Mean Growth Inhibition Research Articles

Bioefficacy of propiconazole alone or in combination with other fungicides against Alternaria alternata causing leaf blight in cowpea

In the present study, the bioefficacy of propiconazole alone or in combination with other fungicides was evaluated for the management of Alternaria leaf blight in cowpeas under in vitro and field conditions. For this, propiconazole was employed in different fungicidal combination (viz., propiconazole 25 EC + chlorothalonil 75WP, propiconazole 25 EC + propineb 70 WP and propiconazole 25 EC + metiram 60 WG) with standard fungicidal check (viz., propiconazole 25 EC, tebuconazole 50 + trifloxystrobin 25 WG, pyraclostrobin 5 + metiram 55 WG and carbendazim 25 + mancozeb 50 WS) along with native isolate of Trichoderma spp. and untreated control. Among all fungicides, the mean colony diameter observed ranged from 0.00 to 31.68 mm at different concentrations of different fungicides with the mean growth inhibition ranging from 63 to 100%. The maximum 100% mean growth inhibition was recorded in propiconazole 25 EC, while a minimum 63% mean growth inhibition was recorded in carbendazim 25 + mancozeb 50 WS with 31.7 mm colony diameter under in-vitro condition. Among all the treatments, the highest reduction in disease incidence was observed in tebuconazole 50 + trifloxystrobin 25 WG with 71.6% disease reduction which was at par with propiconazole 25 EC + metiram 60 WG and propiconazole 25 EC + chlorothalonil 75WP with 70 and 62% disease reduction, respectively. The least effective treatment recorded pyraclostrobin 5 WG + metiram 55 WG with 33% disease reduction but effective over the control.

New S-substituted-3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one scaffold with promising anticancer activity profile through the regulation and inhibition of mutated B-RAF signaling pathway.

Novel 3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives were synthesized and screened for their antiproliferative activity against a panel of 60 cancer cell lines. Derivatives 5b, 5f, and 9c showed significant antitumor activity at a single dose with mean growth inhibition of 55.62%, 55.79%, and 71.40%, respectively. These compounds were further investigated against HCT-116, colon cancer cell line, and FHC, normal colon cell line. Compound 9c showed the highest activity with IC50 = 0.904 ± 0.03 µM and SI = 20.42 excelling doxorubicin which scored IC50 = 2.556 ± 0.09 µM and SI = 6.19. Compound 9c was also the most potent against B-RAFWT and mutated B-RAFV600E with IC50 = 0.145 ± 0.005 and 0.042 ± 0.002 µM, respectively in comparison with vemurafenib with IC50 = 0.229 ± 0.008 and 0.038 ± 0.001 µM, respectively. The cell cycle analysis showed that 9c increased the cell population and induced an arrest in the cell cycle of HCT-116 cancer cells at the G0-G1 stage with 1.23-fold. Apoptosis evaluation showed that compound 9c displayed an 18.18-fold elevation in total apoptosis of HCT-116 cancer cells in comparison to the control. Compound 9c increased the content of caspase-3 by 3.52-fold versus the control. A molecular modeling study determined the binding profile and interaction of 9c with the B-RAF active site.

Novel benzenesulfonamides as dual VEGFR2/FGFR1 inhibitors targeting breast cancer: Design, synthesis, anticancer activity and in silico studies

In the current study, a new series of benzenesulfonamides 6a-r was designed and synthesized as dual VEGFR-2 and FGFR1 kinase inhibitors with anti-cancer activity. The 4-trifluoromethyl benzenesulfonamide 6l exhibited the highest dual VEGFR-2/FGFR1 inhibitory activity with IC50 values of 0.025 and 0.026 µM, respectively. It showed a higher activity than sorafenib and staurosporine by 1.8- and 1.3-fold, respectively. Furthermore, compound 6l was further tested on EGFR and PDGFR-β kinases showing IC50 values of 0.106 and 0.077 µM, respectively. The target compounds were tested for their anticancer activity against NCI-60 panel of cancer cell lines at 10 µM concentration, where compound 6l displayed the highest mean growth inhibition percent % (GI%) of 60.38%. Compounds 6a, 6b, 6e, 6f, 6h-l, and 6n-r revealed promising GI% on breast cancer cell lines (MCF-7, T-47D, and MDA-MB-231), and were subjected to IC50 determination on these cell lines. The tested compounds showed a higher activity on T-47D and MCF-7 cell lines over MDA-MB-231 cell line compared to the used reference standard; sorafenib. Compounds 6e, 6h-j, 6l and 6o revealed IC50 values ≤ 20 µM against T-47D cell line, furthermore, they were found to be non-cytotoxic on Vero normal cell line. Furthermore, the effect of the most active compounds 6i, and 6l in T-47D cells on cell cycle analysis progression, cell apoptosis, and apoptosis markers was investigated. Both compounds arrested cell cycle progression at G1 phase, furthermore, they enhanced early and late apoptosis, as well as necrosis. The capability of compounds 6i, and 6l to induce apoptosis was further confirmed by their ability to raise BAX/BCl-2 ratio and caspase-3 level in the treated cells. Cell migration assay revealed that both compounds 6i and 6l have anti-migratory effects compared to control T-47D cells after 24, and 48 h. Molecular docking studies for compounds 6a-r on VEGFR-2 and FGFR1 binding sites showed that they exhibit an analogous binding mode in both target kinases which agrees with that of type II kinase inhibitors.

Design, Synthesis, and Molecular Docking of Novel Miscellaneous Chalcones as p38α Mitogen-Activated Protein Kinase Inhibitors.

New chalcones were synthesized and evaluated to serve as p38-α type of mitogen-activated protein kinase (MAPK) inhibitors. According to the National Cancer Institute, the findings indicated that at a 10 μM dosage, compounds 3a and 6 were the most active among all the compounds examined, with mean growth inhibition% of 94.83 and 58.49, respectively. In 5-dose testing, they showed anticancer activity in the micro-molar range with GI50 in the range of 1.41-46.1 and 2.07-31.3 μM, respectively. Besides, powerful activity, especially against the leukaemia cell lines and good selectivity to cancer cells compared to normal PCS-800-017 with a selectivity index=12.41 and 23.77, respectively. Compounds 3a and 6 inhibited p38α MAPK with IC50 values of 0.1462±0.0063 and 0.4356±0.0189 μM, correspondingly. 3a showed good inhibition for HL-60(TB) cells and induced cell cycle arrest in HL-60(TB) cells at the G2/M phase. Besides, it elevated the total apoptosis by 14.68-fold and increased the caspase-3 level by 3.52-fold compared with doxorubicin, which raised it by 4.30-fold, inducing apoptosis by acting as caspase-dependent inducers. These results suggest that 3a is a promising antiproliferative and p38α MAPK inhibitor, confirmed by molecular docking with high compatibility 3a with the p38α MAPK binding site.

Receptor-based pharmacophore modeling, molecular docking, synthesis and biological evaluation of novel VEGFR-2, FGFR-1, and BRAF multi-kinase inhibitors

A receptor-based pharmacophore model describing the binding features required for the multi-kinase inhibition of the target kinases (VEGFR-2, FGFR-1, and BRAF) were constructed and validated. It showed a good overall quality in discriminating between the active and the inactive in a compiled test set compounds with F1 score of 0.502 and Mathew’s correlation coefficient of 0.513. It described the ligand binding to the hinge region Cys or Ala, the glutamate residue of the Glu-Lys αC helix conserved pair, the DFG motif Asp at the activation loop, and the allosteric back pocket next to the ATP binding site. Moreover, excluded volumes were used to define the steric extent of the binding sites. The application of the developed pharmacophore model in virtual screening of an in-house scaffold dataset resulted in the identification of a benzimidazole-based scaffold as a promising hit within the dataset. Compounds 8a-u were designed through structural optimization of the hit benzimidazole-based scaffold through (un)substituted aryl substitution on 2 and 5 positions of the benzimidazole ring. Molecular docking simulations and ADME properties predictions confirmed the promising characteristics of the designed compounds in terms of binding affinity and pharmacokinetic properties, respectively. The designed compounds 8a-u were synthesized, and they demonstrated moderate to potent VEGFR-2 inhibitory activity at 10 µM. Compound 8u exhibited a potent inhibitory activity against the target kinases (VEGFR-2, FGFR-1, and BRAF) with IC50 values of 0.93, 3.74, 0.25 µM, respectively. The benzimidazole derivatives 8a-u were all selected by the NCI (USA) to conduct their anti-proliferation screening. Compounds 8a and 8d resulted in a potent mean growth inhibition % (GI%) of 97.73% and 92.51%, respectively. Whereas compounds 8h, 8j, 8k, 8o, 8q, 8r, and 8u showed a mean GI% > 100% (lethal effect). The most potent compounds on the NCI panel of 60 different cancer cell lines were progressed further to NCI five-dose testing. The benzimidazole derivatives 8a, 8d, 8h, 8j, 8k, 8o, 8q, 8r and 8u exhibited potent anticancer activity on the tested cell lines reaching sub-micromolar range. Moreover, 8u was found to induce cell cycle arrest of MCF-7 cell line at the G2/M phase and accumulating cells at the sub-G1 phase as a result of cell apoptosis.

Targeting apoptosis; design, synthesis and biological evaluation of new benzoxazole and thiazole based derivatives

Several novel approaches to target Bcl-2 proteins and apoptotic pathways have been identified in recent years for the treatment of different types of cancer including colorectal cancer. However, no effective treatments were yet developed for colorectal cancer. Twenty two novel benzoxazole and thiazole−based compounds were designed, synthesized, and evaluated as potential Bcl-2 inhibitors with anti−proliferative activity. Compounds 8g, 12e and 13d showed good to moderate anti−proliferative activity against most of the NCI 60 cell line panel with mean growth inhibition percent of 45.13, 42.29 and 29.25%, respectively. They showed the greatest cell growth inhibition percent to HCT-116 cell line with the values of 68.0, 59.11 and 43.44%, respectively. The aforementioned compounds were furtherly investigated for their effect on HCT-116 cell cycle, and they showed increase in the total apoptosis with 17, 22, and 5%, respectively. Also, the apoptotic effect of compounds 8g, 12e and 13d, were tested by their effect on altering caspase-3 expression level in HCT-116 human cell line. The three compounds showed an increase in the caspase-3 levels by 6, 8 and 3 folds, respectively in comparison with the same untreated ones. Moreover, they were evaluated for their in–vitro Bcl-2 inhibitory activity and they showed percent inhibition of 60.2, 69.2 and 50.0%, respectively. Finally, the most potent compounds 8g and 12e showed 3.864 and 2.834 folds increase in Bax level compared to the control respectively. On the other hand, Bcl-2 was down−regulated to 0.31 and 0.415 folds compared to the control. The induction of apoptosis through increase in caspase 3 expression and down−regulation of Bcl-2 is the suggested mechanism of action.

Thiazolation of phenylthiosemicarbazone to access new thiazoles: anticancer activity and molecular docking.

Aim: Novel thiazole hybrids were synthesized via thiazolation of 4-phenylthiosemicarbazone (4). Materials & methods: The anticancer activity against the NCI 60 cancer cell line panel. Results: Methyl 2-(2-((1-(naphthalen-2-yl)ethylidene)hydrazineylidene)-4-oxo-3-phenylthiazolidin-5-ylidene)acetate (6a) showed significant anticancer activity at 10μM with a mean growth inhibition (GI) of 51.18%. It showed the highest cytotoxic activity against the ovarian cancer OVCAR-4 with an IC50 of 1.569±0.06μM. Compound 6a inhibited PI3Kα with IC50=0.225±0.01μM. Moreover, compound 6a revealed a decrease of Akt and mTOR phosphorylation in OVCAR-4 cells. In addition, antibacterial activity showed that compounds 11 and 12 were the most active against Staphylococcusaureus. Conclusion: Compound 6a is a promising molecule that could be a lead candidate for further studies.

Discovery of pyrazole-based analogs as CDK2 inhibitors with apoptotic-inducing activity: design, synthesis and molecular dynamics study.

The discovery of novel CDK2 inhibitors is crucial for developing targeted anticancer therapies. Thus, in this study, we aimed to design, synthesize, and evaluate a series of novel pyrazole derivatives (2a-g, 7a-d, 8a and b, 9, and 10) for their potential as CDK2/cyclin A2 enzyme inhibitors. The newly synthesized compounds were screened in vitro at 50 μM for CDK2 inhibition, followed by IC50 profiling of the most promising candidates. Compounds 4, 7a, 7d, and 9 exhibited the strongest inhibition, with IC50 values of 3.82, 2.0, 1.47, and 0.96 μM, respectively. To assess their anti-proliferative effects, all target compounds were further screened against a panel of 60 National Cancer Institute (NCI) cell lines representing various carcinoma types. Among them, compound 4 demonstrated exceptional anti-proliferative activity with a mean growth inhibition (GI) of 96.47% across the panel, while compound 9 showed a mean GI of 65.90%. Additionally, compounds 2b and 7c exhibited notable inhibition against MCF7 breast cancer cells, with GI rates of 86.1% and 79.41%, respectively. Compound 4 was selected for further five-dose concentration evaluations, displaying a full-panel GI50 value of 3.81 μM, with a subpanel range of 2.36-9.17 μM. Western blot analysis of compounds 4 and 9 in HCT-116 cell lines confirmed their inhibitory effects on CDK2. Furthermore, compound 4 induced significant cell cycle arrest at the G1 phase and promoted apoptosis. In silico molecular docking studies revealed that compounds 4, 7a, 7d, and 9 adopt a similar binding mode as AT7519 (I) within the CDK2 binding site. Molecular dynamics simulations further validated the stability of these compounds within the catalytic domain of CDK2. ADME/TOPKAT analyses indicated their favorable pharmacokinetic profiles, which were confirmed by their low toxicity in normal cell lines. Based on these findings, it was concluded that the synthesized pyrazole derivatives, particularly compound 4, show potent CDK2 inhibition and significant anticancer activity, with promising drug-like properties and minimal toxicity. This positions them as strong candidates for further development as CDK2-targeting anticancer agents.

Synthesis, characterization, and in vitro anticancer evaluation of 2,4 disulfonylsubstituted 5-aminothiazoles

Novel 2,4-disulfonylsubstituted 5-aminothiazoles were synthesized and their anticancer activity was assessed at a high dose (10 μM) against NCI 60 cancer cell lines. Compounds 24 and 25 showed the antiproliferative activity with mean growth inhibition about 66.0%. Replacing 4-hydroxypiperidine 24 with the more hydrophilic N-methyl piperazine 25 increased the number of sensitive cell lines while replacing these hydrophilic groups with lipophilic ones abolished the anticancer activity. The COMPARE analysis showed that the tested compounds had a moderate positive correlation with alkylating agents (CCNU and methyl CCNU) and with a purine nucleotide biosynthesis inhibitor analog (L-cysteine). The results indicate that the above mechanisms of antitumor action of standard compounds are not the main ones for the tested compounds due to the lack of a high correlation. The results of this study allow us to consider compounds 24 and 25 as a basis for their further functionalization to obtain more active compounds.

In-vitro evaluation of fungicides against Alternaria burnsii (Uppal, Patel and Kamat) causing blight of cumin (Cuminum cyminum L.)

The present investigation aimed to determine the per cent growth inhibition of different fungicides against Alternaria burnsii, the causal agent of cumin blight. The study was conducted during 2020-21 at the Experiential Unit of Plant Pathology, College of Agriculture, SKRAU, Bikaner. Using the poisoned food technique, eleven fungicides were tested at varying concentrations (100, 200, 300, and 500 ppm). After seven days of incubation, the radial growth and per cent growth inhibition of A. burnsii were measured. The results revealed that increasing the fungicide concentration led to greater inhibition of mycelium growth. Among the tested fungicides, Tebuconazole 50% + Trifloxystrobin 20% WG exhibited the highest mean inhibition (76.94%), followed by Tebuconazole 2DS (65.09%) and Pyraclostrobin 13.30% + Epoxiconazole 5% SE (58.75%). Notably, Tebuconazole 50% + Trifloxystrobin 20% WG at concentrations of 300 ppm and 500 ppm, as well as Tebuconazole 2DS at 500 ppm, demonstrated the highest effectiveness with cent per cent growth inhibition. On the other hand, Chlorothalonil showed the least mean growth inhibition (22.96%). The results demonstrated that as the fungicide concentration increased, there was a corresponding increase in the inhibition of A. burnsii growth. These findings highlight the potential effectiveness of selected fungicides, particularly Tebuconazole 50% + Trifloxystrobin 20% WG and Tebuconazole 2DS for managing cumin blight caused by A. burnsii.

Anti CD161 Antibody IMT-009 Is a Novel Immunotherapeutic Agent That Effectively Blocks the Inhibitory CLEC2D/CD161 Axis in CLEC2D+ B Cell Hematological Malignancies Reinvigorating T and NK Cell Function Leading to Anti-Tumor Benefit

Background: The CLEC2D/CD161 axis is a ligand-receptor pathway that has been shown to inhibit both T and NK cell function 1,2. CD161 is a C-type lectin-like receptor, which is expressed on NK cells and subsets of both CD4 + and CD8 + T cells. The tumor infiltrating CD161+ T cells have high cytotoxic potential and display an NK cell-like signature 2. Its ligand CLEC2D is expressed on the surface of both malignant cells and immune cells including germinal center B cells, activated T cells and tumor associated macrophages. Owing to its expression in germinal center B cells, CLEC2D is highly expressed in multiple types of B cell lymphomas including Diffuse Large B Cell Lymphoma (DLBCL), Follicular Lymphoma and Burkitt lymphoma 3. Furthermore, subset of infiltrated T cells in these lymphomas are CD161+ making this axis a promising novel target for immunotherapeutic intervention in hematological malignancies (Fig1). Immunitas has developed IMT-009, a monoclonal, Fc silent, fully human IgG1, high affinity antibody to CD161 that selectively blocks its interaction with CLEC2D. We show that IMT-009 effectively reverses CLEC2D-mediated inhibition and restores NK cell and T cell functions, including antigen specific T cell mediated cytotoxicity to lymphoma cell lines. Furthermore, IMT-009 shows monotherapy benefit in reducing tumor burden in a human B cell lymphoma model engrafted in humanized mice in vivo. IMT-009 is currently being evaluated in a Phase 1/2a clinical trial in both solid tumors and heme malignancies. Results: IMT-009 is a highly selective antibody to CD161 that strongly blocks its interaction with CLEC2D. In presence of CLEC2D-expressing target cells, NK cell degranulation, cytokine production and cellular cytotoxicity towards lymphoma tumor targets is highly suppressed which is overcome by treatment with IMT-009. Similarly, IMT-009 reversed CLEC2D-mediated inhibition and restored T cell activity (TCR signaling, cytokine production) in a Jurkat cell reporter system, and enhanced polyfunctionality of primary antigen-specific human T cells shown by secretion of TNF-α, IL-2, and IFN-γ, and direct T cell mediated cytotoxicity. IMT-009 also released CD161-mediated suppression of antigen recall response by PBMC derived effector memory CD161+ CD4+ T cells, resulting in an increased frequency of CD161+ IFN-γ+ cells and an increase in their proliferation. These data together show that IMT-009 is highly effective in overcoming CLEC2D mediated suppression of both T and NK cell functions. To prioritize indications that will likely benefit from IMT-009, we performed IHC for CLEC2D in a diverse set of tumor indications and found that B cell lymphomas of various subtypes have high CLEC2D protein expression by H score. Also, DLBCL was found to have the second highest median RNA expression of CLEC2D in TCGA. Furthermore, analysis of publicly available single-cell RNA-sequencing (scRNA-seq) data from B cell lymphoma including CNS lymphoma revealed CLEC2D to be highly expressed within the B lineage cells including the abundant malignant cell population (Fig2). KLRB1 (gene encoding for CD161) was also found to be expressed on a subset of tumor infiltrating CD4 and CD8 T cells in these datasets (Fig2). To confirm this, we tested CD161 expression in B cell lymphomas by immunofluorescence. Results showed CD161+ cells infiltrated in Hodgkin Lymphoma, and post-R-CHOP treated DLBCL, highlighting the potential sensitivity of these malignancies to IMT-009 treatment. Together, these results indicate that B cell lymphomas may exhibit an immunosuppressive environment mediated by the CLEC2D/CD161 axis. To test the anti-tumor benefit of IMT-009 in a human B cell lymphoma model, we treated CD34+ humanized mice implanted with Raji, a Burkitt lymphoma cell line with IMT-009. The group of mice treated with IMT-009 had a mean tumor growth inhibition of 35% and the anti-tumor response correlated with increased frequency of CD161+ T and NK cells. We further show that IMT-009 can synergize with Rituximab in NK cell mediated killing of B cell lymphoma cell lines in vitro. Conclusion: B cell malignancies tend to respond poorly to anti-PD-1 therapy 4,5. This lack of efficacy could be driven by a highly immunosuppressive environment mediated by the CLEC2D/CD161 axis. Our results support evaluation of IMT-009 as a novel cancer immunotherapy to disrupt CLEC2D/CD161 signaling, with strong therapeutic potential in lymphomas.

Discovery of a new potent oxindole multi-kinase inhibitor among a series of designed 3-alkenyl-oxindoles with ancillary carbonic anhydrase inhibitory activity as antiproliferative agents

An optimization strategy was adopted for designing and synthesizing new series of 2-oxindole conjugates. Selected compounds were evaluated for their antiproliferative effect in vitro against NCI-60 cell lines panel, inhibitory effect on carbonic anhydrase (CA) isoforms (hCAI, II, IX and XII), and protein kinases. Compounds 5 and 7 showed promising inhibitory effects on hCA XII, whereas compound 4d was the most potent inhibitor with low nanomolar CA inhibition against all tested isoforms. These results were rationalized by using molecular docking. Despite its lack of CA inhibitory activity, compound 15c was the most active antiproliferative candidate against most of the 60 cell lines with mean growth inhibition 61.83% and with IC50 values of 4.39, 1.06, and 0.34 nM against MCT-7, DU 145, and HCT-116 cell lines, respectively. To uncover the mechanism of action behind its antiproliferative activity, compound 15c was assessed against a panel of protein kinases (RET, KIT, cMet, VEGFR1,2, FGFR1, PDFGR and BRAF) showing % inhibition of 74%, 31%, 62%, 40%, 73%, 74%, 59%, and 69%, respectively, and IC50 of 1.287, 0.117 and 1.185 μM against FGFR1, VEGFR, and RET kinases, respectively. These results were also explained through molecular docking.

GC–MS screening of the phytochemical composition of Ziziphus honey: ADME properties and in vitro/in silico study of its antimicrobial activity

A revival interest has been given to natural products as sources of phytocompounds to be used as alternative treatment against infectious diseases. In this context, we aimed to investigate the antimicrobial potential of Ziziphus honey (ZH) against twelve clinical bacterial strains and several yeasts and molds using in vitro and computational approaches. The well-diffusion assay revealed that ZH was able to induce growth inhibition of most Gram-positive and Gram-negative bacteria. The high mean growth inhibition zone (mGIZ) was recorded in E. coli (Clinical strain, 217), S. aureus followed by E. coli ATCC 10536 (mGIZ values: 41.00 ± 1 mm, 40.67 ± 0.57 mm, and 34.67 ± 0.57 mm, respectively). The minimal bactericidal concentrations (MBCs) and minimal fungicidal concentration values (MFCs) from approximately 266.33 mg/mL to over 532.65 mg/mL. Molecular docking results revealed that the identified compounds maltose, 2-furoic acid, isopropyl ester, 2,4-imidazolidinedione, 5-(2-methylpropyl)-(S)- and 3,4,5-trihydroxytoluene, S-Methyl-L-Cysteine, 2-Furancarboxylic acid, L-Valine-N-ethoxycarbonyl, Hexanoic acid, 3,5,5-trimethyl-, Methyl-beta-D-thiogalactoside, gamma-Sitosterol, d-Mannose, 4-O-Methylmannose, 2,4-Imidazolidinedione, 5-(2-methylpropyl)- (S) were found to have good affinity for targeted receptor, respectively. Through a 100-ns dynamic simulation research, binding interactions and stability between promising phytochemicals and the active residues of the studied enzymes were confirmed. The ADMET profiling of all identified compounds revealed that most of them could be qualified as biologically active with good absorption and permeation. Overall, the results highlighted the efficiency of ZH against the tested clinical pathogenic strains. The antimicrobial potential and the potency displayed by the identified compounds could imply their further pharmacological applications. Communicated by Ramaswamy H. Sarma

Abstract 2930: ADG153, a novel masked anti-CD47 IgG1 SAFEbody, demonstrates strong in vivo anti-tumor activities in preclinical solid tumor models and preferential CD47 target engagement in the tumor microenvironment

Abstract Background: Anti-CD47 therapies have demonstrated promising clinical activities; however, expression of CD47 on many different normal human cell types, including RBCs, serves as a large antigen sink for anti-CD47 antibodies. Blocking CD47 on RBCs, such as by magrolimab, has led to anemia, requiring a priming and maintenance dosing schedule in the clinic. ADG153 is a highly differentiated masked anti-CD47 SAFEbody in IgG1 isotype with enhanced ADCC and ADCP functions, in contrast to magrolimab of IgG4 isotype that lacks ADCC and has weaker ADCP effector functions. In normal tissues, the SAFEbody masking moiety is expected to shield ADG153 from binding to CD47; however, in the presence of highly upregulated CD47 in protease-rich tumor microenvironment (TME), the masked antibody can engage dynamically with highly expressed CD47 and can be cleaved, enabling efficient binding to CD47, blocking CD47/SIRPα signaling, and triggering strong anti-tumor activities in solid tumors. Methods: The in vivo anti-tumor efficacy of ADG153 or magrolimab analog (magrolimab) was assessed across several solid tumor xenograft models. Human CD47/SIRPα knock-in mice, harboring CD47-positive xenograft tumors, were used to determine CD47 receptor occupancy (RO) on normal tissues vs. tumors following dosing with ADG153 or magrolimab. Results: ADG153 monotherapy demonstrated strong anti-tumor activities in SCID mice in multiple solid tumor xenograft models, including gastric cancer, SCLC, TNBC, and ovarian cancer models, with mean tumor growth inhibition (TGI) ranging from 75%-99%. Notably, in 2 of these models, the ADG153 efficacy was significantly stronger than that of magrolimab at the same dose level, supporting the importance of IgG1 in introducing ADCC- and ADCP-mediated solid tumor killing effects. In the human CD47/SIRPα knock-in xenograft mouse model, ADG153 and magrolimab dosing resulted in <10% and ~75% CD47 RO on RBCs, respectively. Magrolimab dosing resulted in high RO on normal tissues, but very low RO on tumors. In contrast, ADG153 treatment resulted in low RO on the majority of the normal tissues and RO higher than that achieved by magrolimab on tumors, consistent with the significantly dampened antigen sink liabilities for the masked ADG153. Conclusion: ADG153 demonstrates significantly reduced antigen sink liabilities and favorable CD47 engagement in the TME, which are highly differentiated from other anti-CD47 agents. ADG153 is locally enriched and efficiently cleaved in tumors, engages its target, and elicits potent anti-tumor activities in multiple solid tumor xenograft models. These results indicate that the ADG153 SAFEbody is a novel anti-CD47 IgG1 antibody prodrug with strong ADCC and ADCP capacities and substantially reduced liabilities, supporting its advancement into clinical development. Citation Format: Aaron Nguyen, Peng Zou, Songmao Zheng, Jianfeng Shi, Guizhong Liu, Yan Li, Felix Du, Peter Luo, Jiangchun Xu. ADG153, a novel masked anti-CD47 IgG1 SAFEbody, demonstrates strong in vivo anti-tumor activities in preclinical solid tumor models and preferential CD47 target engagement in the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2930.

Promising Antimicrobial Action of Sustained Released Curcumin-Loaded Silica Nanoparticles against Clinically Isolated Porphyromonas gingivalis.

Porphyromonas gingivalis (P. gingivalis) has always been one of the leading causes of periodontal disease, and antibiotics are commonly used to control it. Numerous side effects of synthetic drugs, as well as the spread of drug resistance, have led to a tendency toward using natural antimicrobials, such as curcumin. The present study aimed to prepare and physicochemically characterize curcumin-loaded silica nanoparticles and to detect their antimicrobial effects on P. gingivalis. Curcumin-loaded silica nanoparticles were prepared using the chemical precipitation method and then were characterized using conventional methods (properties such as the particle size, drug loading percentage, and release pattern). P. gingivalis was isolated from one patient with chronic periodontal diseases. The patient's gingival crevice fluid was sampled using sterile filter paper and was transferred to the microbiology laboratory in less than 30 min. The disk diffusion method was used to determine the sensitivity of clinically isolated P. gingivalis to curcumin-loaded silica nanoparticles. SPSS software, version 20, was used to compare the data between groups with a p value of <0.05 as the level of significance. Then, one-way ANOVA testing was utilized to compare the groups. The curcumin-loaded silica nanoparticles showed a nanometric size and a drug loading percentage of 68% for curcumin. The nanoparticles had a mesoporous structure and rod-shaped morphology. They showed a relatively rapid release pattern in the first 5 days. The release of the drug from the nanoparticles continued slowly until the 45th day. The results of in vitro antimicrobial tests showed that P. gingivalis was sensitive to the curcumin-loaded silica nanoparticles at concentrations of 50, 25, 12.5, and 6.25 µg/mL. One-way ANOVA showed that there was a significant difference between the mean growth inhibition zone, and the concentration of 50 µg/mL showed the highest inhibition zone (p ≤ 0.05). Based on the obtained results, it can be concluded that the local nanocurcumin application for periodontal disease and implant-related infections can be considered a promising method for the near future in dentistry.

Discovery of novel enasidenib analogues targeting inhibition of mutant isocitrate dehydrogenase 2 as antileukaemic agents

Mutant isocitrate dehydrogenase (IDH) 2 “IDH2m” acquires a neo-enzymatic activity reducing α-ketoglutarate to an oncometabolite, D-2-hydroxyglutarate (2-HG). Three s-triazine series were designed and synthesised using enasidenib as a lead compound. In vitro anticancer screening via National Cancer Institute “NCI” revealed that analogues 6a, 6c, 6d, 7g, and 7l were most potent, with mean growth inhibition percentage “GI%” = 66.07, 66.00, 53.70, 35.10, and 81.15, respectively, followed by five-dose screening. Compounds 6c, 6e, and 7c were established as the best IDH2R140Q inhibitors compared to enasidenib, reporting IC50 = 101.70, 67.01, 88.93, and 75.51 nM, respectively. More importantly, 6c, 6e, and 7c displayed poor activity against the wild-type IDH2, IC50 = 2928, 2295, and 3128 nM, respectively, which implementing high selectivity and accordingly safety. Furthermore, 6c was screened for cell cycle arrest, apoptosis induction, and western blot analysis. Finally, computational tools were applied to predict physicochemical properties and binding poses in IDH2R140Q allosteric site.

Design and synthesis of new series of chiral pyrimidine and purine analogs as COX-2 inhibitors: Anticancer screening, molecular modeling, and in silico studies

Two series of chiral novel compounds were designed and synthesized using a one-pot double Mannich-type reaction, with pyrimidine, purine, and purine bioisosteres as a central heterocyclic scaffold with a methylamino chain as a linear core 3a-e (formula A) or a purine nucleus as a central core bearing two vicinal phenyl and different heteroaryl moieties 5a-e (formula B). The NCI selected all the designed compounds for anticancer testing against 60 distinct human cancer cell lines. Compounds 3d and 5d demonstrated strong antitumor activity against a wide range of cancers, with mean growth inhibition of 59.61% and 44.30%, respectively. Both compounds showed the highest anticancer activity against breast cancer cell lines MCF-7 (94.62%, 99.76%) and MDA-MB-468 (85.81%, 92.64%). Interestingly, almost all leukemia cell lines were sensitive to both 3d and 5d Besides, compound 3d was sensitive to all-colon, ovarian, and prostate cancer cell lines. Additionally, the IC50 values of compounds 3d and 5d against the most sensitive leukemia (HL-60 (TB)), ovarian cancer (SK-OV-3), and breast carcinoma (MCF-7) cell lines were determined to be (3d, IC50 =11.96±2.74, 9.46±2.27, and 6.68±2.14 µM) and (5d, IC50 = 17.89±2.19, 8.89±2.50, and 8.75±1.99 µM), respectively. Both compounds exhibited strong antiproliferative activity that was nearly comparable to or half that of doxorubicin (IC50 = 12.54±2.10, 7.7±0.48, and 3.34±0.21 µM) and about 2- and 3-fold better than 5-FU (IC50 = 19.99±2.81, 21.8±2.09, and 16.79±2.18 µM). A COX-2 inhibition assay was performed to assess the target compounds' ability to inhibit COX-2. Compounds 3d and 5d displayed interesting COX-2 inhibition activity, exerting IC50 values in the nanomolar range in comparison to celecoxib (IC50 = 53.76±2.05 nM). However, compound 3d exerted higher anti-COX-2 activity, with an IC50 value of 69.79±2.14 nM, than compound 5d (89.92±2.17 nM). Further, compound 3d was able to arrest cell growth at the S and G2/M phases, indicating apoptosis induction. Moreover, the molecular docking of both compounds revealed a high affinity for the COX-2 receptor, with energy scores (S) = −6.63 and −7.00 kcal/mol, which were comparable to celecoxib (S) = −6.42 kcal/mol. Besides, in silico studies of compounds 3d and 5d revealed good pharmacokinetics profiles, physicochemical features, and drug-likeness data that were nearly identical to celecoxib.

A Comparative Study of Plant Extracts and Biocontrol Agents for Managing Alternaria burnsii in Cumin (Cuminum cyminum L.): An In-vitro Assessment

The objective of the current study was to assess the in-vitro efficacy of plant extracts and bio-agents in managing Alternaria burnsii, the causal agent of blight disease in cumin. Eleven plants extract were selected based on their availability in the local region and evaluated for antifungal activity in the laboratory for their effectiveness against A. burnsii. Plants extract was tested at four different concentrations 5%, 10%, 15% and 20% each by food poisoning technique. Additionally, four bio-agents, namely Trichoderma harzianum, T. viride, Pseudomonas fluorescens and Bacillus subtilis were evaluated against A. burnsii. The experiments were conducted from 2019 to 2021 at the Advanced Laboratory on Bioagents in the Plant Pathology Department, SKRAU, Bikaner. Among the plant extracts, Neem Seed Kernel Extract (NSKE) and Neem leaf extract were found to be the most effective, resulting in mean growth inhibition of 48.88 per cent and 45.85 per cent, respectively. The least per cent mean growth inhibition, 13.14 per cent, was recorded with Eucalyptus (Eucalyptus globulus). Among the four different bio-agents, Trichoderma harzianum was found to be the most effective in suppressing the growth of the pathogen, achieving a growth inhibition of 69.63 per cent. This study provides valuable insights into the use of locally available plant extracts and bio-agents for the management of cumin blight, promoting eco-friendly approaches.

In vitro antimicrobial efficacy of riboflavin, ultraviolet-A radiation, and combined riboflavin/ultraviolet-A radiation on ocular pathogens.

There is a lack of studies evaluating the antimicrobial effect of riboflavin and ultraviolet-A (UVA) radiation using an epithelium-off cross-linking technique (Dresden protocol) in the literature. This study aimed to demonstrate the antimicrobial properties of riboflavin and UVA radiation and combined riboflavin/UVA radiation on various ocular pathogens Dresden protocol. This was a prospective and comparative study. This study included four groups: Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Acanthamoeba. All the groups were tested 12 different times with riboflavin alone, UVA light alone, and combined riboflavin with UVA. The growth inhibition zones were measured. Descriptive statistics were expressed as mean and standard deviation. The main outcome was measurement and analysis of growth inhibition zones. The mean growth inhibition zones following riboflavin and UVA exposure were 9.70 ± 1.63 mm for P. aeruginosa and 7.70 ± 1.08 mm for S. aureus. The mean growth inhibition zones for P. aeruginosa were greater than for S. aureus (t = 2.395, P = 0.038). The mean growth inhibition zones for C. albicans and Acanthamoeba were 0. The mean growth inhibition zones following UVA exposure alone and riboflavin alone for all organisms were also 0. Combined riboflavin and UVA in the clinical dose was effective against P. aeruginosa and S. aureus but ineffective against C. albicans and Acanthamoeba. Our study shows the potential of combined riboflavin and UVA in the treatment of bacterial keratitis.

Phytochemical Analysis, Antioxidant, and Antimicrobial Activities of Ducrosia flabellifolia: A Combined Experimental and Computational Approaches.

Ducrosia flabellifolia Boiss. is a rare desert plant known to be a promising source of bioactive compounds. In this paper, we report for the first time the phytochemical composition and biological activities of D. flabellifolia hydroalcoholic extract by using liquid chromatography-electrospray tandem mass spectrometry (ESI-MS/MS) technique. The results obtained showed the richness of the tested extract in phenols, tannins, and flavonoids. Twenty-three phytoconstituents were identified, represented mainly by chlorogenic acid, followed by ferulic acid, caffeic acid, and sinapic acid. The tested hydroalcoholic extract was able to inhibit the growth of all tested bacteria and yeast on agar Petri dishes at 3 mg/disc with mean growth inhibition zone ranging from 8.00 ± 0.00 mm for Enterococcus cloacae (E. cloacae) to 36.33 ± 0.58 mm for Staphylococcus epidermidis. Minimal inhibitory concentration ranged from 12.5 mg/mL to 200 mg/mL and the hydroalcoholic extract from D. flabellifolia exhibited a bacteriostatic and fungistatic character. In addition, D. flabellifolia hydroalcoholic extract possessed a good ability to scavenge different free radicals as compared to standard molecules. Molecular docking studies on the identified phyto-compounds in bacterial, fungal, and human peroxiredoxin 5 receptors were performed to corroborate the in vitro results, which revealed good binding profiles on the examined protein targets. A standard atomistic 100 ns dynamic simulation investigation was used to further evaluate the interaction stability of the promising phytocompounds, and the results showed conformational stability in the binding cavity. The obtained results highlighted the medicinal use of D. flabellifolia as source of bioactive compounds, as antioxidant, antibacterial, and antifungal agent.