Novel imidazo[2,1-b]thiazoles and imidazo[1,2-a]pyridines tethered with indolinone motif as VEGFR-2 inhibitors and apoptotic inducers: Design, synthesis and biological evaluations.

The current study investigates the anticancer and VEGFR-2 inhibitory activities of 16 novel indolinone-grafted imidazo[2,1-b]thiazole and imidazo[1,2-a]pyridine derivatives (6a-h and 10a-h). The structures of these target compounds were confirmed using elemental and spectral analyses. All compounds were evaluated for their VEGFR-2 inhibitory activity in vitro, with eight compounds demonstrating promising results, exhibiting IC50 values in the sub-micromolar range (0.22 µM - 0.95 µM). Additionally, the anticancer potential of these compounds was assessed using an MTT assay against two breast cancer cell lines, MCF-7 and MDA-MB-231. Compounds 6a, 6f, 6 h, and 10f showed superior performance (IC50 = 9.79, 8.78, 8.35, and 10.88 µM, respectively) compared to the reference drug cisplatin (IC50 = 11.50 µM) against MDA-MB-231 cells. Based on their consistent VEGFR-2 inhibitory activity, compounds 6a, 6 h, and 10f were selected for further analysis. Molecular docking studies with VEGFR-2 (PDB ID: 4AGD) revealed binding behaviors similar to the co-crystallized ligand sunitinib. Among the reported target molecules, compound 10f exhibited the most desirable characteristics in terms of efficacy and safety and was further analyzed using density-functional theory (DFT) simulations to better understand its physical properties.

Design and synthesis of benzo[b]thiophene-based hybrids as novel antitubercular agents against MDR/XDR Mycobacterium tuberculosis.

In an effort to support the global fight against tuberculosis (TB), which is widely recognized as the most lethal infectious disease worldwide, we present the design and synthesis of new benzo[b]thiophene-based hybrids as promising candidates for the management of multidrug-resistant (MDR)/extensively drug-resistant (XDR) Mycobacterium tuberculosis. The isatin motif was incorporated into the target hybrids as it represents a privileged scaffold in antitubercular drug discovery. Since lipophilicity plays a pivotal role in the anti-TB agents' activity, the lipophilicity of the target hybrids was manipulated via the development of two series of N-1 methyl and N-1 benzyl substituted isatins (6a-h and 9a-h, respectively). Screening of the target hybrids was first performed against drug-sensitive M. tuberculosis (ATCC 25177). The structure-activity relationship outputs highlighted that incorporation of 3-unsubstituted benzo[b]thiophene and 5-methoxy isatin moieties was favorable for the antimycobacterial activity. Thereafter, the most potent molecules (6b-h, 9c-e, and 9h) were evaluated against the resistant strains MDR-TB (ATCC 35822) as well as against XDR-TB (RCMB 2674) where they displayed promising activity. To evaluate the safety of the target hybrids, an sulforhodamine B assay was conducted to determine their possible cytotoxic effects on VERO cells.

Phthalimide-tethered isatins as novel poly(ADP-ribose) polymerase inhibitors: Design, synthesis, biological evaluations, and molecular modeling investigations.

Humanity is currently facing various diseases with significant mortality rates, particularly those associated with malignancies. Numerous enzymes and proteins have been identified as highly promising targets for the treatment of cancer. The poly(ADP-ribose) polymerases (PARPs) family comprises 17 members which are essential in DNA damage repair, allowing the survival of cancer cells. Unlike other PARP family members, PARP-1 and, to a lesser extent, PARP-2 show more than 90% activity in response to DNA damage. PARP-1 levels were shown to be elevated in various tumor cells, including breast, lung, ovarian, and prostate cancer and melanomas. Accordingly, novel series of phthalimide-tethered isatins (6a-n, 10a-e, and 11a-e) were synthesized as potential PARP-1 inhibitors endowed with anticancer activity. All the synthesized molecules were assessed against PARP-1, where compounds 6f and 10d showed nanomolar activities with IC50 = 15.56 ± 2.85 and 13.65 ± 1.42 nM, respectively. Also, the assessment of the antiproliferative effects of the synthesized isatins was conducted on four cancer cell lines: leukemia (K-562), liver (HepG2), and breast (MCF-7 and HCC1937) cancers. Superiorly, compounds 6f and 10d demonstrated submicromolar IC50 values against breast cancer MCF-7 (IC50 = 0.92 ± 0.18 and 0.67 ± 0.12 µM, respectively) and HCC1937 (IC50 = 0.88 ± 0.52 and 0.53 ± 0.11 µM, respectively) cell lines. In addition, compounds 6f and 10d induced arrest in the G2/M phase of the cell cycle as compared to untreated cells. Finally, in silico studies, including docking and molecular dynamic simulations, were performed to justify the biological results.

Identification of 3-(5-cyano-6-oxo-pyridin-2-yl)benzenesulfonamides as novel anticancer agents endowed with EGFR inhibitory activity.

New 5-cyano-6-oxo-pyridine-based sulfonamides (6a-m and 8a-d) were designed and synthesized to potentially inhibit both the epidermal growth factor receptor (EGFR) and carbonic anhydrase (CA), with anticancer properties. First, the in vitro anticancer activity of each target substance was tested using Henrietta Lacks cancer cell line and M.D. anderson metastasis breast cancer cell line cells. Then, the possible CA inhibition against the human CA isoforms I, II, and IX was investigated, together with the EGFR inhibitory activity, with the most powerful derivatives. The neighboring methoxy group may have had a steric effect on the target sulfonamides, which prevented them from effectively inhibiting the CA isoforms while effectively inhibiting the EGFR. The effects of the 5-cyanopyridine derivatives 6e and 6l on cell-cycle disruption and the apoptotic potential were then investigated. To investigate the binding mechanism and stability of the target molecules, thorough molecular modeling assessments, including docking and dynamic simulation, were performed.

Development of novel anilinoquinazoline-based carboxylic acids as non-classical carbonic anhydrase IX and XII inhibitors.

As part of our ongoing endeavour to identify novel inhibitors of cancer-associated CA isoforms IX and XII as possible anticancer candidates, here we describe the design and synthesis of small library of 2-aryl-quinazolin-4-yl aminobenzoic acid derivatives (6a-c, 7a-c, and 8a-c) as new non-classical CA inhibitors. On account of its significance in the anticancer drug discovery and in the development of effective CAIs, the 4-anilinoquinazoline privileged scaffold was exploited in this study. Thereafter, the free carboxylic acid functionality was appended in the ortho (6a-c), meta (7a-c), or para-positon (8a-c) of the anilino motif to furnish the target inhibitors. All compounds were assessed for their inhibitory activities against the hCA I, II (cytosolic), IX, and XII (trans-membrane, tumour-associated) isoforms. Moreover, six quinazolines (6a-c, 7b, and 8a-b) were chosen by the NCI-USA for in vitro anti-proliferative activity evaluation against 59 human cancer cell lines representing nine tumour subpanels.

Discovery of sulfonamide-tethered isatin derivatives as novel anticancer agents and VEGFR-2 inhibitors.

In this work, new isatin-based sulphonamides (6a-i, 11a-c, 12a-c) were designed and synthesised as potential dual VEGFR-2 and carbonic anhydrase inhibitors with anticancer activities. Firstly, all target isatins were examined for in vitro antitumor action on NCI-USA panel (58 tumour cell lines). Then, the most potent derivatives were examined for the potential CA inhibitory action towards the physiologically relevant hCA isoforms I, II, and tumour-linked hCA IX isoform, in addition, the VEGFR-2 inhibitory activity was evaluated. The target sulphonamides failed to inhibit the CA isoforms that could be attributable to the steric effect of the neighbouring methoxy group, whereas they displayed potent VEGFR-2 inhibitory effect. Following that, isatins 11b and 12b were tested for their influence on the cell cycle disturbance, and towards the apoptotic potential. Finally, detailed molecular modelling analyses, including docking and molecular dynamics, were carried out to assess the binding mode and stability of target isatins.

1-Benzyl-5-bromo-3-hydrazonoindolin-2-ones as Novel Anticancer Agents: Synthesis, Biological Evaluation and Molecular Modeling Insights.

Human health is experiencing several obstacles in the modern medical era, particularly cancer. As a result, the cancer therapeutic arsenal should be continually expanded with innovative small molecules that preferentially target tumour cells. In this study, we describe the development of two small molecule series (7a-d and 12a-e) based on the 1-benzyl-5-bromoindolin-2-one scaffold that connected through a hydrazone linker to a 4-arylthiazole (7a-d) or 4-methyl-5-(aryldiazenyl)thiazole (12a-e) moiety. The anticancer activity of all the reported indolin-2-one derivatives was assessed against breast (MCF-7) and lung (A-549) cancer cell lines. The 4-arylthiazole-bearing derivatives 7c and 7d revealed the best anticancer activity toward MCF-7 cells (IC50 = 7.17 ± 0.94 and 2.93 ± 0.47, respectively). Furthermore, the VEGFR-2 inhibitory activity for 7c and 7d was evaluated. Both molecules disclosed good inhibitory activity, and their IC50 values were equal to 0.728 µM and 0.503 µM, respectively. Additionally, the impacts of 7d on the cell cycle phases as well as on the levels of different apoptotic markers (caspase-3, caspase-9, Bax, and Bcl-2) were assessed. Molecular docking and dynamic simulations are carried out to explore the binding mode of 7d within the VEGFR-2 active site.

GC/MS Profiling of the Essential Oil and Lipophilic Extract of Moricandia sinaica Boiss. and Evaluation of Their Cytotoxic and Antioxidant Activities.

The genus Moricandia (Brassicaceae) comprises about eight species that were used in traditional medicine. Moricandia sinaica is used to alleviate certain disorders such as syphilis and exhibits analgesic, anti-inflammatory, antipyretic, antioxidant, and antigenotoxic properties. Throughout this study, we aimed to figure out the chemical composition of lipophilic extract and essential oil obtained from M. sinaica aerial parts using GC/MS analysis, as well as their cytotoxic and antioxidant activities correlated with the major detected compounds' molecular docking. The results revealed that both the lipophilic extract and the oil were found to be rich in aliphatic hydrocarbons, accounting for 72.00% and 79.85%, respectively. Furthermore, the lipophilic extract's major constituents are octacosanol, γ-sitosterol, α-amyrin, ß-amyrin acetate, and α-tocopherol. Contrarily, monoterpenes and sesquiterpenes accounted for the majority of the essential oil. The essential oil and the lipophilic extract of M. sinaica showed cytotoxic properties towards human liver cancer cells (HepG2) with IC50 values of 126.65 and 220.21 µg/mL, respectively. The lipophilic extract revealed antioxidant activity in the DPPH assay with an IC50 value of 2679 ± 128.13 µg/mL and in the FRAP assay, moderate antioxidant potential was expressed as 44.30 ± 3.73 µM Trolox equivalent/mg sample. The molecular docking studies revealed that ꞵ-amyrin acetate, α -tocopherol, γ-sitosterol, and n-pentacosaneachieved the best docking scores for NADPH oxidase, phosphoinositide-3 kinase, and protein kinase B. Consequently, M. sinaica essential oil and lipophilic extract can be employed as a viable management strategy for oxidative stress conditions and the formulation of improved cytotoxic treatment regimens.

Synergistic Effect of Sophora japonica and Glycyrrhiza glabra Flavonoid-Rich Fractions on Wound Healing: In Vivo and Molecular Docking Studies.

Glycyrrhiza glabra and Sophora japonica (Fabaceae) are well-known medicinal plants with valuable secondary metabolites and pharmacological properties. The flavonoid-rich fractions of G. glabra roots and S. japonica leaves were prepared using Diaion column chromatography, and the confirmation of flavonoid richness was confirmed using UPLC-ESI-MS profiling and total phenolics and flavonoids assays. UPLC-ESI-MS profiling of the flavonoid-rich fraction of G. glabra roots and S. japonica leaves resulted in the tentative identification of 32 and 23 compounds, respectively. Additionally, the wound healing potential of topical preparations of each fraction, individually and in combination (1:1) ointment and gel preparations, were investigated in vivo, supported by histopathological examinations and biomarker evaluations, as well as molecular docking studies for the major constituents. The topical application of G. glabra ointment and gel, S. japonica ointment and gel and combination preparations significantly increase the wound healing rate and the reduction of oxidative stress in the wound area via MDA reduction and the elevation of reduced GSH and SOD levels as compared to the wound and Nolaver®-treated groups. The molecular docking study revealed that that major compounds in G. glabra and S. japonica can efficiently bind to the active sites of three proteins related to wound healing: glycogen synthase kinase 3-ß (GSK3-ß), matrix metalloproteinases-8 (MMP-8) and nitric oxide synthase (iNOS). Consequently, G. glabra roots and S. japonica leaves may be a rich source of bioactive metabolites with antioxidant, anti-inflammatory and wound healing properties.

Novel 3-(6-methylpyridin-2-yl)coumarin-based chalcones as selective inhibitors of cancer-related carbonic anhydrases IX and XII endowed with anti-proliferative activity.

Carbonic anhydrases (CAs) are one of the promising targets for the development of anticancer agents. CA isoforms are implicated in various physiological processes and are expressed in both normal and cancerous cells. Thus, non-isoform selective inhibitors are associated with several side effects. Consequently, designing selective inhibitors towards cancer-related hCA IX/XII rather than the ubiquitous cytosolic isozymes hCA I and II is the main research objective in the field. Herein, a new series of 3-(6-methylpyridin-2-yl)coumarin derivatives 3 and 5a-o was designed and synthesised. The CA inhibition activities for the synthesised coumarins were analysed on isoforms hCA I, II, IX, and XII. Interestingly, both cancer-linked isoforms hCA IX/XII were inhibited by the prepared coumarins with inhibition constants ranging from sub- to low-micromolar range, whereas hCA I and II isoforms haven't been inhibited up to 100 µM. Furthermore, the target coumarins were assessed for their antitumor activity on NCI-59 human cancer types.

Enaminone-based carboxylic acids as novel non-classical carbonic anhydrases inhibitors: design, synthesis and in vitro biological assessment.

In searching for new molecular drug targets, Carbonic Anhydrases (CAs) have emerged as valuable targets in diverse diseases. CAs play critical functions in maintaining pH and CO2 homeostasis, metabolic pathways, and much more. So, it is becoming attractive for medicinal chemists to design novel inhibitors for this class of enzymes with improved potency and selectivity towards the different isoforms. In the present study, three sets of carboxylic acid derivatives 5a-q, 7a-b and 12a-c were designed, developed and evaluated for the hCA inhibitory effects against hCA I, II, IX and XII. Compounds 5l, 5m, and 5q elicited the highest inhibitory activities against hCA II, IX and XII. In summary, structural rigidification, regioisomerism and structural extension, all played obvious roles in the degree of hCA inhibition. This present work could be a good starting point for the design of more non-classical selective hCA inhibitors as potential targets for several diseases.

Identification of 3-(piperazinylmethyl)benzofuran derivatives as novel type II CDK2 inhibitors: design, synthesis, biological evaluation, and in silico insights.

In the current work, a hybridisation strategy was adopted between the privileged building blocks, benzofuran and piperazine, with the aim of designing novel CDK2 type II inhibitors. The hybrid structures were linked to different aromatic semicarbazide, thiosemicarbazide, or acylhydrazone tails to anchor the designed inhibitors onto the CDK2 kinase domain. The designed compounds showed promising CDK2 inhibitory activity. Compounds 9h, 11d, 11e and 13c showed potent inhibitory activity (IC50 of 40.91, 41.70, 46.88, and 52.63 nM, respectively) compared to staurosporine (IC50 of 56.76 nM). Moreover, benzofurans 9e, 9h, 11d, and 13b showed promising antiproliferative activities towards different cancer cell lines, and non-significant cytotoxicity on normal lung fibroblasts MRC-5 cell line. Furthermore, a cell cycle analysis as well as Annexin V-FITC apoptosis assay on Panc-1 cell line were performed. Molecular docking simulations were performed to explore the ability of target benzofurans to adopt the common binding pattern of CDK2 type II inhibitors.

Development of Novel Isatin-Tethered Quinolines as Anti-Tubercular Agents against Multi and Extensively Drug-Resistant Mycobacterium tuberculosis.

We describe the design and synthesis of two isatin-tethered quinolines series (Q6a-h and Q8a-h), in connection with our research interest in developing novel isatin-bearing anti-tubercular candidates. In a previous study, a series of small molecules bearing a quinoline-3-carbohydrazone moiety was developed as anti-tubercular agents, and compound IV disclosed the highest potency with MIC value equal to 6.24 µg/mL. In the current work, we adopted the bioisosteric replacement approach to replace the 3,4,5-trimethoxy-benzylidene moiety in the lead compound IV with the isatin motif, a privileged scaffold in the TB drug discovery, to furnish the first series of target molecules Q6a-h. Thereafter, the isatin motif was N-substituted with either a methyl or benzyl group to furnish the second series Q8a-h. All of the designed quinoilne-isatin conjugates Q6a-h and Q8a-h were synthesized and then biologically assessed for anti-tubercular actions towards drug-susceptible, MDR, and XDR strains. Superiorly, the N-benzyl-bearing compound Q8b possessed the best activities against the examined M. tuberculosis strains with MICs equal 0.06, 0.24, and 1.95 µg/mL, respectively.

Novel benzofuran-based sulphonamides as selective carbonic anhydrases IX and XII inhibitors: synthesis and in vitro biological evaluation.

Pursuing on our efforts toward searching for efficient hCA IX and hCA XII inhibitors, herein we report the design and synthesis of new sets of benzofuran-based sulphonamides (4a,b, 5a,b, 9a-c, and 10a-d), featuring the zinc anchoring benzenesulfonamide moiety linked to a benzofuran tail via a hydrazine or hydrazide linker. All the target benzofurans were examined for their inhibitory activities toward isoforms hCA I, II, IX, and XII. The target tumour-associated hCA IX and XII isoforms were efficiently inhibited with KIs spanning in ranges 10.0-97.5 and 10.1-71.8 nM, respectively. Interestingly, arylsulfonehydrazones 9 displayed the best selectivity toward hCA IX and XII over hCA I (SIs: 39.4-250.3 and 26.0-149.9, respectively), and over hCA II (SIs: 19.6-57.1 and 13.0-34.2, respectively). Furthermore, the target benzofurans were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Only benzofurans 5b and 10b possessed selective and moderate growth inhibitory activity toward certain cancer cell lines.

Novel [(N-alkyl-3-indolylmethylene)hydrazono]oxindoles arrest cell cycle and induce cell apoptosis by inhibiting CDK2 and Bcl-2: synthesis, biological evaluation and in silico studies.

As a continuation for our previous work, a novel set of N-alkylindole-isatin conjugates (7, 8a-c, 9 and 10a-e) is here designed and synthesised with the prime aim to develop more efficient isatin-based antitumor candidates. Utilising the SAR outputs from the previous study, our design here is based on appending four alkyl groups with different length (ethyl and n-propyl), bulkiness (iso-propyl) and unsaturation (allyl) on N-1 of indole motif, with subsequent conjugation with different N-unsubstituted isatin moieties to furnish the target conjugates. As planned, the adopted strategy achieved a substantial improvement in the growth inhibitory profile for the target conjugates in comparison to the reported lead VI. The best results were obtained with N-propylindole -5-methylisatin hybrid 8a which displayed broad spectrum anti-proliferative action with efficient sub-panel GI50 (MG-MID) range from 1.33 to 4.23 µM, and promising full-panel GI50 (MG-MID) equals 3.10 µM, at the NCI five-dose assay. Also, hybrid 8a was able to provoke cell cycle disturbance and apoptosis in breast T-47D cells as evidenced by the DNA flow cytometry and Annexin V-FITC/PI assays. Furthermore, hybrid 8a exhibited good inhibitory action against cell cycle regulator CDK2 protein kinase and the anti-apoptotic Bcl-2 protein (IC50= 0.85 ± 0.03 and 0.46 ± 0.02 µM, respectively). Interestingly, molecular docking for hybrid 8a in CDK2 and Bcl-2 active sites unveiled that N-propyl group is involved in significant hydrophobic interactions. Taken together, the results suggested conjugate 8a as a promising lead for further development and optimisation as an efficient antitumor drug.

Development of novel synthesized phthalazinone-based PARP-1 inhibitors with apoptosis inducing mechanism in lung cancer.

Herein we report the synthesis of two series of 4-phenylphthalazin-1-ones 11a-i and 4- benzylphthalazin-1-ones 16a-h as anti-lung adenocarcinoma agents with potential inhibitory activity against PARP-1. All the newly synthesized phthalazinones were evaluated for their anti-proliferative activity against A549 lung carcinoma cell line. Phthalazinones 11c-i and 16b, c showed significant cytotoxic activity against A549 cells at different concentrations (0.1, 1 and 10 µM) for two time intervals (24 h and 48 h). These nine phthalazinones were further examined for their inhibitory activity towards PARP-1. Compound 11c emerged as the most potent PARP-1 inhibitor with IC50 value of 97 nM, compared to that of Olaparib (IC50 = 139 nM). Furthermore, all these nine phthalazinones passed the filters of Lipinski and Veber rules, and predicted to have good pharmacokinetics properties in a theoretical kinetic study. On the other hand, western blotting in A549 cells revealed the enhanced expression of the cleaved PARP-1, alongside, with the reduced expression of pro-caspase-3 and phosphorylated AKT. In addition, ELISA assay confirmed the up-regulation of active caspase-3 and caspase-9 levels compared to the control, suggesting the activation of the apoptotic machinery in the A549 cells. Finally, molecular docking of 11c into PARP-1 active site (PDB: 5WRZ) was performed to explore the probable binding mode.

Pyridine-Ureas as Potential Anticancer Agents: Synthesis and In Vitro Biological Evaluation.

In our endeavor towards the development of effective anticancer agents, a novel series of pyridine-ureas 8a⁻n were synthesized. All the newly prepared derivatives were evaluated in vitro for their growth inhibitory activity towards the proliferation of breast cancer MCF-7 cell line. Compounds 8e and 8n were found to be the most active congeners against MCF-7 cells (IC50 = 0.22 and 1.88 µM after 48 h treatment; 0.11 and 0.80 µM after 72 h treatment, respectively) with increased activity compared to the reference drug doxorubicin (IC50 = 1.93 µM). Moreover, eight selected pyridines 8b, 8d, 8e, 8i, 8j and 8l⁻n were evaluated for their in vitro anticancer activity according to the US-NCI protocol. Pyridines 8b and 8e proved to be the most effective anticancer agents in the NCI assay with mean inhibition = 43 and 49%, respectively. Both 8b and 8e exhibited anti-proliferative activity against all tested cancer cell lines from all subpanels growth inhibition (GI for 8b; 12⁻78%, GI for 8e; 15⁻91%). Pyridines 8b and 8e were screened in vitro for their inhibitory activity against VEGFR-2. Both compounds inhibited VEGFR-2 at micromolar IC50 values 5.0 ± 1.91 and 3.93 ± 0.73 µM, respectively. The most active pyridines were filtered according to the Lipinski and Veber rules and all of them passed these filters. Finally, several ADME descriptors were predicted for the active pyridines through a theoretical kinetic study.

Novel Thiazolidinone/Thiazolo[3,2-a]Benzimidazolone-Isatin Conjugates as Apoptotic Anti-proliferative Agents Towards Breast Cancer: One-Pot Synthesis and In Vitro Biological Evaluation.

In connection with our research program on the development of new isatin-based anticancer candidates, herein we report the synthesis of two novel series of thiazolidinone-isatin conjugates (4a⁻n) and thiazolo[3,2-a]benzimidazolone-isatin conjugates (7a⁻d), and in vitro evaluation of their antiproliferative activity towards two breast cancer cell lines; triple negative MDA-MB-231, and MCF-7. Compounds 4m and 7b emerged as the most active congeners against MDA-MB-231 cells (IC50 = 7.6 ± 0.5 and 13.2 ± 1.1 µM, respectively). Compounds 4m and 7b were able to provoke apoptosis in MDA-MB-231 cells, evidenced by the up-regulation of Bax and down-regulation of Bcl-2, besides boosting caspase-3 levels. Hybrid 4m induced a fourfold increase in the percentage of cells at Sub-G1, with concurrent arrest in G2-M phase by 2.5-folds. Furthermore, hybrid 4m resulted in a sixfold increase in the percentage of annexin V-FITC positive apoptotic MDA-MB-231 cells as compared with the control. Moreover, the cytotoxic activities of the active conjugates were assessed towards two nontumorigenic cell lines (breast MCF-10A and lung WI-38) where both conjugates 4m and 7b displayed mean tumor selectivity index: 9.6 and 13.9, respectively. Finally, several ADME descriptors were predicted for the active conjugates via a theoretical kinetic study.

Synthesis and in vitro anti-proliferative activity of some novel isatins conjugated with quinazoline/phthalazine hydrazines against triple-negative breast cancer MDA-MB-231 cells as apoptosis-inducing agents.

Treatment of patients with triple-negative breast cancer (TNBC) is challenging due to the absence of well- defined molecular targets and the heterogeneity of such disease. In our endeavor to develop potent isatin-based anti-proliferative agents, we utilized the hybrid-pharmacophore approach to synthesize three series of novel isatin-based hybrids 5a-h, 10a-h and 13a-c, with the prime goal of developing potent anti-proliferative agents toward TNBC MDA-MB-231 cell line. In particular, compounds 5e and 10g were the most active hybrids against MDA-MB-231 cells (IC50 = 12.35 ± 0.12 and 12.00 ± 0.13 µM), with 2.37- and 2.44-fold increased activity than 5-fluorouracil (5-FU) (IC50 = 29.38 ± 1.24 µM). Compounds 5e and 10g induced the intrinsic apoptotic mitochondrial pathway in MDA-MB-231; evidenced by the reduced expression of the anti-apoptotic protein Bcl-2, the enhanced expression of the pro-apoptotic protein Bax and the up-regulated active caspase-9 and caspase-3 levels. Furthermore, 10g showed significant increase in the percent of annexin V-FITC positive apoptotic cells from 3.88 to 31.21% (8.4 folds compared to control).

Synthesis, Biological Evaluation and Molecular Docking of Certain Sulfones as Potential Nonazole Antifungal Agents.

We reported herein the synthesis, antifungal activity, docking and in silico ADME prediction studies of four novel series of sulfones 6a-f, 8a-c, 10a-f and 12a-c. All the newly synthesized sulfones were tested against four strains of Candida (including fluconazole-resistant Candida), two strains of Aspergillus, two dermatophytic fungi (Trichophytons mentagrophyte and Microsporum canis) and Syncephalastrum sp. with fluconazole as a reference drug. In general, compounds 8a and 10b showed selective and potent anticandidal activity (MIC: 0.19-0.81 µM) relative to fluconazole (MIC = 1.00 µM). Furthermore, 10e and 12a elicited a remarkable and selective antifungal activity against Aspergillus sp. and the dermatophytic fungi (MIC: 0.16-0.79 µM) relative to fluconazole (MIC: 2-2.6 µM). Moreover, the docking results of the sulfones 6a, 8a, 10a and 10b at the active site of CYT P450 14α-sterol demethylase showed a comparable binding interaction (interaction Energy = -34.87 to -42.43 kcal/mol) with that of fluconazole (IE = -40.37 kcal/mol).