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In this study, we present the design, synthesis, and evaluation of six new thiadiazole derivatives designed as VEGFR-2 inhibitors. The most promising compound, 18b, demonstrated promising inhibitory activity against VEGFR-2, with an IC 50 value of 0.165 µg/mL. The in vitro assessments on MCF-7 and HepG2 cell lines revealed the superior anti-proliferative effects of compound 18b, exhibiting IC 50 values of 0.06 and 0.17 µM, respectively. Further investigations into the cell cycle distribution of compound 18b on MCF-7 cells exhibited a cell cycle arrest at the S phase (52.96 %) and significantly reducing the percentage of cells in the G0-G1 and G2/M phases. Additionally, compound 18b demonstrated a remarkable pro-apoptotic effect, with 45.29 % total apoptosis, characterized by both early and late apoptosis, and minimal necrosis. These findings were corroborated by RT-PCR analysis, revealing a significant downregulation of the anti-apoptotic gene Bcl2 and upregulation of the pro-apoptotic gene BAX in compound 18b-treated cells compared to control MCF-7 cells. Moreover, in silico studies involving molecular docking, Density Functional Theory (DFT) calculations, Molecular Dynamics (MD) simulations, MM-GBSA, Principle Component Analysis of Trajectories (PCAT), in addition to Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) predictions underscored the molecular interactions, energetics, and pharmacokinetic properties of compound 18b and the other derivatives further supporting its potential. Our integrated approach, combining in vitro experimens with in silico predictions provides valuable insights into the therapeutic potential of compound 18b as a robust VEGFR-2 inhibitor and lays the groundwork for future optimization., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: Pulmonary fibrosis is a life threating disease which requires an immediate treatment and due to the limited medications, this study focused on synthesizing a series of quinoline-based pyrimidodiazepines 4a-f as a novel antifibrotic hit. Materials & methods: The target compounds were synthesized via a one-pot reaction then investigated in a rat model of lung fibrosis induced by bleomycin (BLM). Results: Results revealed significant attenuation of the tested pro-inflammatory cytokines, fibrotic genes and apoptotic markers; however, Bcl-2 was upregulated, indicating a protective effect against fibrosis. Moreover, the molecular docking studies highlighted promising interactions between compounds 4b and 4c and specific amino acids within the protein pockets of caspase-3 (ARG341 and THR177), malondialdehyde (LYS195, LYS118 and ARG188) and TNF-α (SER99 and NME102). Conclusion: Compounds 4b and 4c emerge as promising candidates for further preclinical investigation as pulmonary antifibrotic agents.

Background: VEGFR-2 has emerged as a prominent positive regulator of cancer progression., Aim: Discovery of new anticancer agents and apoptotic inducers targeting VEGFR-2., Methods: Design and synthesis of new thiazolidine-2,4-diones followed by extensive in vitro studies, including VEGFR-2 inhibition assay, MTT assay, apoptosis analysis, and cell migration assay. In silico investigations including docking, MD simulations, ADMET, toxicity, and DFT studies were performed., Results: Compound 15 showed the strongest VEGFR-2 inhibitory activity with an IC 50 value of 0.066 μM. Additionally, most of the synthesized compounds showed anti-proliferative activity against HepG2 and MCF-7 cancer cell lines at the micromolar range with IC 50 values ranging from 0.04 to 4.71 μM, relative to sorafenib (IC 50  = 2.24 ± 0.06 and 3.17 ± 0.01 μM against HepG2 and MCF-7, respectively). Also, compound 15 showed selectivity indices of 1.36 and 2.08 against HepG2 and MCF-7, respectively. Furthermore, compound 15 showed a significant apoptotic effect and arrested the cell cycle of MCF-7 cells at the S phase. Moreover, compound 15 had a significant inhibitory effect on the ability of MCF-7 cells to heal from. Docking studies revealed that the synthesized thiazolidine-2,4-diones have a binding pattern approaching sorafenib. MD simulations indicated the stability of compound 15 in the active pocket of VEGFR-2 for 200 ns. ADMET and toxicity studies indicated an acceptable pharmacokinetic profile. DFT studies confirmed the ability of compound 15 to interact with VEGFR-2., Conclusion: Compound 15 has promising anticancer activity targeting VEGFR-2 with significant activity as an apoptosis inducer., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A new theobromine-derived EGFR inhibitor (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(2,6-dimethylphenyl)acetamide) has been developed that has the essential structural characteristics to interact with EGFR's pocket. The designed compound is 2,6-di ortho methylphenyl)acetamide derivative of the well-known alkaloid, theobromine, (T-1-DOMPA). Firstly, deep DFT studies have been conducted to study the optimized chemical structure, molecular orbital and chemical reactivity analysis of T-1-DOMPA. Then, T-1-DOMPA's anticancer potentialities were estimated first through a structure-based computational approach. Utilizing molecular docking, molecular dynamics, MD, simulations over 100 ns, MM-PBSA and PLIP studies, T-1-DOMPA bonded to and inhibited the EGFR protein effectively. Subsequently, the ADMET profiles of T-1-DOMPA were computed before preparation, and its drug-likeness was anticipated. Therefore, T-1-DOMPA was prepared for the purposes of scrutinizing both the design and the results obtained in silico. The in vitro potential of T-1-DOMPA against triple-negative breast cancer cell lines, MDA- MB-231, was very promising with an IC 50 value of1.8 µM, comparable to the reference drug (0.9 µM), and a much higher selectivity index of 2.6. Interestingly, T-1-DOMPA inhibited three other cancer cell lines (CaCO-2, HepG-2, and A549) with IC 50 values of 1.98, 2.53, and 2.39 µM exhibiting selectivity index values of 2,4, 1.9, and 2, respectively. Additionally, T-1-DOMPA prevented effectively the MDA-MB-231cell line's healing and migration abilities. Also, T-1-DOMPA's abilities to induce apoptosis were confirmed by acridine orange/ethidium bromide (AO/EB) staining assay. Finally, T-1-DOMPA caused an up-regulation of the gene expression of the apoptotic gene, Caspase-3, in the treated MDA-MB-231cell., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Protein kinases regulate cellular activities and make up over 60% of oncoproteins and proto-oncoproteins. Among these kinases, FLT3 is a member of class III receptor tyrosine kinase family which is abundantly expressed in individuals with acute leukemia. Our previous oxindole-based hit has a particular affinity toward FLT3 (IC 50 = 2.49 μM) and has demonstrated selectivity towards FLT3 ITD-mutated MV4-11 AML cells, with an IC 50 of 4.3 μM. By utilizing the scaffold of the previous hit, sixteen new compounds were synthesized and screened against NCI-60 human cancer cell lines. This leads to the discovery of a potent antiproliferative compound, namely 5l , with an average GI 50 value against leukemia and colon cancer subpanels equalling 3.39 and 5.97 µM, respectively. Screening against a specific set of 10 kinases that are associated with carcinogenesis indicates that compound 5l has a potent FLT3 inhibition (IC 50 = 36.21 ± 1.07 nM). Remarkably, compound 5l was three times more effective as a CDK2 inhibitor (IC 50 = 8.17 ± 0.32 nM) compared to sunitinib (IC 50 = 27.90 ± 1.80 nM). Compound 5l was further analyzed by means of docking and molecular dynamics simulation for CDK2 and FLT3 active sites which provided a rational for the observed strong inhibition of kinases. These results suggest a novel structural scaffold candidate that simultaneously inhibits CDK2 and FLT3 and gives encouragement for further development as a potential therapeutic for leukemia and colon cancer.

Vascular endothelial cell proliferation and angiogenesis are all crucially impacted by Endothelial Growth Factor Receptor-2 (VEGFR-2). Its expression is significantly boosted throughout pathologic angiogenesis causing the development of tumors. Sothat, inhibition of VEGFR-2 has crucial role in cancer treatment. In this study, novel semisynthetic theobromine derivatives were rationally designed as VEGFR-2 inhibitors and subjected to in vitro testing for their ability to block VEGFR-2 activation. Furthermore, the antiproliferative effects of these derivatives were evaluated. Compound 7 g exhibited the most potent anti-VEGFR-2 activity, with an IC 50 value of 0.072 µM, and demonstrated excellent dose-dependent inhibitory activity against both MCF-7 and HepG2 cancer cells with IC 50 values of 19.35 and 27.89 µM, respectively. Notably, compound 7 g exhibited high selectivity indices of 2.6 and 1.8 against MCF-7 and HepG2 cells, respectively. Compound 7 g induced G2/M phase cell cycle arrest, promoted apoptosis, and boosted immunomodulation by downregulating TNF- α expression and upregulating IL-2 levels in MCF-7 cells. The molecular docking analysis revealed that compound 7 g could bind effectively to the active site of VEGFR-2, and molecular dynamic simulations confirmed the stability of the VEGFR-2/compound 7 g complex. Furthermore, ADME and toxicity profiling indicated the potential suitability of these compounds as drug candidates. In summary, compound 7 g hold promise as a VEGFR-2 inhibitor.Communicated by Ramaswamy H. Sarma.

Aim: The aim of this study was to design and examine a novel epidermal growth factor receptor (EGFR) inhibitor with apoptotic properties by utilizing the essential structural characteristics of existing EGFR inhibitors as a foundation., Method: The study began with the natural alkaloid theobromine and developed a new semisynthetic derivative ( T-1-PMPA ). Computational ADMET assessments were conducted first to evaluate its anticipated safety and general drug-likeness. Deep density functional theory (DFT) computations were initially performed to validate the three-dimensional (3D) structure and reactivity of T-1-PMPA . Molecular docking against the EGFR proteins was conducted to investigate T-1-PMPA 's binding affinity and inhibitory potential. Additional molecular dynamics (MD) simulations over 200 ns along with MM-GPSA, PLIP, and principal component analysis of trajectories (PCAT) experiments were employed to verify the binding and inhibitory properties of T-1-PMPA . Afterward, T-1-PMPA was semisynthesized to validate the proposed design and in silico findings through several in vitro examinations., Results: DFT studies indicated T-1-PMPA 's reactivity using electrostatic potential, global reactive indices, and total density of states. Molecular docking, MD simulations, MM-GPSA, PLIP, and ED suggested the binding and inhibitory properties of T-1-PMPA against the EGFR protein. The in silico ADMET predicted T-1-PMPA 's safety and general drug-likeness. In vitro experiments demonstrated that T-1-PMPA effectively inhibited EGFR WT and EGFR 790m , with IC 50 values of 86 and 561 nM, respectively, compared to Erlotinib (31 and 456 nM). T-1-PMPA also showed significant suppression of the proliferation of HepG2 and MCF7 malignant cell lines, with IC 50 values of 3.51 and 4.13 μM, respectively. The selectivity indices against the two cancer cell lines indicated the overall safety of T-1-PMPA . Flow cytometry confirmed the apoptotic effects of T-1-PMPA by increasing the total percentage of apoptosis to 42% compared to 31, and 3% in Erlotinib-treated and control cells, respectively. The qRT-PCR analysis further supported the apoptotic effects by revealing significant increases in the levels of Casp3 and Casp9. Additionally, T-1-PMPA controlled the levels of TNFα and IL2 by 74 and 50%, comparing Erlotinib's values (84 and 74%), respectively., Conclusion: In conclusion, our study's findings suggest the potential of T-1-PMPA as a promising apoptotic anticancer lead compound targeting the EGFR., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Depending on the pharmacophoric characteristics of EGFR inhibitors, a new thieno[2,3-d]pyrimidine derivative has been developed. Firstly, the potential inhibitory effect of the designed compound against EGFR has been proven by docking experiments that showed correct binding modes and excellent binding energies of -98.44 and -88.00 kcal/mol, against EGFR wild-type and mutant type, respectively. Furthermore, MD simulations studies confirmed the precise energetic, conformational, and dynamic alterations that occurred after binding to EGFR. The correct binding was also confirmed by essential dynamics studies. To further investigate the general drug-like properties of the developed candidate, in silico ADME and toxicity studies have also been carried out. The thieno[2,3-d]pyrimidine derivative was synthesized following the earlier promising findings. Fascinatingly, the synthesized compound ( 4 ) showed promising inhibitory effects against EGFR WT and EGFR T790M with IC 50 values of 25.8 and 182.3 nM, respectively. Also, it exhibited anticancer potentialities against A549 and MCF-7cell lines with IC 50 values of 13.06 and 20.13 µM, respectively. Interestingly, these strong activities were combined with selectivity indices of 2.8 and 1.8 against the two cancer cell lines, respectively. Further investigations indicated the ability of compound 4 to arrest the cancer cells' growth at the G2/M phase and to increase early and late apoptosis percentages from 2.52% and 2.80 to 17.99% and 16.72%, respectively. Additionally, it was observed that compound 4 markedly increased the levels of caspase-3 and caspase-9 by 4 and 3-fold compared to the control cells. Moreover, it up-regulated the level of BAX by 3-fold and down-regulated the level of Bcl-2 by 3-fold affording a BAX/Bcl-2 ratio of 9.Communicated by Ramaswamy H. Sarma.

This work presents the synthesis and in vitro , and in silico analyses of new thiadiazole derivatives that are designed to mimic the pharmacophoric characteristics of vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors. A comprehensive evaluation of the inhibitory properties of the synthesized thiadiazole derivatives against the cancer cell lines MCF-7 and HepG2 identified several auspicious candidates. Among them, compound 14 showed remarkably low IC 50 values of 0.04 μM and 0.18 μM against MCF-7 and HepG2, respectively. VEGFR-2 inhibitory evaluation of compound 14 revealed a promising IC 50 value in the nanomolar range (103 nM). Further examination of the cell cycle revealed that compound 14 has the ability to stop the progression of the cell cycle in MCF-7 cells via G0-G1 phase arrest. Interestingly, compound 14 also demonstrated a noteworthy pro-apoptotic effect in MCF-7 cells, with notable increases in early apoptosis (16.53%) and late apoptosis (29.57%), along with a slight increase in the population of necrotic cells (5.95%). Furthermore, compound 14 showed a significant drop in MCF-7 cells' ability to migrate and heal wounds. Additionally, compound 14 promoted apoptosis by boosting BAX (6-fold) while lowering Bcl-2 (6.2-fold). The binding affinities of the synthesized candidates to their target (VEGFR-2) were confirmed by computational investigations, including molecular docking, principal component analysis of trajectories (PCAT), and molecular dynamics (MD) simulations. Additionally, compound 14's stability and reactivity were investigated using density functional theory (DFT). These thorough results highlight compound 14's potential as a lead contender for additional research in the creation of anticancer drugs that target VEGFR-2. This work establishes a foundation for promising thiadiazole derivatives for future therapeutic developments in anticancer- and angiogenesis-related scientific fields., Competing Interests: None., (This journal is © The Royal Society of Chemistry.)

VEGFR-2 is a significant target in cancer treatment, inhibiting angiogenesis and impeding tumor growth. Utilizing the essential pharmacophoric structural properties, a new semi-synthetic theobromine analogue ( T-1-MBHEPA ) was designed as VEGFR-2 inhibitor. Firstly, T-1-MBHEPA 's stability and reactivity were indicated through several DFT computations. Additionally, molecular docking, MD simulations, MM-GPSA, PLIP, and essential dynamics (ED) experiments suggested T-1-MBHEPA 's strong binding capabilities to VEGFR-2. Its computational ADMET profiles were also studied before the semi-synthesis and indicated a good degree of drug-likeness. T-1-MBHEPA was then semi-synthesized to evaluate the design and the in silico findings. It was found that, T-1-MBHEPA inhibited VEGFR-2 with an IC 50 value of 0.121 ± 0.051 µM, as compared to sorafenib which had an IC 50 value of 0.056 µM. Similarly, T-1-MBHEPA inhibited the proliferation of HepG2 and MCF7 cell lines with IC 50 values of 4.61 and 4.85 µg/mL respectively - comparing sorafenib's IC 50 values which were 2.24 µg/mL and 3.17 µg/mL respectively. Interestingly, T-1-MBHEPA revealed a noteworthy IC 50 value of 80.0 µM against the normal cell lines exhibiting exceptionally high selectivity indexes (SI) of 17.4 and 16. 5 against the examined cell lines, respectively. T-1-MBHEPA increased the percentage of apoptotic MCF7 cells in early and late stages, respectively, from 0.71 % to 7.22 % and from 0.13 % to 2.72 %, while the necrosis percentage was increased to 11.41 %, in comparison to 2.22 % in control cells. Furthermore, T-1-MBHEPA reduced the production of pro-inflammatory cytokines TNF-α and IL-2 in the treated MCF7 cells by 33 % and 58 %, respectively indicating an additional anti-angiogenic mechanism. Also, T-1-MBHEPA decreased significantly the potentialities of MCF7 cells to heal and migrate from 65.9 % to 7.4 %. Finally, T-1-MBHEPA 's oral treatment didn't show toxicity on the liver function (ALT and AST) and the kidney function (creatinine and urea) levels of mice., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

A group of theobromine derivatives was designed based on the key pharmacophoric characteristics of VEGFR-2 inhibitors. HepG2 and MCF-7 cancer cell lines were used to test the obtained compounds for their in vitro anti-proliferative activities. Compound 15 (2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-(4-(1-(2-(4-hydroxybenzoyl)hydrazono)ethyl) phenyl)acetamide) was the most potent cytotoxic member against MCF-7 (IC 50 = 0.42 µM) and HepG2 (IC 50 = 0.22 µM). The effectiveness of VEGFR-2 inhibition was assessed for compound 15, and its IC 50 value was calculated to be 0.067 µM. Additional cellular mechanistic investigations showed that compound 15 dramatically increased the population of apoptotic HepG2 cells in both early and late apoptosis. The investigation of apoptotic markers confirmed that compound 15 upregulated the levels of BAX (2.26-fold) and downregulated the levels of Bcl-2 (4.4-fold). The molecular docking investigations, MM-GPSA, PLIP studies, and MD simulations validated the potential of compound 15 to be a VEGFR-2 inhibitor. DFT calculations have been completed to comprehend how the electrical charge is distributed within compound 15 and to predict how it would bond to VEGFR-2. Lastly, ADMET prediction showed that the designed members have drug-like characteristics and minimal levels of toxicity. In conclusion, our in vitro and in silico investigations showed that compound 15 exhibited promising apoptotic anticancer potential through the suppression of VEGFR-2., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The overexpression of the Epidermal Growth Factor Receptor (EGFR) marks it as a pivotal target in cancer treatment, with the aim of reducing its proliferation and inducing apoptosis. This study aimed at the CADD of a new apoptotic EGFR inhibitor. The natural alkaloid, theobromine, was used as a starting point to obtain a new semisynthetic (di-ortho-chloro acetamide) derivative ( T-1-DOCA ). Firstly, T-1-DOCA 's total electron density, energy gap, reactivity indices, and electrostatic surface potential were determined by DFT calculations, Then, molecular docking studies were carried out to predict the potential of T-1-DOCA against wild and mutant EGFR proteins. T-1-DOCA 's correct binding was further confirmed by molecular dynamics (MD) over 100 ns, MM-GPSA, and PLIP experiments. In vitro, T-1-DOCA showed noticeable efficacy compared to erlotinib by suppressing EGFR WT and EGFR T790M with IC 50 values of 56.94 and 269.01 nM, respectively. T-1-DOCA inhibited also the proliferation of H1975 and HCT-116 malignant cell lines, exhibiting IC 50 values of 14.12 and 23.39 µM, with selectivity indices of 6.8 and 4.1, respectively, indicating its anticancer potential and general safety. The apoptotic effects of T-1-DOCA were indicated by flow cytometric analysis and were further confirmed through its potential to increase the levels of BAX, Casp3, and Casp9, and decrease Bcl-2 levels. In conclusion, T-1-DOCA , a new apoptotic EGFR inhibitor, was designed and evaluated both computationally and experimentally. The results suggest that T-1-DOCA is a promising candidate for further development as an anti-cancer drug., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

A group of EGFR inhibitors derived from thieno[2,3- d ]pyrimidine nucleus was designed, synthesised, and examined as anti-proliferative lead compounds. MCF-7 and A549 cell lines were inhibited by 5b , the most active member. It had inhibitory partialities of 37.19 and 204.10 nM against EGFR WT and EGFR T790M , respectively. Compound 5b was 2.5 times safer against the WI-38 normal cell lines than erlotinib. Also, it demonstrated considerable potentialities for both early and late apoptosis induction in A549. Simultaneously, 5b arrested A549's growth at G1 and G2/M phases. Harmoniously, 5b upregulated the BAX and downregulated the Bcl-2 genes by 3-fold and increased the BAX/Bcl-2 ratio by 8.3-fold comparing the untreated A549 cells. Molecular docking against EGFR WT and EGFR T790M indicated the correct binding modes. Furthermore, MD simulations confirmed the precise binding of 5b against the EGFR protein over 100 ns. Finally, various computational ADMET studies were carried out and indicated high degrees of drug-likeness and safety.

In this study, new thieno[2,3-d]pyrimidine derivatives that could have potential anticancer activity by inhibiting the VEGFR-2 receptor have been designed, synthesized, and investigated. The thieno[2,3-d]pyrimidine derivatives showed strong in vitro abilities to inhibit VEGFR-2 and to prevent cancer cell growth in two different types of cancer cells, MCF-7 and HepG2. Particularly, compound 22 showed the most potent anti-VEGFR-2 activity with an IC 50 value of 0.58 µM. Additionally, compound 22 exhibited good anti-proliferative activity against both MCF-7 and HepG2 cancer cell lines, with IC 50 values of 11.32 ± 0.32 and 16.66 ± 1.22 µM, respectively. Further investigations revealed that compound 22 induced cell cycle arrest at the G2/M phase and promoted both early and late apoptosis in the MCF-7 cancer cells. Compound 22 also increased the level of BAX (2.8-fold), and reduced the level of Bcl-2 (2.2-fold), hence increasing the rate of apoptosis. Compound 22 also revealed 2.9-fold and 2.8-fold higher levels of caspase-8 and caspase-9, respectively, in the treated MCF-7 cancer cells compared to the control cell lines. The MD simulations showed that the VEGFR-2-22 complex was structurally and energytically stable over 100 ns, while the MM-GBSA study indicated its stable thermodynamic behavior. The bi-dimensional projection analysis confirmed the proper binding of the VEGFR-2-22 complex, while the DFT studies provided optimized geometry, charge distribution, FMO, ESP, the total density of state, and QTAIM maps of compound 22. Finally, computational ADMET studies were performed to assess the drug development potential of the thieno[2,3-d]pyrimidine derivatives. Overall, this study suggests that compound 22 has the potential as an anticancer lead compound by inhibiting VEGFR-2, which may be a guide for future drug design and development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

A computer-assisted drug design (CADD) approach was utilized to design a new acetamido-N-(para-fluorophenyl)benzamide) derivative of the naturally occurring alkaloid, theobromine, (T-1-APFPB), following the pharmacophoric features of VEGFR-2 inhibitors. The stability and reactivity of T-1-AFPB were assessed through density functional theory (DFT) calculations. Molecular docking assessments showed T-1-AFPB's potential to bind with and inhibit VEGFR-2. The precise binding of T-1-AFPB against VEGFR-2 with optimal energy was further confirmed through several molecular dynamics (MD) simulations, PLIP, MM-GBSA, and PCA studies. Then, T-1-AFPB (4-(2-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetamido)-N-(4-fluorophenyl)benzamide) was semi-synthesized and the in vitro assays showed its potential to inhibit VEGFR-2 with an IC 50 value of 69 nM (sorafenib's IC 50 was 56 nM) and to inhibit the growth of HepG2 and MCF-7 cancer cell lines with IC 50 values of 2.24±0.02 and 3.26±0.02 μM, respectively. Moreover, T-1-AFPB displayed very high selectivity indices against normal Vero cell lines. Furthermore, T-1-AFPB induced early (from 0.72 to 19.12) and late (from 0.13 to 6.37) apoptosis in HepG2 cell lines. In conclusion, the combined computational and experimental approaches demonstrated the efficacy and safety of T-1-APFPB providing it as a promising lead VEGFR-2 inhibitor for further development aiming at cancer therapy., (© 2023 The Authors. ChemistryOpen published by Wiley-VCH GmbH.)

A new compound, C 23 H 20 BrN 3 OS, containing a quinoline-based iminothiazoline with a thiazoline ring, was synthesized and its crystal and molecular structures were analyzed through single crystal X-ray analysis. The compound belongs to the triclinic system P - 1 space group, with dimensions of a = 9.2304 (6) Å, b = 11.1780 (8) Å, c = 11.3006 (6) Å, α = 107.146 (5)°, β = 93.701 (5)°, γ = 110.435 (6)°, Z = 2 and V = 1025.61 (12) Å 3 . The crystal structure showed that C-H···N and C-H···O hydrogen bond linkages, forming infinite double chains along the b-axis direction, and enclosing R 2 2 (14) and R 2 2 (16) ring motifs. The Hirshfeld surface analysis revealed that H…H (44.1%) and H…C/C…H (15.3%) interactions made the most significant contribution. The newly synthesized (Z)-4-bromo-N-(4-butyl-3 (quinolin-3-yl)thiazol-2(3H)-ylidene)benzamide, in comparison to oleanolic acid, exhibited more strong potential against elastase with an inhibition value of 1.21 µM. Additionally, the derivative was evaluated using molecular docking and molecular dynamics simulation studies, which showed that the quinoline based iminothiazoline derivative has the potential to be a novel inhibitor of elastase enzyme. Both theoretical and experimental findings suggested that this compound could have a number of biological activities., (© 2023. Springer Nature Switzerland AG.)

This study aimed to design anticancer theobromine derivatives inhibiting VEGFR-2. The new compounds were tested in vitro to evaluate their effectiveness against MCF-7 and HepG2 cancer cell lines. Among these compounds, 15a showed the highest cytotoxicity against HepG2, with an IC 50 value of 0.76 μM, and significant anti-proliferative effects on MCF-7, with an IC 50 value of 1.08 μM. Notably, the selectivity index of 15a against the two cancer cells was 98.97 and 69.64, respectively. Moreover, 15a demonstrated potent VEGFR-2 inhibitory activity (IC 50 = 0.239 μM). Further investigations revealed that 15a induced apoptosis in HepG2 cells, significantly increasing early-stage and late-stage apoptosis percentages from 3.06% and 0.71% to 29.49% and 9.63%, respectively. It also upregulated caspase-3 and caspase-9 levels by 3.45-fold and 2.37-fold, respectively compared to control HepG2 cells. Additionally, 15a inhibited the migration and wound healing ability of HepG2 cells. Molecular docking confirmed the binding affinities of the semi-synthesized compounds to VEGFR-2, consistent with in vitro results. Several computational analyses (DFT, MD simulations, MM-GBSA, PLIP, and essential dynamics) supported the stability of the 15a-VEGFR-2 complex. Overall, the biological and computational findings suggest that compound 15a could be a promising lead compound for the development of a novel apoptotic anticancer agent., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

This study describes the synthesis and biological activity of new imadazopyrazines as first-in-class CDK9 inhibitors. The inhibition of CDK9 is a well-established therapeutic target in cancer therapy. The new compounds were assessed using an in vitro kinase assay against CDK9. In this assay, compound 1d exhibited the highest CDK9 inhibition with an IC 50 of 0.18 µM. The cytotoxicity effect of the novel compounds was evaluated in three cancer cell lines: HCT116, K652, and MCF7. The results of this assay showed a correlation between the antiproliferative effect of the inhibitors and their CDK9 inhibitory effect in the biochemical assay. This suggests CDK9 inhibition as a mechanistic pathway for their anticancer effect. Several compounds demonstrated potent cytotoxic effects with single-digit micromolar IC 50 values yielded through an MTT assay. The compounds with the most promising data were further assessed for their antiviral activity against human Coronavirus 229E. The results showed that compound 4a showed the highest antiviral potency with an IC 50 of 63.28 µM and a selectivity index of 4.8. In silico target prediction data showed that 4a displayed a good affinity to proteases. The result of the docking studies of 4a with COVID-19 main protease revealed a high binding affinity, which confirmed the results obtained from in vitro study. The physiochemical and in silico pharmacokinetic parameters indicated reasonable drug-likeness properties of the new compounds, including solubility, lipophilicity, absorption, oral bioavailability, and metabolic stability. Further lead optimization of this novel scaffold could lead to a revolution of a new class of preclinical CDK9 agents.

Background: EGFR has been considered a vital molecular target in cancer management. Aim: The discovery of new thieno[2,3- d ]pyrimidine derivatives as EGFR tyrosine kinase inhibitors. Methods: Nine derivatives were designed, synthesized and subjected to in vitro and in silico studies. Results: Compound 7a significantly inhibited the growth of HepG2 and PC3 cells for both EGFR wild-type and EGFR T790M . Compound 7a caused a significant apoptotic effect, arresting HepG2 cells' growth in the S and G2/M phases. Docking and molecular dynamics simulation studies confirmed the correct and stable binding modes of the synthesized compounds against the active sites. Conclusion: Compound 7a is a promising dual EGFR inhibitor for cancer treatment.

In the last twenty years, protein kinases have been identified as important targets for cancer therapy. In order to prevent unexpected toxicity, medicinal chemists have always focused on discovering selective protein kinase inhibitors. However, cancer is a multifactorial process and its formation and progression depend on different stimuli. Therefore, it is imperative to develop anticancer therapy that targets multiple kinases associated cancer progression. In this research a series of hybrid compounds was designed and synthesized successfully with the aim of producing anticancer activity through the induction of multiple protein kinase inhibition. The designed derivatives comprise isatin and pyrrolo[2,3-d]pyrimidine scaffolds in their structures with a hydrazine linking the two pharmacophores. Antiproliferative and kinase inhibition assays revealed promising anticancer and multi-kinase inhibitory effects of compound 7 with comparable results with the reference standards. Moreover, compound 7 suppressed cell cycle progression and induced apoptosis in HepG2 cells. Finally, molecular docking simulation was performed to investigate the potential types of interactions between the protein kinase enzymes and the designed hybrid compounds. The results of this research indicated the promising anticancer effect of compound 7 through the inhibition of a number of protein kinase receptors and the suppression of cell cycle and the induction of apoptosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

The traditional single-treatment strategy for cancer is frequently unsuccessful due to the complexity of cellular signaling. However, suppression of multiple targets is vital to defeat tumor cells. In this research, new compounds for the treatment of cancer were developed successfully as novel hybrid anticancer agents. Based on a molecular hybridization strategy, we designed hybrid agents that target multiple protein kinases to fight cancer cells. The proposed hybrid agents combined purine and isatin moieties in their structures with 4-aminobenzohydrazide and hydrazine as different linkers. Having those two moieties in one molecule enabled the capability to inhibit multiple kinases, such as human epidermal receptor (EGFR), human epidermal growth factor receptor 2 (HER2), vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 2 (CDK2). Anticancer activity was evaluated by performing cytotoxicity assays, kinase inhibition assays, cell cycle analysis, and BAX, Bcl-2, Caspase 3 and Caspase 9 protein level determination assays. The results showed that the designed hybrids tackled the cancer by inhibiting both cell proliferation and metastasis. A molecular docking study was performed to predict possible binding interactions in the active site of the investigated protein kinase enzymes.

A new semisynthetic derivative of the natural alkaloid, theobromine, has been designed as a lead antiangiogenic compound targeting the EGFR protein. The designed compound is an (m-tolyl)acetamide theobromine derivative, (T-1-MTA). Molecular Docking studies have shown a great potential for T-1-MTA to bind to EGFR. MD studies (100 ns) verified the proposed binding. By MM-GBSA analysis, the exact binding with optimal energy of T-1-MTA was also identified. Then, DFT calculations were performed to identify the stability, reactivity, electrostatic potential, and total electron density of T-1-MTA. Furthermore, ADMET analysis indicated the T-1-MTA's general likeness and safety. Accordingly, T-1-MTA has been synthesized to be examined in vitro. Intriguingly, T-1-MTA inhibited the EGFR protein with an IC50 value of 22.89 nM and demonstrated cytotoxic activities against the two cancer cell lines, A549, and HCT-116, with IC50 values of 22.49, and 24.97 μM, respectively. Interestingly, T-1-MTA's IC50 against the normal cell lines, WI-38, was very high (55.14 μM) indicating high selectivity degrees of 2.4 and 2.2, respectively. Furthermore, the flow cytometry analysis of A549 treated with T-1-MTA showed significantly increased ratios of early apoptosis (from 0.07% to 21.24%) as well as late apoptosis (from 0.73% to 37.97%)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Eissa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: To evaluate the rate and determinants of non-adherence to antipsychotic medications in Saudi Arabia., Materials and Methods: This was a cross-sectional study that included a questionnaire, interview, and data extraction from medical records of adult patients on antipsychotic medications. The study was conducted at outpatient clinics at the psychological care department at King Fahad Medical City, Riyadh, Saudi Arabia, between October 25 and November 26, 2020. Data collection included three parts: patients' sociodemographic characteristics; antipsychotic medications used and patients' clinical characteristics; and adherence to antipsychotic medications measured by the Medication Adherence Rating Scale (MARS)., Results: Out of 220 patients, 122 (55.5%) were considered non-adherent (MARS scores 6 or less). The MARS items contributing most to non-adherence were "the medication makes me feel tired and sluggish" and "forget to take the medication", 55 and 40.9%, respectively. Additionally, adverse drug effect significantly increased the risk of poor adherence in regression analysis (odds ratio = 1.97, p = 0.028). The model also showed that female sex, low income, cigarette smoking, substance abuse, uncontrolled disease, comorbidity, and use of Ruqyah religious therapy were associated with increased risk of poor adherence, but were however not statistically significant (p < 0.05)., Conclusion: This study showed high non-adherence rate to antipsychotic medications. Adverse drug effects and forgetting to take medications were the main patient-reported barriers to adherence. Likewise, sociodemographic, clinical, and spiritual factors affected medication adherence. Knowing these predictors helps in early identification of patients who are predisposed to medication non-adherence and allows personalized interventions that improve adherence and treatment outcomes.

A new lead compound has been designed as an antiangiogenic EGFR inhibitor that has the pharmacophoric characteristics to bind with the catalytic pocket of EGFR protein. The designed lead compound is a (para-chloro)acetamide derivative of the alkaloid, theobromine, ( T-1-PCPA ). At first, we started with deep density functional theory (DFT) calculations for T-1-PCPA to confirm and optimize its 3D structure. Additionally, the DFT studies identified the electrostatic potential, global reactive indices and total density of states expecting a high level of reactivity for T-1-PCPA . Secondly, the affinity of T-1-PCPA to bind and inhibit the EGFR protein was studied and confirmed through detailed structure-based computational studies including the molecular docking against EGFR WT and EGFR T790M , Molecular dynamics (MD) over 100 ns, MM-GPSA and PLIP experiments. Before the preparation, the computational ADME and toxicity profiles of T-1-PCPA have been investigated and its safety and the general drug-likeness predicted. Accordingly, T-1-PCPA was semi-synthesized to scrutinize the proposed design and the obtained in silico results. Interestingly, T-1-PCPA inhibited in vitro EGFR WT with an IC 50 value of 25.35 nM, comparing that of erlotinib (5.90 nM). Additionally, T-1-PCPA inhibited the growth of A549 and HCT-116 malignant cell lines with IC 50 values of 31.74 and 20.40 µM, respectively, comparing erlotinib that expressed IC 50 values of 6.73 and 16.35 µM, respectively.

Opioids are a class of chemicals, naturally occurring in the opium poppy plant, and act on the brain to cause a range of impacts, notably analgesic and anti-inflammatory actions. Moreover, an overview was taken in consideration for SARS-CoV-2 incidence and complications, as well as the medicinal uses of opioids were discussed being a safe analgesic and anti-inflammatory drug in a specific dose. Also, our article focused on utilization of opioids in the medication of SARS-CoV-2. Therefore, the major objective of this study was to investigate the antiviral effect of opioids throughout an in silico study by molecular docking study to fifteen opioid compounds against SARS-CoV-2 main protease (PDB ID 6LU7, M pro ). The docking results revealed that opioid complexes potentially inhibit the M pro active site and exhibiting binding energy (-11.0 kcal/mol), which is comparably higher than the ligand. Furthermore, ADMET prediction indicated that all the tested compounds have good oral absorption and bioavailability and can transport via biological membranes. Finally, M pro -pholcodine complex was subjected to five MD (RMSD, RMSF, SASA, Rg, and hydrogen bonding) and two MM-PBSA, and conformational change studies, for 100 ns, confirmed the stability of pholcodine, as a representative example, inside the active site of M pro ., Competing Interests: All authors declared no financial or commercial conflicts of interest., (Copyright © 2022 Samaher S. A. Mahmoud et al.)

Background: Breast cancer is the most common type of cancer in women, and vast research is being conducted throughout the world for the treatment of this malignancy by natural products using various computational approaches. Xanthohumol, a prenylated flavonoid, is known for its anticancer activity; however, the mechanism behind its action is still in the preliminary stage., Methods: The current study aimed to analyze the efficacy of xanthohumol compared to the currently available anticancer drugs targeting phosphoinositide-3-kinase (PI3K), serine/threonine kinase (AKT) receptors, and human epidermal growth factor receptor 2 (HER2) for breast cancer treatment through in silico analysis., Results: The result revealed that the target compound showed significant binding affinity to targets within the PI3K, AKT, and HER2 signaling pathways with a binding energy of -7.5, -7.9, and -7.9 kcal/mol, respectively. Further prediction studies were then made concerning this compound's absorption, distribution, metabolism, and excretion (ADME) as well as drug-likeness properties, resulting in its oral bioavailability with only a single violation of Lipinski's rule of five., Conclusions: The finding revealed the ability of xanthohumol to bind with multiple cancer cell signaling molecules including PI3K, AKT kinase, and HER2. The current novel study opened the door to advancing research into the management and treatment of breast cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gupta, Sharma, Chandra, Panwar, Bhardwaj, Altwaijry, Alsfouk, Dlamini, Afzal, Altamimi, Khan and Mishra.)

A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound 12a was found to be the most potent candidate against the investigated cell lines with IC 50 values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested in vitro for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound 12a was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound 12a against VEGFR-2.

In this study, a set of novel benzoxazole derivatives were designed, synthesised, and biologically evaluated as potential VEGFR-2 inhibitors. Five compounds ( 12d , 12f , 12i , 12l , and 13a ) displayed high growth inhibitory activities against HepG2 and MCF-7 cell lines and were further investigated for their VEGFR-2 inhibitory activities. The most potent anti-proliferative member 12 l ( IC 50 = 10.50 μM and 15.21 μM against HepG2 and MCF-7, respectively ) had the most promising VEGFR-2 inhibitory activity (IC 50 = 97.38 nM). A further biological evaluation revealed that compound 12l could arrest the HepG2 cell growth mainly at the Pre-G1 and G1 phases. Furthermore, compound 12l could induce apoptosis in HepG2 cells by 35.13%. likely, compound 12l exhibited a significant elevation in caspase-3 level (2.98-fold) and BAX (3.40-fold), and a significant reduction in Bcl-2 level (2.12-fold). Finally, docking studies indicated that 12l exhibited interactions with the key amino acids in a similar way to sorafenib.

A library of modified VEGFR-2 inhibitors was designed as VEGFR-2 inhibitors. Virtual screening was conducted for the hypothetical library using in silico docking, ADMET, and toxicity studies. Four compounds exhibited high in silico affinity against VEGFR-2 and an acceptable range of the drug-likeness. These compounds were synthesised and subjected to in vitro cytotoxicity assay against two cancer cell lines besides VEGFR-2 inhibitory determination. Compound D-1 showed cytotoxic activity against HCT-116 cells almost double that of sorafenib. Compounds A-1 , C-6 , and D-1 showed good IC 50 values against VEGFR-2. Compound D-1 markedly increased the levels of caspase-8 and BAX expression and decreased the anti-apoptotic Bcl-2 level. Additionally, compound D-1 caused cell cycle arrest at pre-G1 and G2-M phases in HCT-116 cells and induced apoptosis at both early and late apoptotic stages. Compound D-1 decreased the level of TNF-α and IL6 and inhibited TNF-α and IL6. MD simulations studies were performed over 100 ns.

Four compounds, hippacine, 4,2'-dihydroxy-4'-methoxychalcone, 2',5'-dihydroxy-4-methoxychalcone, and wighteone, were selected from 4924 African natural metabolites as potential inhibitors against SARS-CoV-2 papain-like protease (PLpro, PDB ID: 3E9S). A multi-phased in silico approach was employed to select the most similar metabolites to the co-crystallized ligand ( TTT ) of the PLpro through molecular fingerprints and structural similarity studies. Followingly, to examine the binding of the selected metabolites with the PLpro (molecular docking. Further, to confirm this binding through molecular dynamics simulations. Finally, in silico ADMET and toxicity studies were carried out to prefer the most convenient compounds and their drug-likeness. The obtained results could be a weapon in the battle against COVID-19 via more in vitro and in vivo studies.

As an extension of our research against COVID-19, a multiphase in silico approach was applied in the selection of the three most common inhibitors (Glycyrrhizoflavone ( 76 ), Arctigenin ( 94 ) , and Thiangazole ( 298 )) against papain-like protease, PLpro (PDB ID: 4OW0), among 310 metabolites of natural origin. All compounds of the exam set were reported as antivirals. The structural similarity between the examined compound set and S88 , the co-crystallized ligand of PLpro, was examined through structural similarity and fingerprint studies. The two experiments pointed to Brevicollin ( 28 ), Cryptopleurine ( 41 ), Columbamine ( 46 ), Palmatine ( 47 ), Glycyrrhizoflavone ( 76 ), Licochalcone A ( 87 ), Arctigenin ( 94 ), Termilignan ( 98 ), Anolignan B ( 99 ), 4,5-dihydroxy-6″-deoxybromotopsentin ( 192 ), Dercitin ( 193 ), Tryptanthrin ( 200 ), 6-Cyano-5-methoxy-12-methylindolo [2, 3A] carbazole ( 211 ), Thiangazole ( 298 ), and Phenoxan ( 300 ). The binding ability against PLpro was screened through molecular docking, disclosing the favorable binding modes of six metabolites. ADMET studies expected molecules 28 , 76 , 94 , 200 , and 298 as the most favorable metabolites. Then, molecules 76 , 94 , and 298 were chosen through in silico toxicity studies. Finally, DFT studies were carried out on glycyrrhizoflavone ( 76 ) and indicated a high level of similarity in the molecular orbital analysis. The obtained data can be used in further in vitro and in vivo studies to examine and confirm the inhibitory effect of the filtered metabolites against PLpro and SARS-CoV-2.

Based on the pharmacophoric features of EGFR inhibitors, a new semisynthetic theobromine-derived compound was designed to interact with the catalytic pocket of EGFR. Molecular docking against wild (EGFR WT ; PDB: 4HJO) and mutant (EGFR T790M ; PDB: 3W2O) types of EGFR-TK indicated that the designed theobromine derivative had the potential to bind to that pocket as an antiangiogenic inhibitor. The MD and MM-GBSA experiments identified the exact binding with optimum energy and dynamics. Additionally, the DFT calculations studied electrostatic potential, stability, and total electron density of the designed theobromine derivative. Both in silico ADMET and toxicity analyses demonstrated its general likeness and safety. We synthesized the designed theobromine derivative (compound XI ) which showed an IC 50 value of 17.23 nM for EGFR inhibition besides IC 50 values of 21.99 and 22.02 µM for its cytotoxicity against A549 and HCT-116 cell lines, respectively. Interestingly, compound XI expressed a weak cytotoxic potential against the healthy W138 cell line (IC 50 = 49.44 µM, 1.6 times safer than erlotinib), exhibiting the high selectivity index of 2.2. Compound XI arrested the growth of A549 at the G2/M stage and increased the incidence of apoptosis., Competing Interests: The authors declare no conflict of interest.

The encapsulation of the famous alkaloid, anabasine, with β-CD was studied to obtain a more stable and bioavailable inclusion complex. Various in silico and experimental studies of the obtained β-CD-anabasine complex are presented. Firstly, molecular docking studies were conducted against the α, β, and γ cyclodextrins to explore which subclass is the best for encapsulation. The obtained results that pointed at β-cyclodextrin were further confirmed by five MD simulations and MM-PBSA studies. Experimentally, the spectral properties of the anabasine β-cyclodextrin complex were determined by FT-IR, 1 H, and 13 C-NMR spectroscopic methods. Additionally, the surface morphology of the anabasine β-cyclodextrin was investigated using a scanning electron microscope. Furthermore, the outputs of the thermographic measurements utilizing a differential scanning calorimeter were displayed. The activation energy of the reaction of thermo-oxidative destruction of the clathrate complex was calculated, and the kinetic parameters of the thermal destruction processes were decided using the Freeman-Carroll, Sharpe-Wentworth, Achar, and Coates-Redfern methods. The kinetic parameters of the thermal decomposition of the anabasine β-cyclodextrin were in agreement and verified the reliability of the obtained results. The obtained computational, spectral, morphological, and thermogravimetric results verified the successful formation of the anabasine β-cyclodextrin complex.

This work is one of our efforts to discover potent anticancer agents. We modified the most promising derivative of our previous work concerned with the development of VEGFR-2 inhibitor candidates. Thirteen new compounds based on benzoxazole moiety were synthesized and evaluated against three human cancer cell lines, namely, breast cancer (MCF-7), colorectal carcinoma (HCT116), and hepatocellular carcinoma (HepG2). The synthesized compounds were also evaluated against VEGFR-2 kinase activity. The biological testing fallouts showed that compound 8d was more potent than standard sorafenib. Such compound showed IC 50 values of 3.43, 2.79, and 2.43 µM against the aforementioned cancer cell lines, respectively, compared to IC 50 values of 4.21, 5.30, and 3.40 µM reported for sorafenib. Compound 8d also was found to exert exceptional VEGFR-2 inhibition activity with an IC 50 value of 0.0554 μM compared to sorafenib (0.0782 μM). In addition, compound 8h revealed excellent cytotoxic effects with IC 50 values of 3.53, 2.94, and 2.76 µM against experienced cell lines, respectively. Furthermore, compounds 8a and 8e were found to inhibit VEGFR-2 kinase activity with IC 50 values of 0.0579 and 0.0741 μM, exceeding that of sorafenib. Compound 8d showed a significant apoptotic effect and arrested the HepG2 cells at the pre-G1 phase. In addition, it exerted a significant inhibition for TNF-α (90.54%) and of IL-6 (92.19%) compared to dexamethasone (93.15%). The molecular docking studies showed that the binding pattern of the new compounds to VEGFR-2 kinase was similar to that of sorafenib.

Among a group of 310 natural antiviral natural metabolites, our team identified three compounds as the most potent natural inhibitors against the SARS-CoV-2 main protease (PDB ID: 5R84), M pro . The identified compounds are sattazolin and caprolactin A and B. A validated multistage in silico study was conducted using several techniques. First, the molecular structures of the selected metabolites were compared with that of GWS , the co-crystallized ligand of M pro , in a structural similarity study. The aim of this study was to determine the thirty most similar metabolites (10%) that may bind to the M pro similar to GWS . Then, molecular docking against M pro and pharmacophore studies led to the choice of five metabolites that exhibited good binding modes against the M pro and good fit values against the generated pharmacophore model. Among them, three metabolites were chosen according to ADMET studies. The most promising M pro inhibitor was determined by toxicity and DFT studies to be caprolactin A ( 292 ). Finally, molecular dynamics (MD) simulation studies were performed for caprolactin A to confirm the obtained results and understand the thermodynamic characteristics of the binding. It is hoped that the accomplished results could represent a positive step in the battle against COVID-19 through further in vitro and in vivo studies on the selected compounds.

In this work, novel imadazo[1,2- a ]pyrazine derivatives were synthesized and evaluated as CDK9 inhibitors. The results of CDK9 assay showed that the derivatives with pyridin-4-yl in position 2 and benzyl in position 3 of imadazo[1,2- a ]pyrazine 3c displayed the most potent CDK9 inhibitory activity with IC 50 of 0.16 µM. The anti-proliferative effect of the new compounds was examined against breast cancer (MCF7), colorectal cancer (HCT116), and chronic myelogenous leukaemia (K652) cell lines. The data of MTT assay showed that the cytotoxic effect of the inhibitors is correlated to their inhibitory activity against CDK9. Compound 3c exhibited the most potent cytotoxicity effect with average IC 50 s of three cell lines of 6.66 µM. The drug likeness properties of 3c were predicated in silico and demonstrated that 3c have reasonable physiochemical and pharmacokinetic properties. Selected derivatives were assessed in antiviral assay against human coronavirus 229E. The results of this assay showed that the derivative with pyridin-4-yl in position 2 and cyclohexyl in position 3 of imadazo[1,2- a ]pyrazine 3b exhibited the most potent anti-coronaviral activity with IC 50 of 56.96 µM and selectivity index of 7.14. The target predication result revealed that 3b showed high affinity to protease enzyme. Docking studies of 3b with COVID-19 main protease was conducted and showed good binding affinity, which confirmed the in vitro assay data.

The results of the computational and the physicochemical studies of the encapsulation of resveratrol with β-cyclodextrin are presented here. At first, the molecular docking experiments predicted good binding. Several MD simulations and MM-PBSA experiments confirmed the reliable binding, showing optimal kinetics and energy. As an application, resveratrol inclusion complexes with β-cyclodextrin were obtained in an aqueous alcohol medium via microwave treatment. The results of thermographic measurements of the obtained clathrates using a differential scanning calorimeter are presented, and the obtained activation energy was calculated using the Ozawa-Flynn-Wall and Friedman methods, as well as nonparametric kinetics. The effect of complexation on the kinetic parameters of thermal destruction of the β-cyclodextrin-resveratrol inclusion complex was considered. The morphology of the surface of the obtained clathrate complexes was described using a scanning electron microscope. The spectral properties of the inclusion complex were characterized by FT-IR, 1 H, and 13 С NMR spectroscopic data. The obtained in silico, morphological, thermogravimetric, and spectral results confirmed the formation of the resveratrol-β-cyclodextrin complex. The antioxidant activities of the inclusion complex were determined to be 12.1 μg/mL, compared to 14.3 μg/mL for free resveratrol, indicating an improvement in the bioactivity.

In continuation of our antecedent work against COVID-19, three natural compounds, namely, Luteoside C ( 130 ), Kahalalide E ( 184 ), and Streptovaricin B ( 278 ) were determined as the most promising SARS-CoV-2 main protease (M pro ) inhibitors among 310 naturally originated antiviral compounds. This was performed via a multi-step in silico method. At first, a molecular structure similarity study was done with PRD&#95;002214 , the co-crystallized ligand of M pro (PDB ID: 6LU7), and favored thirty compounds. Subsequently, the fingerprint study performed with respect to PRD&#95;002214 resulted in the election of sixteen compounds ( 7 , 128 , 130 , 156 , 157 , 158 , 180 , 184 , 203 , 204 , 210 , 237 , 264 , 276 , 277 , and 278 ). Then, results of molecular docking versus M pro PDB ID: 6LU7 favored eight compounds ( 128 , 130 , 156 , 180 , 184 , 203 , 204 , and 278 ) based on their binding affinities. Then, in silico toxicity studies were performed for the promising compounds and revealed that all of them have good toxicity profiles. Finally, molecular dynamic (MD) simulation experiments were carried out for compounds 130 , 184 , and 278 , which exhibited the best binding modes against M pro . MD tests revealed that luteoside C ( 130 ) has the greatest potential to inhibit SARS-CoV-2 main protease.

A new dicoumarin, jusan coumarin, ( 1 ), has been isolated from Artemisia glauca aerial parts. The chemical structure of jusan coumarin was estimated, by 1D, 2D NMR as well as HR-Ms spectroscopic methods, to be 7-hydroxy-6-methoxy-3-[(2-oxo-2H-chromen-6-yl)oxy]-2H-chromen-2-one. As the first time to be introduced in nature, its potential against SARS-CoV-2 has been estimated using various in silico methods. Molecular similarity and fingerprints experiments have been utilized for 1 against nine co-crystallized ligands of COVID-19 vital proteins. The results declared a great similarity between Jusan Coumarin and X77 , the ligand of COVID-19 main protease (PDB ID: 6W63), M pro . To authenticate the obtained outputs, a DFT experiment was achieved to confirm the similarity of X77 and 1 . Consequently, 1 was docked against M pro . The results clarified that 1 bonded in a correct way inside M pro active site, with a binding energy of -18.45 kcal/mol. Furthermore, the ADMET and toxicity profiles of 1 were evaluated and showed the safety of 1 and its likeness to be a drug. Finally, to confirm the binding and understand the thermodynamic characters between 1 and M pro , several molecular dynamics (MD) simulations studies have been administered. Additionally, the known coumarin derivative, 7-isopentenyloxycoumarin ( 2 ), has been isolated as well as β-sitosterol ( 3 ).

Aim: To evaluate patterns of antiseizure medication (ASM) prescription in pregnancy and changes over a 16-year period: 2005-2020, and to investigate maternal complications in pregnant women with epilepsy (WWE)., Method: Data of pregnant WWE was retrospectively reviewed at the King Faisal Specialist Hospital and Research Centre, Riyadh and Jeddah, Saudi Arabia., Results: Out of 162 pregnancies, 81.5% were prescribed ASMs. During the study period, the prescription rate increased from 68.8% to 93.5%. Between 2005 and 2020, the use of new ASMs increased from 15.4% to 75.5% (p < 0.0001). Furthermore, valproate use markedly decreased from 23.08% to 2.04%. The rate of maternal and delivery complications was 29.6%; the most frequent was gestational diabetes (5.6%), followed by bleeding during pregnancy (4.9%). Furthermore, preeclampsia and eclampsia were documented in 3.7% and 1.8%, respectively. ASMs use and other factors were not found to be associated with maternal complications (p > 0.05). However, first generation ASMs, i.e. carbamazepine (38.71%) and valproate (41.67%), were associated with higher maternal complication rates than new ASMs, i.e. levetiracetam (25%) and lamotrigine (20%), but the difference was not statistically significant (p = 0.4403)., Conclusion: ASM prescription in pregnancy is increasing as is the use of new ASMs. The rate of maternal and delivery complications was relatively low, particularly preeclampsia and eclampsia. ASMs use was not found to associated with these complications. However, exposure to first generation ASMs seemed to be a predictor of adverse pregnancy outcomes., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Two rare 2-phenoxychromone derivatives, 6-demethoxy-4`-O-capillarsine ( 1 ) and tenuflorin C ( 2 ), were isolated from the areal parts of Artemisia commutata and A. glauca, respectively, for the first time. Being rare in nature, the inhibition potentialities of 1 and 2 against SARS-CoV-2 was investigated using multistage in silico techniques. At first, molecular similarity and fingerprint studies were conducted for 1 and 2 against co-crystallized ligands of eight different COVID-19 enzymes. The carried-out studies indicated the similarity of 1 and 2 with TTT , the co-crystallized ligand of COVID-19 Papain-Like Protease (PLP), (PDB ID: 3E9S). Therefore, molecular docking studies of 1 and 2 against the PLP were carried out and revealed correct binding inside the active site exhibiting binding energies of -18.86 and -18.37 Kcal/mol, respectively. Further, in silico ADMET in addition to toxicity evaluation of 1 and 2 against seven models indicated the general safety and the likeness of 1 and 2 to be drugs. Lastly, to authenticate the binding and to investigate the thermodynamic characters, molecular dynamics (MD) simulation studies were conducted on 1 and PLP.

Papain-like protease is an essential enzyme in the proteolytic processing required for the replication of SARS-CoV-2. Accordingly, such an enzyme is an important target for the development of anti-SARS-CoV-2 agents which may reduce the mortality associated with outbreaks of SARS-CoV-2. A set of 69 semi-synthesized molecules that exhibited the structural features of SARS-CoV-2 papain-like protease inhibitors (PLPI) were docked against the coronavirus papain-like protease (PLpro) enzyme (PDB ID: (4OW0). Docking studies showed that derivatives 34 and 58 were better than the co-crystallized ligand while derivatives 17 , 28 , 31 , 40 , 41 , 43 , 47 , 54 , and 65 exhibited good binding modes and binding free energies. The pharmacokinetic profiling study was conducted according to the four principles of the Lipinski rules and excluded derivative 31. Furthermore, ADMET and toxicity studies showed that derivatives 28 , 34 , and 47 have the potential to be drugs and have been demonstrated as safe when assessed via seven toxicity models. Finally, comparing the molecular orbital energies and the molecular electrostatic potential maps of 28 , 34 , and 47 against the co-crystallized ligand in a DFT study indicated that 28 is the most promising candidate to interact with the target receptor (PLpro).

In continuation of our previous effort, different in silico selection methods were applied to 310 naturally isolated metabolites that exhibited antiviral potentialities before. The applied selection methods aimed to pick the most relevant inhibitor of SARS-CoV-2 nsp10. At first, a structural similarity study against the co-crystallized ligand, S-Adenosyl Methionine ( SAM ), of SARS-CoV-2 nonstructural protein (nsp10) (PDB ID: 6W4H) was carried out. The similarity analysis culled 30 candidates. Secondly, a fingerprint study against SAM preferred compounds 44 , 48 , 85 , 102 , 105 , 182 , 220 , 221 , 282 , 284 , 285 , 301 , and 302 . The docking studies picked 48 , 182 , 220 , 221 , and 284 . While the ADMET analysis expected the likeness of the five candidates to be drugs, the toxicity study preferred compounds 48 and 182 . Finally, a density-functional theory (DFT) study suggested vidarabine ( 182 ) to be the most relevant SARS-Cov-2 nsp10 inhibitor.

In response to the urgent need to control Coronavirus disease 19 (COVID-19), this study aims to explore potential anti-SARS-CoV-2 agents from natural sources. Moreover, cytokine immunological responses to the viral infection could lead to acute respiratory distress which is considered a critical and life-threatening complication associated with the infection. Therefore, the anti-viral and anti-inflammatory agents can be key to the management of patients with COVID-19. Four bioactive compounds, namely ferulic acid 1 , rutin 2 , gallic acid 3 , and chlorogenic acid 4 were isolated from the leaves of Pimenta dioica (L.) Merr (ethyl acetate extract) and identified using spectroscopic evidence. Furthermore, molecular docking and dynamics simulations were performed for the isolated and identified compounds ( 1 - 4 ) against SARS-CoV-2 main protease (Mpro) as a proposed mechanism of action. Furthermore, all compounds were tested for their half-maximal cytotoxicity (CC 50 ) and SARS-CoV-2 inhibitory concentrations (IC 50 ). Additionally, lung toxicity was induced in rats by mercuric chloride and the effects of treatment with P. dioca aqueous extract, ferulic acid 1 , rutin 2 , gallic acid 3 , and chlorogenic acid 4 were recorded through measuring TNF-α, IL-1β, IL-2, IL-10, G-CSF, and genetic expression of miRNA 21-3P and miRNA-155 levels to assess their anti-inflammatory effects essential for COVID-19 patients. Interestingly, rutin 2 , gallic acid 3 , and chlorogenic acid 4 showed remarkable anti-SARS-CoV-2 activities with IC 50 values of 31 µg/mL, 108 μg/mL, and 360 µg/mL, respectively. Moreover, the anti-inflammatory effects were found to be better in ferulic acid 1 and rutin 2 treatments. Our results could be promising for more advanced preclinical and clinical studies especially on rutin 2 either alone or in combination with other isolates for COVID-19 management.

Aim: To evaluate the incidence of congenital malformations in children exposed prenatally to antiseizure medications (ASMs), to assess other perinatal and fetal complications, and to determine the potential predictors for these complications., Method: A retrospective review of pregnancy outcomes of women with epilepsy. Patients were followed up at the King Faisal Specialist Hospital and Research Centre, Riyadh and Jeddah, Saudi Arabia, between Dec 1993 and Oct 2020., Results: Of 162 pregnancies included, 10 (6.17%) congenital malformations were observed, 6.82% in ASM-exposed babies versus 3.33% in babies of epilepsy-untreated mothers (P = 0.69). The overall incidence of perinatal and fetal complications was 53%; most frequent were low birth weight (24%), preterm birth (19%), transfer to neonatal intensive care unit (18%) and abortion (8%). These complications were higher in the untreated group (66.67%) than in the ASM group (50%). The use of other non-antiseizure medications during pregnancy was the only factor that significantly increased the risk of complications., Conclusion: Prenatal exposure to ASMs was associated with increased risk of congenital malformations. However, overall perinatal and fetal complications were higher in the untreated group than in the ASM group, which could be explained by maternal seizures. Therefore, taking ASMs to control epilepsy and prevent perinatal complications may outweigh the risks of teratogenicity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Objective: To evaluate the long-term pharmacological outcomes in teenagers with different epilepsies., Method: This study included teenagers aged 13-19 years at treatment initiation who were newly treated with antiepileptic drugs (AEDs) at the epilepsy unit of the Western Infirmary in Glasgow, Scotland, between 1 September 1982 and 30 September 2012. Patients were prospectively followed until 30 April 2016, or death, with at least a 2-year follow-up., Results: A total of 332 adolescent patients (53% female; median age 16 years; 54% with generalized epilepsy) were included. At the end of the study, 221 patients (67%) were seizure-free. A higher seizure-free rate was observed in those with generalized compared to focal epilepsy (72% versus 60%, P = 0.01). During the study, 108 patients had relapses after periods of being seizure-free, most commonly due to poor adherence to AEDs (49%, n = 53/108). AED withdrawal was associated with a high risk of seizure recurrence (70%, n = 26/37), but 56% (n = 61/108) of relapsed patients became seizure-free again by the end of the study, with only 9% (n = 31/332) meeting the International League Against Epilepsy (ILAE) definition of pharmacoresistance during follow-up. Of the 221 seizure-free patients, 83% achieved this on monotherapy. There was no significant difference in efficacy rate between new and standard AED monotherapy (74% versus 77%, P = 0.66). The overall poor tolerability rate of AEDs was 21% (n = 69/332). Among the different new and standard AEDs used as initial monotherapy, lamotrigine was associated with the lowest rate of adverse effects (12%, n = 15/124), while topiramate was associated with the highest rate (56%, n = 5/9)., Significance: Teenagers with epilepsy showed good seizure control, particularly those with generalized epilepsy. However, relapse was common and there was high risk of seizure recurrence after treatment withdrawal. Most patients were controlled on monotherapy. As the efficacy of AEDs was comparable, tolerability can be a primary consideration for AED selection in this population., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)