugs for cancer treatment. In this work, a new set of 2-(2-(substituted) hydrazinyl)-4-(1-methyl-1 H -benzo d imidazol-2-yl) thiazoles 4a-q were designed as epidermal growth factor receptor (EGFR) inhibitors and synthesized using concise synthetic methods. The new target compounds have been evaluated in vitro for their suppression activity against EGFR TK. Compounds 4n , 4h , 4i, 4a and 4d exhibited significant potency in comparison with erlotinib which served as a reference drug (IC50, 71.67–152.59 nM; IC50 erlotinib, 152.59 nM). Furthermore, MTT assay revealed that compounds 4j , 4a, 4f, 4h, 4n produced the most promising cytotoxic potency against the human breast cancer cell line (MCF-7) (IC50; 5.96–11.91 µM; IC50 erlotinib; 4.15 µM). Compound 4a showed promising activity as EGFR TK inhibitor as well as anti-breast cancer agent. In addition, 4a induced apoptotic effect and cell cycle arrest at G2/M phase preventing the mitotic cycle in MCF-7 cells. Moreover, 4a upregulated the oncogenic parameters; caspase-3, p53, Bax/Bcl-2 as well as it inhibited the level of PARP-1 enzyme. QSAR study was carried out for the new derivatives and it revealed the goodness of the models. Furthermore, molecular docking studies represented the binding modes of the promising compounds in the active pocket of EGFR. [ABSTRACT FROM AUTHOR]

Background: Extensive research has been conducted on aspirin, a widely recognized NSAID medication, regarding its potential as an anticancer agent. Studies have revealed its ability to trigger cell death in different types of cancer cells., Methods: A set of aspirin-chalcone mimic conjugates 5a-k and 6a-d utilizing the freshly prepared acid chloride of aspirin moiety has been designed and synthesized. To evaluate the newly developed compounds, the NCI 60- cell line panel was employed to assess their anti-proliferative properties. Subsequently, cell cycle analysis was conducted along with an examination of the compounds' impact on the levels of p53, Bax, Bcl-2, active caspase- 3, and their inhibition mechanism of tubulin polymerization., Results: Derivative 6c displayed the best anticancer activity among the tested series while 6d was the best against breast cancer MDA-MB-468, therefore both of them were selected for the 5-dose stage, however, targeting MDA-MB-468, PI-flow cytometry of compound 6d proved the triggered cell growth arrest at the G1/S phase avoiding the mitotic cycle in MDA-MB-468 cells. Similarly, the upregulation of oncogenic parameters such as caspase-3, p53, and Bax/Bcl-2, along with the inhibition of PARP-1 enzyme level, was observed with compound 6d. This compound also exhibited a significant ability to induce apoptosis and disrupt the intracellular microtubule network through a promising activity as a tubulin polymerization inhibitor with IC 50 = 1.065 ± 0.024 ng/ml. Furthermore, to examine the manner in which compound 6d binds to the active pocket of the tubulin polymerization enzyme, a molecular docking study was conducted., Conclusion: The study indicated that compound 6d could be a powerful microtubule-destabilizing agent. Therefore, further research on 6d could be worthwhile., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

2-[(4-Acetyl-phen-yl)carbamo-yl]phenyl acetate, C 17 H 15 NO 4 , has been synthesized and structurally characterized. In the structure, N-H⋯O hydrogen-bonding inter-actions form chains of mol-ecules aligned along the [101] direction. The chains are linked by π-π and C-H⋯π inter-actions, forming a three dimensional network. The compound has been screened for in vitro anti-proliferative activity revealing considerable activity., (© Mohamed-Ezzat et al. 2023.)

Background & Objective: Glycosyl heterocycles, being as nucleoside analogs with modified glycon and hybrid heterocycle motifs, are of considerable interest, and thus, the targeted compounds were synthesized via a convenient and efficient approach., Methods: New indolyl-thiadiazolyl thioglycosides scaffolds were synthesized, starting with the reaction of indole-3-carbaldehyde with 2-aminothiadiazole-5-thiole followed by glycosylation and deprotection. Likewise, new molecular hybrids comprising indole, thiadiazole, triazole and glycosyl moieties were synthesized utilizing click chemistry strategy. The cytotoxic activities of the newly synthesized compounds were studied on colon carcinoma HCT116, breast carcinoma MCF-7, lung carcinoma A549 and hepatocellular carcinoma HepG2 cell lines using Sulphorhodamine-B (SRB) assay., Results: The 1,3,4-thiadiazole thioglycoside and the 1,2,3-triazole N 1 -glycoside possessing xylose moiety, compounds 8 and 15 revealed the most potent bio-activity among the new chemical entities; therefore, they undertook for further analysis of apoptosis., Conclusion: IC 50 s of Compound 8 were 38, 36, 33 and 158μg/ml, while they were 41, 44, 32 and 25μg/ml for compound 15 on HepG2, MCF7, HCT116 and A549 cell lines, respectively; furthermore, the total apoptosis rate (%) for control untreated cells were 9.63, 28.4, 25.4 (%), compounds 8 and 15 respectively, they produced a significant increase in total and early apoptosis rate (%) compared to control (P=0.0001). At the same time, no significant difference was detected in the late apoptosis rate (%), which means that both derivatives have the potential to be developed into potent anticancer agents., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Curcumin is a well-known example of plant origin exhibiting promising diverse biological properties such as, anti-inflammatory and antitumor as well as poor pharmacokinetic/pharmacodynamic properties. This is why effective agents based on its chemical scaffold were explored., Methods: A set of 3,5-bis(ylidene)-1-(alkylsulfonyl)piperidin-4-ones were synthesized in excellent yield (80- 96%) through dehydrohalogenation reaction of 3,5-bis(ylidene)-4-piperidinones with the corresponding alkane sulfonyl chloride in the presence of triethylamine. Antiproliferative properties of the synthesized compounds (dienone/curcumin inspired analogues) were studied by the standard MTT technique., Results: Most of the synthesized compounds revealed antiproliferative properties against HCT116 (colon) and A431 (skin/squamous) cancer cell lines with IC50 values at sub-micromolar level. Compound 36 also exhibited potency against MCF7 (breast) and A549 (lung) cancer cell lines (IC50 = 2.23, 4.27µM, respectively) higher than that of the reference standards (IC50 = 3.15, 5.93µM for 5-fluorouracil and doxorubicin against MCF7 and A549 cell lines, respectively). Cytotoxic properties of the synthesized compounds against non-cancer RPE1 cell line supported the safety profile of the effective agents against normal cells. Molecular modeling (3Dpharmacophore and 2D-QSAR) studies validated the observed bio-properties and explained the parameters governing activity. Inhibitory properties of compounds 27 and 29 (representative examples of the promising antiproliferative agents synthesized) supported their mode of action against topoisomerase IIα., Conclusion: The synthesized scaffold is a promising antitumor agent (with special selectivity against colon and skin/squamous cancer cell lines) so, it can be considered for further investigation and development of highly effective hits/leads based on the computational models obtained., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A diverse training set composed of 76 in-house synthesized and 61 collected from the literature was subjected to molecular field topology analysis. This resulted in a high-quality quantitative structure-activity relationships model (R² = 0.932, Q² = 0.809) which was used for the topological functional core identification and prediction of vasodilatory activity of 19 novel pyridinecarbonitriles, which turned out to be active in experimental bioassay.

A series of 1-(1H-benzimidazol-2-yl)-3-(substituted)-2-propen-1-one and its 1-methyl analogues 2c-h were synthesized and cyclized with different reagents such as ethyl cyanoacetate, thiourea, hydroxylamine hydrochloride, guanidinium sulfate, methylhydrazine, phenylhydrazine and/or hydrogen peroxide in different reactions to produce pyridones 3a,b, pyrimidinethione 4a,b, isoxazole 5a,b, aminopyrimidine 6a,b, pyrazoline 7i-k and epoxy derivative 8, respectively. Acetohydrazide 10 reacted with formic acid, acetic anhydride, carbon disulfide and/or thiosemicarbazide to yield compounds 11-19. Also compound 21a,b was condensed with different monosaccharides to yield the corresponding N-glycoside Schiff's bases derivatives 22a-h, which upon treatment with acetic anhydride afforded 23a-h derivatives. The anticancer activity of some of the newly synthesized compounds was evaluated against HEPG2 (human liver carcinoma cell line) and PC12 (pheochromocytoma of the rat adrenal medulla) cells. Benzimidazole-2-isoxazole 5a derivative exhibited high potency against HEPG2 and PC12 cells. Benzimidazole chalcones 2c,e, benzimidazole mercaptoacetohydrazide 14 and benzimidazole thiosemicarbazide 15a,b derivatives gave high potency against PC12 cells.

The pyrimidine thione derivatives 2a-d were prepared by the reaction of thiourea, ethyl cyanoacetate and several aromatic aldehydes. The acyclic thioglycosides 4a-7d were prepared by the reaction of the synthesized pyrimidine thiones 2a-d with different alkyl halides, whereas the reaction of 2a-d with 2,3,4,6-tetra-O-acetyl-alpha-D-glucopyranosyl bromide afforded the cyclic thioglycosides 8a-d whose deprotection afforded 9a-d. The obtained compounds were tested for their antischistosomal and antiviral activity against hepatitis B virus (HBV). Compounds 5a, 5d, 7a showed high activity against HBV using the MTT assay; moreover compounds 5c, 6d, 7a, 9a, 9c exhibited high activity as antischistosomal agents.