Search

© 2022 Deutsche Pharmazeutische Gesellschaft.FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients. In the current study, the oxindole chemotype is employed as a structural motif for the design of new FLT3 inhibitors as potential hits for AML irradiation. Cell-based screening was performed with 18 oxindole derivatives and 5a–c inhibited 68%–73% and 83%–91% of internal tandem duplication (ITD)-mutated MV4-11 cell growth for 48- and 72-h treatments while only 0%–2% and 27%–39% in wild-type THP-1 cells. The most potent compound 5a inhibited MV4-11 cells with IC50 of 4.3 µM at 72 h while it was 8.7 µM in THP-1 cells, thus showing two-fold selective inhibition against the oncogenic ITD mutation. The ability of 5a to modulate cell death was examined. High-throughput protein profiling revealed low levels of the growth factors IGFBP-2 and -4 with the blockage of various apoptotic inhibitors such as Survivin. p21 with cellular stress mechanisms was characterized by increased expression of HSP proteins along with TNF-β. Mechanistically, compounds 5a and 5b inhibited FLT3 kinase with IC50 values of 2.49 and 1.45 µM, respectively. Theoretical docking studies supported the compounds' ability to bind to the FLT3 ATP binding site with the formation of highly stable complexes as evidenced by molecular dynamics simulations. The designed compounds also provide suitable drug candidates with no violation of drug likeability rules.

The global COVID-19 pandemic became more threatening especially after the introduction of the second and third waves with the current large expectations for a fourth one as well. This urged scientists to rapidly develop a new effective therapy to combat SARS-CoV-2. Based on the structures of β-adrenergic blockers having the same hydroxyethylamine and hydroxyethylene moieties present in the HIV-1 protease inhibitors which were found previously to inhibit the replication of SARS-CoV, we suggested that they may decrease the SARS-CoV-2 entry into the host cell through their ability to decrease the activity of RAAS and ACE2 as well. Herein, molecular docking of twenty FDA-approved β-blockers was performed targeting SARS-CoV-2 Mpro. Results showed promising inhibitory activities especially for Carvedilol (CAR) and Nebivolol (NEB) members. Moreover, these two drugs together with Bisoprolol (BIS) as an example from the lower active ones were subjected to molecular dynamics simulations at 100 ns. Great stability across the whole 100 ns timeframe was observed for the top docked ligands, CAR and NEB, over BIS. Conformational analysis of the examined drugs and hydrogen bond investigation with the pocket's crucial residues confirm the great affinity and confinement of CAR and NEB within the Mpro binding site. Moreover, the binding-free energy analysis and residue-wise contribution analysis highlight the nature of ligand–protein interaction and provide guidance for lead development and optimization. Furthermore, the examined three drugs were tested for their in vitro inhibitory activities towards SARS-CoV-2. It is worth mentioning that NEB achieved the most potential anti-SARS-CoV-2 activity with an IC50 value of 0.030 μg ml−1. Besides, CAR was found to have a promising inhibitory activity with an IC50 of 0.350 μg ml−1. Also, the IC50 value of BIS was found to be as low as 15.917 μg ml−1. Finally, the SARS-CoV-2 Mpro assay was performed to evaluate and confirm the inhibitory effects of the tested compounds (BIS, CAR, and NEB) towards the SARS-CoV-2 Mpro enzyme. The obtained results showed very promising SARS-CoV-2 Mpro inhibitory activities of BIS, CAR, and NEB (IC50 = 118.50, 204.60, and 60.20 μg ml−1, respectively) compared to lopinavir (IC50 = 73.68 μg ml−1) as a reference standard.

Spironolactone (SP) is a potassium sparing diuretic with antiandrogenic properties. This study aimed at formulating SP into hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism. HAECs were prepared by ethanol injection method, according to D-optimal design, after a proper in silico study. HAECs were evaluated by measuring their entrapment efficiency (EE%), particle size (PS), and polydispersity index (PDI). Optimal hyaluronic acid enriched cerosomes (OHAECs) were subjected to further in vitro and ex-vivo and in-vivo studies. The in silico study concluded better interactions between SP and phosphatidyl choline in presence of hyaluronic acid (HA) and high stability of their binding in water. The prepared HAECs had acceptable EE%, PS, and PDI values. The statistical optimization process suggested OHAEC containing 10.5 mg ceramide III and 15 mg HA, utilizing Kolliphor® RH40. OHAEC had EE% and PS of 89.3 ± 0.3% and 261.8 ± 7.0 nm, respectively. OHAEC was stable for up to 3 months. It also showed a mixed tubular and vesicular appearance under transmission electron microscope. The ex vivo and in vivo studies concluded better skin deposition and accumulation of SP from OHAEC. The histopathological study demonstrated the safety of OHAEC for topical application. Therefore, OHAEC could be considered as effective system for topical application of SP to manage hirsutism, with prolonged action, coupled with minimized side effects.

A series of 3-benzylideneindolin-2-one compounds was designed and synthesized based on combretastatin A-4 and compound IC261, a dual casein kinase (CK1)/tubulin polymerization inhibitor, taking into consideration the pharmacophore required for EGFR-tyrosine kinase inhibition. The new molecular entities provoked significant growth inhibition against PC-3, MCF-7 and COLO-205 at a 10 μM dose. Compounds 6-chloro-3-(2,4,6-trimethoxybenzylidene) indolin-2-one, 4b, and 5-methoxy-3-(2,4,6-trimethoxybenzylidene)indolin-2-one, 4e, showed potent activity against the colon cancer COLO-205 cell line with an IC50 value of 0.2 and 0.3 μM. A mechanistic study demonstrated 4b’s efficacy in inhibiting microtubule assembly (IC50 = 1.66 ± 0.08 μM) with potential binding to the colchicine binding site (docking study). With an IC50 of 1.92 ± 0.09 μg/mL, 4b inhibited CK1 almost as well as IC261. Additionally, 4b and 4e were effective inhibitors of EGFR-TK with IC50s of 0.19 μg/mL and 0.40 μg/mL compared to Gifitinib (IC50 = 0.05 μg/mL). Apoptosis was induced in COLO-205 cells treated with 4b, with apoptotic markers dysregulated. Caspase 3 levels were elevated to more than three-fold, while Cytochrome C levels were doubled. The cell cycle was arrested in the pre-G1 phase with extensive cellular accumulation in the pre-G1 phase, confirming apoptosis induction. Levels of cell cycle regulating proteins BAX and Bcl-2 were also defective. The binding interaction patterns of these compounds at the colchicine binding site of tubulin and the Gifitinib binding site of EGFR were verified by molecular docking, which adequately matched the reported experimental result. Hence, 4b and 4e are considered promising potent multitarget agents against colon cancer that require optimization.

A series of novel thieno[2,3-d]pyrimidine derivatives was designed and synthesized based on multitarget directed drug design strategy. All the newly synthesized compounds were evaluated for their antiproliferative activity in the National Cancer Institute (NCI) against a panel of 60 tumor cell lines. Compounds 4a and 4b showed a significant antiproliferative activity at 10 µM dose, and were accordingly evaluated at five dose concentrations. They showed potent and broad-spectrum antiproliferative activity, with GI

Novel diarylpyrazole (5a-d, 6a-e, 12, 13, 14, 15a-c and 11a-g) derivatives were designed, synthesized and evaluated for their dual COX-2/sEH inhibitory activities via recombinant enzyme assays to explore their anti-inflammatory activities and cardiovascular safety profiles. Comprehensively, the structures of the synthesized compounds were established via spectral and elemental analyses, followed by the assessment of both their in vitro COX inhibitory and in vivo anti-inflammatory activities. The most active compounds as COX inhibitors were further evaluated for their in vitro 5-LOX and sEH inhibitory activities, alongside with their in vivo analgesic and ulcerogenic effects. Compounds 6d and 11f showed excellent inhibitory activities against both COX-2 and sEH (COX-2 IC50 = 0.043 and 0.048 µM; sEH IC50 = 83.58 and 83.52 μM, respectively). Moreover, the compounds demonstrated promising results as anti-inflammatory and analgesic agents with considerable ED50 values and gastric safety profiles. Remarkably, the most active COX inhibitors 6d and 11f possessed improved cardiovascular safety profiles, if compared to celecoxib, as shown by the laboratory evaluation of both essential cardiac biochemical parameters (troponin-1, prostacyclin, tumor necrosis factor-α, lactate dehydrogenase, reduced glutathione and creatine kinase-M) and histopathological studies. On the other hand, docking simulations confirmed that the newly synthesized compounds displayed sufficient structural features required for binding to the target COX-2 and sEH enzymes. Also, in silico ADME studies prediction and drug-like properties of the compounds revealed favorable oral bioavailability results. Collectively, the present work could be featured as a promising future approach towards novel selective COX-2 inhibitors with declined cardiovascular risks.

The global COVID-19 pandemic became more threatening especially after the introduction of the second and third waves with the current large expectations for a fourth one as well. This urged scientists to rapidly develop a new effective therapy to combat SARS-CoV-2. Based on the structures of β-adrenergic blockers having the same hydroxyethylamine and hydroxyethylene moieties present in the

The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure–activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.

The global prevalence of COVID-19 disease and the overwhelming increase in death toll urge scientists to discover new effective drugs. Although the drug discovery process is a challenging and time-consuming, fortunately, the plant kingdom was found to have many active therapeutics possessing broad-spectrum antiviral activity including those candidates active against severe acute respiratory syndrome coronaviruses (SARS-CoV). Herein, nine traditional Chinese medicinal plant constituents from different origins (Glycyrrhizin 1, Lycorine 2, Puerarin 3, Daidzein 4, Daidzin 5, Salvianolic acid B 6, Dihydrotanshinone I 7, Tanshinone I 8, Tanshinone IIa 9) previously reported to exhibit antiviral activity against SARS-CoV were virtually screened in silico (molecular docking) as potential inhibitors of SARS-CoV-2 target proteins. The tested medicinal plant compounds were in silico screened for their activity against two key SARS-CoV-2 target proteins; 3CLpro, and Spike binding-domain proteins. Among the tested medicinal plant compounds, Salvianolic acid B 6 (Sal-B) showed promising binding affinities against the two specified SARS-CoV-2 target proteins compared to the reference standards used. Hence molecular dynamics simulations followed by calculating the free-binding energy were carried out for Sal-B providing information on its affinity, stability, and thermodynamic behavior within the two SARS-CoV-2 target proteins as well as key ligand-protein binding aspects. Besides, the quantum mechanical calculations showed that Sal-B can adopt different conformations due to the existence of various rotatable bonds. Therefore, the enhanced antiviral activity of Sal-B among other studied compounds can be also attributed to the structural flexibility of Sal-B. Our study gives an explanation of the structure activity relationship required for targeting SARS-CoV-2 3CLpro and Spike proteins and also facilitates the future design and synthesis of new potential drugs exhibiting better affinity and specificity. Besides, an ADME study was carried out on screened compounds and reference controls revealing their pharmacokinetics properties. Communicated by Ramaswamy H. Sarma

Spironolactone (SP) is a potassium sparing diuretic with antiandrogenic properties. This study aimed at formulating SP into hyaluronic acid enriched cerosomes (HAECs) for topical management of hirsutism. HAECs were prepared by ethanol injection method, according to D-optimal design, after a proper in silico study. HAECs were evaluated by measuring their entrapment efficiency (EE%), particle size (PS), and polydispersity index (PDI). Optimal hyaluronic acid enriched cerosomes (OHAECs) were subjected to further in vitro and ex-vivo and in-vivo studies. The in silico study concluded better interactions between SP and phosphatidyl choline in presence of hyaluronic acid (HA) and high stability of their binding in water. The prepared HAECs had acceptable EE%, PS, and PDI values. The statistical optimization process suggested OHAEC containing 10.5 mg ceramide III and 15 mg HA, utilizing Kolliphor® RH40. OHAEC had EE% and PS of 89.3 ± 0.3% and 261.8 ± 7.0 nm, respectively. OHAEC was stable for up to 3 months. It also showed a mixed tubular and vesicular appearance under transmission electron microscope. The ex vivo and in vivo studies concluded better skin deposition and accumulation of SP from OHAEC. The histopathological study demonstrated the safety of OHAEC for topical application. Therefore, OHAEC could be considered as effective system for topical application of SP to manage hirsutism, with prolonged action, coupled with minimized side effects.

Novel tolmetin derivatives 5a–f to 8a–c were designed, synthesised, and evaluated for antiproliferative activity by NCI (USA) against a panel of 60 tumour cell lines. The cytotoxic activity of the most active tolmetin derivatives 5b and 5c was examined against HL-60, HCT-15, and UO-31 tumour cell lines. Compound 5b was found to be the most potent derivative against HL-60, HCT-15, and UO-31 cell lines with IC50 values of 10.32 ± 0.55, 6.62 ± 0.35, and 7.69 ± 0.41 µM, respectively. Molecular modelling studies of derivative 5b towards the VEGFR-2 active site were performed. Compound 5b displayed high inhibitory activity against VEGFR-2 (IC50 = 0.20 µM). It extremely reduced the HUVECs migration potential exhibiting deeply reduced wound healing patterns after 72 h. It induced apoptosis in HCT-15 cells (52.72-fold). This evidence was supported by an increase in the level of apoptotic caspases-3, -8, and -9 by 7.808-, 1.867-, and 7.622-fold, respectively. Compound 5b arrested the cell cycle in the G0/G1 phase. Furthermore, the ADME studies showed that compound 5b possessed promising pharmacokinetic properties.

The global breakout of COVID-19 and raised death toll has prompted scientists to develop novel drugs capable of inhibiting SARS-CoV-2. Conducting studies on repurposing some FDA-approved glucocorticoids can be a promising prospective for finding a treatment for COVID-19. In addition, the use of anti-inflammatory drugs, such as glucocorticoids, is a pivotal step in the treatment of critical cases of COVID-19, as they can provoke an inflammatory cytokine storm, damaging lungs. In this study, 22 FDA-approved glucocorticoids were identified through in silico (molecular docking) studies as the potential inhibitors of COVID-19's main protease. From tested compounds, ciclesonide 11, dexamethasone 2, betamethasone 1, hydrocortisone 4, fludrocortisone 3, and triamcinolone 8 are suggested as the most potent glucocorticoids active against COVID-19's main protease. Moreover, molecular dynamics simulations followed by the calculations of the binding free energy using MM-GBSA were carried out for the aforementioned promising candidate-screened glucocorticoids. In addition, quantum chemical calculations revealed two electron-rich sites on ciclesonide where binding interactions with the main protease and cleavage of the prodrug to the active metabolite take place. Our results have ramifications for conducting preclinical and clinical studies on promising glucocorticoids to hasten the development of effective therapeutics against COVID-19. Another advantage is that some glucocorticoids can be prioritized over others for the treatment of inflammation accompanying COVID-19.

Opioid analgesics are widely used for the treatment of moderate to severe pain. However, the analgesic efficacy of opioids is well known to vary widely among individuals, making it difficult to predict optimal pain management for each patient. The current clinical study was designed to investigate the association of the A118G single nucleotide polymorphism of the μ-opioid receptor gene with the individual variation in pain sensitivity and fentanyl consumption with patient-controlled analgesia (PCA) in 60 adult female Egyptian patients after total abdominal hysterectomy. All patients received general anesthesia according to the same protocol. During the first 24 h after surgery, pain was assessed using a visual analogue scale. In addition, total amount of fentanyl consumption, sedation score, and any other side effects of opioids were recorded; the A118G single nucleotide polymorphism of the μ-opioid receptor gene was detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Our main finding was that in Egyptian gynecological patients, subjects homozygous for the 118G allele needed more fentanyl (488.5 ± 23.91 μg) for 24-h postoperative analgesia than 118A homozygotes (359.82 ± 19.63 μg) and heterozygotes (400± 8.99 μg) (P = 0.001). There was no association of G or A allele and opioid side effects. This study may provide support for the potential use of genetic data in predicting patient’s individual fentanyl doses for adequate postoperative pain control.