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Phytochemical investigation of Gardenia thunbergia L. f. aerial parts led to the isolation of a previously undescribed neolignan 13, designated (thunbergiside A). This compound is classified as 2,3-dihydrobenzofuran that features a unique, highly substituted skeleton with functional diversity. The absolute configuration was established by comparing its experimental ECD spectrum and optical rotation values with those of related neolignans. In addition, seventeen diverse phytoconstituents were identified for the first time from this plant, expanding our knowledge of its chemical composition. These included oleanane-type saponins, phenolic derivatives, lignans, and neolignans, which serve as valuable chemotaxonomic markers. Considering the frequent emergence of infectious diseases, it is worth exploring additional antimicrobial agents. Selected isolated compounds were assessed for their antimycotic properties in an investigation for potential anti-infective agents. Various chromatographic procedures, spectroscopic, spectrometric analyses, and molecular modelling studies were employed for phytochemical investigation and structural characterization. Furthermore, the alamarBlue-based viability assay was employed for antifungal evaluation against three pathogenic fungi. Specifically, saponin 17 , 3- O -(β-ᴅ-glucuronopyranoside) oleanolic acid, displayed moderate antifungal activity (IC 50 = 11 µg/mL) against Candida albicans. Overall, this study identified an unprecedented neolignan along with other diverse constituents from Gardenia thunbergia. Moreover, the study presented a potential scaffold for antifungal drug development. [Display omitted] • A unique previously undescribed neolignan, thunbergiside A, was isolated. • Valuable chemotaxonomic markers were reported from Gardenia thunbergia. • Antifungal activity of oleanolic acid 3-glucuronide was confirmed. [ABSTRACT FROM AUTHOR]

A new series of indole-2-carboxamides 5a-g, 6a-f and pyrido[3,4-b]indol-1-ones 7a and 7b have been developed as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of the new compounds was studied. 5c, 5d, 5f, 5 g, 6e, and 6f have the highest antiproliferative activity with GI50 values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI50 = 33 nM). Compounds 5d, 5f, and 5 g inhibited EGFRWT with IC50 values ranging from 68 to 85 nM while the GI50 of erlotinib is 80 nM. Moreover, compounds 5f and 5 g had the most potent inhibitory activity against EGFRT790M with IC50 values of 9.5 ± 2 and 11.9 ± 3 nM, respectively, being equivalent to the reference osimertinib (IC50 = 8 ± 2 nM). Compounds 5f and 5 g demonstrated excellent caspase-3 protein overexpression levels of 560.2 ± 5.0 and 542.5 ± 5.0 pg/mL, respectively, being more active than the reference staurosporine (503.2 ± 4.0 pg/mL). they also increase the level of caspase 8, and Bax while decreasing the levels of anti-apoptotic Bcl2 protein. Computational docking studies supported the enzyme inhibition results and provided favourable dual binding modes for both compounds 5f and 5 g within EGFRWT and EGFRT790M active sites. Finally, in silico ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds. [ABSTRACT FROM AUTHOR]

A small set of indole-based derivatives, IV and Va–I, was designed and synthesized. Compounds Va–i demonstrated promising antiproliferative activity, with GI50 values ranging from 26 nM to 86 nM compared to erlotinib's 33 nM. The most potent antiproliferative derivatives—Va, Ve, Vf, Vg, and Vh—were tested for EGFR inhibitory activity. Compound Va demonstrated the highest inhibitory activity against EGFR with an IC50 value of 71 ± 06 nM, which is higher than the reference erlotinib (IC50 = 80 ± 05 nM). Compounds Va, Ve, Vf, Vg, and Vh were further tested for BRAFV600E inhibitory activity. The tested compounds inhibited BRAFV600E with IC50 values ranging from 77 nM to 107 nM compared to erlotinib's IC50 value of 60 nM. The inhibitory activity of compounds Va, Ve, Vf, Vg, and Vh against VEGFR-2 was also determined. Finally, in silico docking experiments attempted to investigate the binding mode of compounds within the active sites of EGFR, BRAFV600E, and VEGFR-2. [ABSTRACT FROM AUTHOR]

Mutant EGFR/BRAF pathways are thought to be crucial targets for the development of anticancer drugs since they are over-activated in several malignancies. We present here the development of a novel series of 5-chloro-indole-2-carboxylate 3a–e, 4a–c and pyrrolo[3,4-b]indol-3-ones 5a–c derivatives as potent inhibitors of mutant EGFR/BRAF pathways with antiproliferative activity. The cell viability assay results of 3a–e, 4a–c, and 5a–c revealed that none of the compounds tested were cytotoxic, and that the majority of those tested at 50 µM had cell viability levels greater than 87%. Compounds 3a–e, 4a–c, and 5a–c had significant antiproliferative activity with GI50 values ranging from 29 nM to 78 nM, with 3a–e outperforming 4a–c and 5a–c in their inhibitory actions against the tested cancer cell lines. Compounds 3a–e were tested for EGFR inhibition, with IC50 values ranging from 68 nM to 89 nM. The most potent derivative was found to be the m-piperidinyl derivative 3e (R = m-piperidin-1-yl), with an IC50 value of 68 nM, which was 1.2-fold more potent than erlotinib (IC50 = 80 nM). Interestingly, all the tested compounds 3a–e had higher anti-BRAFV600E activity than the reference erlotinib but were less potent than vemurafenib, with compound 3e having the most potent activity. Moreover, compounds 3b and 3e showed an 8-fold selectivity index toward EGFRT790M protein over wild-type. Additionally, molecular docking of 3a and 3b against BRAFV600E and EGFRT790M enzymes revealed high binding affinity and active site interactions compared to the co-crystalized ligands. The pharmacokinetics properties (ADME) of 3a–e revealed safety and good pharmacokinetic profile. [ABSTRACT FROM AUTHOR]

One of the promising therapeutic strategies for corona virus 2019 (COVID-19) is tolook for enzyme inhibitors. COVID-19 virus main protease (Mpro) plays a vital role in mediating viral transcription and replication, introducing it as an attractive antiviral agent target. LC–ESI–HDMS based metabolic profiling of Citrus nobilis Lour. ×Citrus deliciosa Ten. (Rutaceae) annotated 21 compounds belonging to diverse classes. Molecular docking studies were carried out to ascertain the inhibitory action of studied dereplicated compounds through the interactions within the active site of SARS-CoV-2 (Mpro). Among which, quercetin-7-O-glucoside-3-O-rutinoside (21) possessed the best binding affinity (–9.47 kcal/mol), followed by luteoline-7-rutinoside (18), quercetin-3-O-rutinoside (19) and apigenin-8-C-glucoside (15) showed less binding affinities ranging at −8.27, −7.97 and −6.94 kcal/mol respectively. [ABSTRACT FROM AUTHOR]

LC-HR-MS-coupled metabolic profiling of the methanol extracts from different parts of Syzygium cumini (L.), which was extensively identified via DNA fingerprinting, led to dereplication of 24 compounds. Cytotoxic investigation highlighted both extracts as the most potent, against both MCF-7 and MDA-231 Cell lines, with IC50 value of 5.86 ± 0.63 µg/ml and against HCT −116 cell line, with IC50 value of 1.24 ± 0.09 µg/ml, respectively. A molecular docking study was performed on the dereplicated compounds, which highlighted myricetin-3-glucoside (7), myricitrin (12), reynoutrin (15) and quercitrin (16) as the top scoring ligands within the protein active site (FIH-1). Interestingly, the extracts were significant against streptozotocin-induced diabetes in the order of flowers > seeds > leaves with BGL level of 98.9 ± 4.3, 123.2 ± 4.9 and 132.8 ± 5.9 mg/dl, respectively. The study highlights the health benefits of Syzygium cumini (L.) as a promising cytotoxic source. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract A series of tricyclic penciclovir (PCV) and hydroxybutylguanine (HBG) derivatives have been prepared with enhanced lipophilicity following an efficient synthetic route. All the novel tricyclic derivatives were evaluated for inhibitory activity against herpes simplex virus 1 and 2 (HSV-1, HSV-2) and thymidine kinase deficient (ACV resistant) HSV-1. The tricyclic HBG derivatives were devoid of inhibitory activity however several of the tricyclic PCV derivatives showed promising antiviral activity, in particular 9g (R = 4-MeO-C 6 H 4) displayed good inhibitory activity (HSV-1 EC 50 1.5 μM, HSV-2 EC 50 0.8 μM) and retained inhibitory activity in HSV-1 TK− cells (EC 50 0.8 μM). Computational docking experiments supported the biological data observed and this preliminary study provides useful data for further development of tricyclic acyclic nucleoside derivatives with improved lipophilicity and retention of activity in HSV-1 TK deficient strains. Also, the new tricyclic derivatives were evaluated against a broad range of other DNA and RNA viruses, but were found to be inactive at subtoxic concentrations. In addition, weak to moderate cytostatic effect was observed for the new compounds. [ABSTRACT FROM AUTHOR]

Bioactivity-guided isolation supported by LC-HRESIMS metabolic profiling led to the isolation of two new compounds, a ceramide, stylissamide A (1), and a cerebroside, stylissoside A (2), from the methanol extract of the Red Sea sponge Stylissa carteri. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR and HRMS. The bioactive extract's metabolomic profiling showed the existence of various secondary metabolites, mainly oleanane-type saponins, phenolic diterpenes, and lupane triterpenes. The in vitro cytotoxic activity of the isolated compounds was tested against two human cancer cell lines, MCF-7 and HepG2. Both compounds, 1 and 2, displayed strong cytotoxicity against the MCF-7 cell line, with IC50 values at 21.1 ± 0.17 µM and 27.5 ± 0.18 µM, respectively. They likewise showed a promising activity against HepG2 with IC50 at 36.8 ± 0.16 µM for 1 and IC50 30.5 ± 0.23 µM for 2 compared to the standard drug cisplatin. Molecular docking experiments showed that 1 and 2 displayed high affinity to the SET protein and to inhibitor 2 of protein phosphatase 2A (I2PP2A), which could be a possible mechanism for their cytotoxic activity. This paper spreads light on the role of these metabolites in holding fouling organisms away from the outer surface of the sponge, and the potential use of these defensive molecules in the production of novel anticancer agents. [ABSTRACT FROM AUTHOR]

• The efficient synthesis of the privileged intermediate 5-azido-2- hydroxyacetophenone. • The synthesis of 20 new 2′-hydroxychalcone-triazole hybrids some endowed with isatin. • Six compounds showed good in vivo anti-inflammatory activity with potent dual inhibition of COX-2 and 15-LOX. • Molecular docking studies disclosed important binding modes with COX-2 and 15-LOX. A hybrid pharmacophore approach is used to design and synthesize two novel series of 2′-hydroxychalcone-triazole hybrid molecules 6a-j and 8a-j. These compounds were fully characterized by spectral and elemental analyses. They were evaluated in vitro and in vivo for anti-inflammatory activity. Most of compounds were selective inhibitors for COX-2. Among them, compounds 6d , 6f , 6i , 8c , 8e and 8h demonstrated highly potent dual inhibition of COX-2 (IC 50 = 0.037–0.041 µM) and 15-LOX (IC 50 = 1.41–1.80 µM). Compounds 6i , 8c and 8h showed 116%, 113% and 109% of the in vivo anti-inflammatory activity of celecoxib. Therefore, compounds 6d , 6f , 6i , 8c , 8e and 8h-j are potent dual inhibitors of COX-2 and 15-LOX. Docking study over COX-2 and 15-LOX active sites ensures the binding affinity and selectivity. These compounds are promising candidates for further development as anti-inflammatory drugs. [ABSTRACT FROM AUTHOR]

A novel series of 1,2,3-triazole/1,2,4-oxadiazole hybrids ( 7a - o ) was developed as dual inhibitors of EGFR/VEGFR-2. Compounds 7a - o were evaluated as antiproliferative agents with Erlotinib as the reference drug. Results demonstrated that most of the tested compounds showed significant antiproliferative action with GI 50 values ranging from 28 to 104 nM, compared to Erlotinib (GI 50 = 33 nM), and compounds 7i - m were the most potent. Compounds 7h , 7i , 7j , 7k , and 7l were evaluated as dual EGFR/VEGFR-2 inhibitors. These in vitro experiments demonstrated that compounds 7j , 7k , and 7l are potent antiproliferative agents that may operate as dual EGFR/VEGFR-2 inhibitors. Compounds 7j , 7k , and 7l were evaluated for their apoptotic potential activity, where findings indicated that compounds 7j , 7k, and 7l promote apoptosis by activating caspase-3, 8, and Bax and down-regulating the anti-apoptotic Bcl-2. Molecular docking simulations show the binding mode of the most active antiproliferative compounds within EGFR and VEGFR-2 active sites.

A new series of indole-2-carboxamides 5a-g , 6a-f and pyrido[3,4-b]indol-1-ones 7a and 7b have been developed as new antiproliferative agents that target both wild and mutant type EGFR. The antiproliferative effect of the new compounds was studied. 5c , 5d , 5f , 5 g , 6e , and 6f have the highest antiproliferative activity with GI 50 values ranging from 29 nM to 47 nM in comparison to the reference erlotinib (GI 50 = 33 nM). Compounds 5d , 5f , and 5 g inhibited EGFR WT with IC 50 values ranging from 68 to 85 nM while the GI 50 of erlotinib is 80 nM. Moreover, compounds 5f and 5 g had the most potent inhibitory activity against EGFR T790M with IC 50 values of 9.5 ± 2 and 11.9 ± 3 nM, respectively, being equivalent to the reference osimertinib (IC 50 = 8 ± 2 nM). Compounds 5f and 5 g demonstrated excellent caspase-3 protein overexpression levels of 560.2 ± 5.0 and 542.5 ± 5.0 pg/mL, respectively, being more active than the reference staurosporine (503.2 ± 4.0 pg/mL). they also increase the level of caspase 8, and Bax while decreasing the levels of anti-apoptotic Bcl2 protein. Computational docking studies supported the enzyme inhibition results and provided favourable dual binding modes for both compounds 5f and 5 g within EGFR WT and EGFR T790M active sites. Finally, in silico ADME/pharmacokinetic studies predict good safety and pharmacokinetic profile of the most active compounds.

A new series of 5-substituted-3-ethylindole-2-carboxamides 5a-k and 6a-c was designed and synthesised in an attempt to develop a dual targeted antiproliferative agent. Various spectroscopic methods of analysis were used to confirm the structures of the new compounds. The antiproliferative effect of compounds 5a-k and 6a-c against four cancer cell lines was investigated. Compounds 5a-k and 6a-c had significant antiproliferative activity against the four cancer cell lines tested, with mean GI 50 values ranging from 37 nM to 193 nM. The most powerful derivatives were compounds 5g, 5i, and 5j, with GI 50 values of 55 nM, 49 nM, and 37 nM, respectively, in comparison to the reference erlotinib, which had a GI 50 of 33 nM. The four most potent compounds, 5c, 5g, 5i, and 5j, were then investigated for their efficacy as EGFR inhibitors, and the findings showed that the tested compounds inhibited EGFR with IC 50 values ranging from 85 nM to 124 nM when compared to the reference erlotinib (IC 50 = 80 nM). Moreover, compounds 5c and 5g inhibited CDK2 with IC 50 values of 46 ± 05 nM and 33 ± 04 nM, respectively. The EGFR and CDK2 assays revealed that compounds 5i and 5j displayed potent antiproliferative activity and can be considered as potential dual EGFR and CDK2 inhibitors., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)