Design, synthesis, docking, and anticancer evaluations of new thiazolo[3,2-a] pyrimidines as topoisomerase II inhibitors

AbstractNew thiazolopyrimidine derivatives 2, 3a-d, 4a-c, 5, 6a-c, and 7a,b were synthesised. All prepared compounds were evaluated by MTT cytotoxicity assay against three human tumour cell lines. Compounds 3c, 3d, 4c, 6a, 6b, and 7b exhibited potent to strong anticancer activity that was nearly comparable or superior to Doxorubicin. Compounds exhibiting significant cytotoxicity were further selected to study their inhibitory activity on the Topo II enzyme. Compound 4c was the most potent Topo II inhibitor with an IC50 value of 0.23 ± 0.01 µM, which was 1.4-fold and 3.6-fold higher than the IC50 values of Etoposide and Doxorubicin. Furthermore, compound 4c showed significant cell cycle disruption and apoptosis on A549 cells compared to control cells. Molecular docking of the most active compounds illustrated proper fitting to the Topo II active site, suggesting that our designed compounds are promising candidates for the development of effective anticancer agents acting through Topo II inhibition

New Pyrimidine-5-Carbonitriles as COX-2 Inhibitors: Design, Synthesis, Anticancer Screening, Molecular Docking, and In Silico ADME Profile Studies

Two series of cyanopyrimidine hybrids were synthesized bearing either benzo[d]imidazole, benzo[d]oxazole, benzo[d]thiazole, and benzo[b]thiophene derivatives via methylene amino linker 3a–3d (Formula A) or various sulphonamide phenyl moieties 5a–5d (Formula B) at the C-2 position. All compounds’ cyclooxygenase COX-2 inhibitory activities were evaluated, and all synthesized compounds demonstrated potent activity at minimal concentrations, with IC50 values in the submicromolar range. Compounds 3b, 5b, and 5d were discovered to be the most active pyrimidine derivatives, with the highest COX-2 percent inhibition and IC50 values being nearly equal to Celecoxib and approximately 4.7-, 9.3-, and 10.5-fold higher than Nimesulide. Furthermore, the pyrimidine derivatives 3b, 5b, and 5d demonstrated anticancer activity comparable to or better than doxorubicin against four cell lines, i.e., MCF-7, A549, A498, and HepG2, with IC50 values in nanomolar in addition to low cytotoxicity on the normal W38-I cell line. The effect of compound 5d on cell cycle progression and apoptosis induction was investigated, and it was found that compound 5d could seize cell growth at the sub-G1 and G2/M phases, as well as increase the proportion of early and late apoptotic rates in MCF-7 cells by nearly 13- and 60-fold, respectively. Moreover, in silico studies for compounds 3b, 5b, and 5d revealed promising findings, such as strong GIT absorption, absence of BBB permeability, nil-to-low drug–drug interactions, good oral bioavailability, and optimal physicochemical properties, indicating their potential as promising therapeutic candidates

Spectral and quantum chemical analysis of ethyl 4-[3-(adamantan- 1-yl)-4-phenyl-5-sulfanylidene-4,5-dihydro-1H-1,2,4- triazole-1-yl]methylpiperazine-1-carboxylate

The Fourier transform infrared and Raman spectra of the adamantane-based compound ethyl 4-[3-(adamantan-1-yl)-4-phenyl-5-sulfanylidene-4,5-dihydro-1H-1,2,4-triazol-1-yl]methylpiper-azine-1-carboxylate were recorded in the ranges of 3200–650cm -1 and 3200–150cm -1 , respectively. The UV/Vis spectrum of solution of the title compound in ethanol was measured in the range of 450–200nm. The DFT calculations at the B3LYP/cc-pVDZ and B3LYP/cc-pVTZ levels of the theory were performed to obtain the equilibrium geometric structure and to predict vibrational IR and Raman spectra of the title molecule. The TDDFT calculations at the CAM-B3LYP/cc-pVTZ level of the theory, as well as MRPT calculations at the CASSCF(4,5)/XMCQDPT2 level of the theory were carried out to reproduce the electronic absorption spectrum. The experimental IR, Raman and UV/Vis spectra were interpreted on the basis of results of quantum chemical modeling. Based on Mulliken and L€ owdin atomic population analysis, it was established that the compound under study exhibits features of an intramolecular charge transfer

Novel Aminopyrimidine-2,4-diones, 2-Thiopyrimidine-4-ones, and 6-Arylpteridines as Dual-Target Inhibitors of BRD4/PLK1: Design, Synthesis, Cytotoxicity, and Computational Studies

Structural-based drug design and solvent-free synthesis were combined to obtain three novel series of 5-arylethylidene-aminopyrimidine-2,4-diones (4, 5a–c, 6a,b), 5-arylethylidene-amino-2-thiopyrimidine-4-ones (7,8), and 6-arylpteridines (9,10) as dual BRD4 and PLK1 inhibitors. MTT assays of synthesized compounds against breast (MDA-MB-231), colorectal (HT-29), and renal (U-937) cancer cells showed excellent-to-good cytotoxic activity, compared to Methotrexate; MDA-MB-231 were the most sensitive cancer cells. The most active compounds were tested against normal Vero cells. Compounds 4 and 7 significantly inhibited BRD4 and PLK1, with IC50 values of 0.029, 0.042 µM, and 0.094, 0.02 µM, respectively, which are nearly comparable to volasertib (IC50 = 0.017 and 0.025 µM). Compound 7 triggered apoptosis and halted cell growth at the G2/M phase, similarly to volasertib. It also upregulated the BAX and caspase-3 markers while downregulating the Bcl-2 gene. Finally, active compounds fitted the volasertib binding site at BRD4 and PLK1 and showed ideal drug-like properties and pharmacokinetics, making them promising anticancer candidates

Synthesis, DFT calculations, and anti-proliferative evaluation of pyrimidine and selenadiazolopyrimidine derivatives as dual Topoisomerase II and HSP90 inhibitors

AbstractNovel series of aminopyrimidines bearing a biologically active cyclohexenone 3a–f and oxo-selaneylidene moiety 4, besides selenadiazolopyrimidines (5a–e and 7), were synthesised using 5,6-diaminouracils as starting materials. Compound 3a exhibited strong anti-proliferative activity against three cell lines: HepG-2 (IC50 14.31 ± 0.83 µM), A-549 (IC50 30.74 ± 0.76 µM), and MCF-7 (IC50 27.14 ± 1.91 µM). Also, it was four times more selectively cytotoxic against WI-38 cell lines than doxorubicin. Furthermore, Topoisomerase II (IC50 4.48 ± 0.65 µM) and HSP90 (IC50 1.78 ± 0.11 µM) were both strongly inhibited in vitro by 3a. The cell cycle was halted at the G1-S phase, and total apoptotic cells were 65 times more than control Hep-G2 cells. Besides, it increased caspase-3 gene expression, triggering mitochondrial cell death. Molecular docking study indicated that it could bind to Topoisomerase II and HSP90 binding sites in an inhibitory mode. Its geometric properties were investigated using the density functional theory (DFT). Furthermore, compound 3a demonstrated in silico good oral bioavailability

(<i>E</i>)-<i>N</i>-(3-(1-(2-(4-(2,2,2-Trifluoroacetamido)benzoyl)hydrazono)ethyl)phenyl)nicotinamide: A Novel Pyridine Derivative for Inhibiting Vascular Endothelial Growth Factor Receptor-2: Synthesis, Computational, and Anticancer Studies

(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

Design, synthesis and mechanistic study of new dual targeting HDAC/tubulin inhibitors

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Synthesis, molecular docking and ADMET studies of bis-benzimidazole-based thiadiazole derivatives as potent inhibitors, in vitro α-amylase and α-glucosidase

Different research synthetic methods have been developed recently for the synthesis of bis-benzimidazole analogs to investigate various biological significances. In this present study, an attempt was made to synthesize a new series of bis-benzimidazole analogs in a fast and efficient method. A variety of spectroscopic techniques, including 13C NMR, 1H NMR, and HREI-MS, were used to establish the existence of every synthesized scaffold. Molecular docking profiles were also carried out to ascertain the binding interactions of the compounds. All derivatives (1–18) were evaluated for their biological potential to investigate the inhibitory activity of α-amylase and α-glucosidase through SAR study. Almost all derivatives were found to be engaged in a highly promising activity when compared to referenced drug acarbose (IC50 = 8.24 ± 0.08 µM), in this regard among the tested series analog 9 (IC50 = 0.10 ± 0.50 and 0.20 ± 0.50 µM respectively), showed excellent activity. Moreover, ADME predictions were also studied for potent compounds, exhibited drug like properties

New Triazinoindole Bearing Benzimidazole/Benzoxazole Hybrids Analogs as Potent Inhibitors of Urease: Synthesis, In Vitro Analysis and Molecular Docking Studies

Twenty-four analogs based on triazinoindole bearing benzimidazole/benzoxazole moieties (1&ndash;25) were synthesized. Utilizing a variety of spectroscopic methods, including 1H-, 13C-NMR, and HREI-MS, the newly afforded compounds (1&ndash;25) were analyzed. The synthesized analogs were tested against urease enzyme (in vitro) as compared to the standard thiourea drug. All triazinoindole-based benzimidazole/benzoxazole analogs (1&ndash;25) exhibited moderate to excellent inhibition profiles, having IC50 values of 0.20 &plusmn; 0.01 to 36.20 &plusmn; 0.70 &mu;M when evaluated under the positive control of thiourea as a standard drug. To better understand the structure&ndash;activity relationship, the synthesized compounds were split into two groups, &ldquo;A&rdquo; and &ldquo;B.&rdquo; Among category &ldquo;A&rdquo; analogs, analogs 8 (bearing tri-hydroxy substitutions at the 2,4,6-position of aryl ring C) and 5 (bearing di-hydroxy substitutions at the 3,4-position of aryl ring C) emerged as the most potent inhibitors of urease enzyme and displayed many times more potency than a standard thiourea drug. Besides that, analog 22 (which holds di-hydroxy substitutions at the 2,3-position of the aryl ring) and analog 23 (bearing ortho-fluoro substitution) showed ten-fold-enhanced inhibitory potential compared to standard thiourea among category &ldquo;B&rdquo; analogs. Molecular docking studies on the active analogs of each category were performed; the results obtained revealed that the presence of hydroxy and fluoro-substitutions on different positions of aryl ring C play a pivotal role in binding interactions with the active site of the targeted urease enzyme