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Levocetirizine hydrochloride (LVC) is an antihistaminic drug that is repurposed for the treatment of alopecia. This investigation is targeted for formulating LVC into cationic ceramide/phospholipid composite (CCPCs) for the management of alopecia. CCPCs were fabricated by ethanol-injection approach, through a central composite experiment. CCPCs were evaluated by inspecting their entrapment efficiency (EE%), polydispersity index (PDI), particle size (PS), and zeta potential (ZP). The optimum CCPCs were additionally studied by

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 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

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.