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

ABSTRACT: 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.

SUBMITTER: Al-Ghulikah HA

PROVIDER: S-EPMC9658812 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Al-Ghulikah Hanan A HA El-Sebaey Samiha A SA Bass Amr K A AKA El-Zoghbi Mona S MS

Molecules (Basel, Switzerland) 20221102 21

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, wi ...[more]

PMID: 36364312

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Project description:Medicinally valuable components derived from natural resources are highly desirable as prospective alternatives to synthetic drugs to treat fatal diseases, such as cancer and diabetes mellitus. Suaeda maritima (L.) Dumort (Amaranthaceae) (S. maritima) is a halophyte plant that can thrive in saline environments and possesses excellent medicinal properties. Hence, for the present investigation, S. maritima has been chosen, and its phytochemical constituents have been extracted utilizing various solvents, including hexane, acetone, and methanol, and identified by GC-MS, LC-MS, and HPLC analyses. The antioxidant activity of the compounds using DPPH, ABTS, and reducing power assays demonstrated that all three extracts of S. maritima possessed significant radical scavenging activity comparable to standard ascorbic acid with lower IC50 values (69.20-95.58 μg/mL). In addition, the evaluation of antidiabetic activity by α-amylase inhibition and α-glucosidase inhibition methods revealed that the acetone extract of S. maritima (SMAE) displayed equipotent activity of standard acarbose with an IC50 of 32.6 μg/mL. Advantageously, SMAE also exhibited better inhibition activity against the growth of lung cancer cells with an IC50 of 78.19. μg/mL and less toxicity on the noncancerous HUVEC cells with a high IC50 of 300 μg/mL. In addition, the cancer cell death mechanism via the apoptotic pathway induced by SMAE was confirmed by DAPI staining and ROS analysis. The analysis of ADME properties, including absorption, distribution, metabolism, and excretion, witnessed that the physicochemical and druglikeness factors were best catered by stigmasterol, γ-sitosterol, and vitamin E. Further, the key phytochemicals identified from SMAE were docked with CtBP1 and SOX2 bound to importin-α target proteins associated with carcinogenic pathways using Schrodinger software. The results showed that the phytochemicals, scilicet, stigmasterol, γ-sitosterol, octadecadienoic acid, and vitamin E, showed a good binding affinity with Glide scores in the range -2.845-4.018 kcal/mol. Overall, the findings support that the least investigated traditional edible medicinal mangrove-related S. maritima is high in pharmacologically active constituents and might be one of the finest sources of naturally derived molecules for drug development and delivery systems.

Dataset Information

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

Publications

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

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