Compound 5a Research Articles

Discovery of Selective Dopamine Receptor Ligands Derived from (-)-Stepholidine via C-3 Alkoxylation and C-3/C-9 Dialkoxylation.

We evaluated C-3 alkoxylated and C-3/C-9 dialkoxylated (-)-stepholidine analogues to probe the tolerance at the C-3 and C-9 positions of the tetrahydroprotoberberine (THPB) template toward affinity for dopamine receptors. A C-9 ethoxyl substituent appears optimal for D1R affinity since high D1R affinities were observed for compounds that contain an ethyl group at C-9, with larger C-9 substituents tending to decrease D1R affinity. A number of novel ligands were identified, such as compounds 12a and 12b, with nanomolar affinities for D1R and no affinity for either D2R or D3R, with compound 12a being identified as a D1R antagonist for both G-protein- and β-arrestin-based signaling. Compound 23b was identified as the most potent and selective D3R ligand containing a THPB template to date and functions as an antagonist for both G-protein- and β-arrestin-based signaling. Molecular docking and molecular dynamics studies validated the D1R and D3R affinity and selectivity of 12a, 12b, and 23b.

Novel salicylic acid derivatives connecting to five-membered cycle through an acyl hydrazone bond as multi-stimuli responsive fluorescent smart materials with photoswitching properties

In order to exploit novel multi-stimuli responsive fluorescent materials, a series of novel fluorescent molecules of salicylic acid derivatives were designed and synthesized via introducing pyrazole or cyclopentane to the salicylic acid scaffold through a special Schiff base–acylhydrazone, and the molecular structures of representative compounds A2 and A4 were verified via single crystal X–ray diffraction. All title molecules could exhibit obvious solvatofluorochromism from cyan to indigo in several solutions with different polarity. The fluorescence titration data exhibited compound A2 and complex A2-Cu2+ with prime detection limits to Cu2+ (0.24 μM) and S2- ions (2.83 μM). The sensitive recognition of A2 to trifluoroacetic (TFA) and A2-TFA to triethylamine (TEA) were also confirmed via fluorescent titration experiments in various solutions, respectively. What’s more, the 1H NMR and UV/Vis absorption spectra further explained the mechanism between molecules and ions or molecules and TFA/TEA. Besides, the photoswitching properties of the compounds A2 and A3 could be demonstrated via the irradiation of special wavelength light or heating accompanied with changes in quantum yields. In addition, these phenomena of multiple responses were explained via Density Functional Theory (DFT) based on the Gaussian calculations. Thus, this work provided a preliminary basis for the research of multi-stimuli responsive fluorescent molecules with photoswitching properties.

Fragment merging approach for the design of thiazole/thiazolidine clubbed pyrazoline derivatives as anti-inflammatory agents: Synthesis, biopharmacological evaluation and molecular modeling studies

Fragment merging approach was applied for the design of thiazole/thiazolidinone clubbed pyrazoline derivatives 5a-e, 6a-c, 7 and 10a-d as dual COX-2 and 5-LOX inhibitors. Compounds 5a, 6a, and 6b were the most potent and COX-2 selective inhibitors (IC50= 0.03–0.06 μM, SI = 282.7–472.9) with high activity against 5-LOX (IC50 = 4.36–4.86 μM), while compounds 5b and 10a were active and selective 5-LOX inhibitors with IC50 = 2.43 and 1.58 μM, respectively. In vivo assay and histopathological examination for most active candidate 6a revealed significant decrease in inflammation with higher safety profile in comparison to standard drugs. Compound 6a exhibited the same orientation and binding interactions as the reference COX-2 and 5-LOX inhibitors (celecoxib and quercetin, respectively). Consequently, compound 6a has been identified as a potential lead for further optimization and the development of safe and effective anti-inflammatory drugs.

Development of novel salicylic acid–donepezil–rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a chronic, progressive brain degenerative disease that is common in the elderly. So far, there is no effective treatment. The multi-target-directed ligands (MTDLs) strategy has been recognised as the most promising approach due to the complexity of the pathogenesis of AD. Herein, novel salicylic acid–donepezil–rivastigmine hybrids were designed and synthesised. The bioactivity results exhibited that 5a was a reversible and selective eqBChE inhibitor (IC50 = 0.53 μM), and the docking provided the possible mechanism. Compound 5a also displayed potential anti-inflammatory effects and significant neuroprotective effect. Moreover, 5a exhibited favourable stabilities in artificial gastrointestinal solution and plasma. Finally, 5a demonstrated potential cognitive improvement in scopolamine-induced cognitive dysfunction. Hence, 5a was a potential multifunctional lead compound against AD.

Discovery of new thieno[2,3-d]pyrimidines as EGFR tyrosine kinase inhibitors for cancer treatment.

Background: EGFR has been considered a vital molecular target in cancer management. Aim: The discovery of new thieno[2,3-d]pyrimidine derivatives as EGFR tyrosine kinase inhibitors. Methods: Nine derivatives were designed, synthesized and subjected to in vitro and in silico studies. Results: Compound 7a significantly inhibited the growth of HepG2 and PC3 cells for both EGFR wild-type and EGFRT790M. Compound 7a caused a significant apoptotic effect, arresting HepG2 cells' growth in the S and G2/M phases. Docking and molecular dynamics simulation studies confirmed the correct and stable binding modes of the synthesized compounds against the active sites. Conclusion: Compound 7a is a promising dual EGFR inhibitor for cancer treatment.

Aminopyridone-linked benzimidazoles: a fragment-based drug design for the development of CDK9 inhibitors.

Aim: A fragment-based design and synthesis of three novel series of aminopyridone-linked benzimidazoles as potential anticancer candidates with significant CDK9 inhibition was implemented. Materials & methods: All synthesized compounds were submitted to National Cancer Institute 60 cell lines and seven-dose cytotoxicity toward three cancer cells. Results: Compounds 2, 4a, 4c, 4d, 6a and 8a exhibited significant cytotoxicity and selectivity with IC50 range of 7.61-57.75μM. Regarding the mechanism either in vitro or in silico, 4a, 6a and 8a displayed potent CDK9 inhibition with IC50 value of 0.424-8.461μM. Compound 6a arrested the cell cycle at S phase and induced apoptosis in MCF-7 cells. Conclusion: Compound 6a is a promising CDK9 inhibitor that warrants additional research for cancer treatment.

Phloroglucinol derivatives, coumarins and an alkaloid from the roots of Evodia lepta Merr.

Two previously undescribed phloroglucinol derivatives [(±) evolephloroglucinols A and B], five unusual coumarins [evolecoumarins A and B and (±) evolecoumarins C–E], and one novel enantiomeric quinoline-type alkaloid [(±) evolealkaloid A], along with 20 known compounds, were isolated from the EtOH extract of the roots of Evodia lepta Merr. Their structures were elucidated by extensive spectroscopic analyses. The absolute configurations of the undescribed compounds were determined by X-ray diffraction or computational calculations. Their anti-neuroinflammatory effects were assayed. Among the identified compounds, compound 5a effectively reduced nitric oxide (NO) production with an EC50 value of 22.08 ± 0.46 μM. Hence, it could indeed inhibit the lipopolysaccharide (LPS)-induced Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome.

Controlling antifungal activity with light: Optical regulation of fungal ergosterol biosynthetic pathway with photo-responsive CYP51 inhibitors.

Invasive fungal infections (IFIs) have been associated with high mortality, highlighting the urgent need for developing novel antifungal strategies. Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14α-demethylase (CYP51) inhibitors. The photocaged triazoles completely shielded the CYP51 inhibition. The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4% and 83.7%, respectively. Importantly, the shielded antifungal activity (MIC80≥64μg/mL) could be efficiently recovered (MIC80=0.5-8μg/mL) by light irradiation. The new chemical tools enable optical control of fungal growth arrest, morphological conversion and biofilm formation. The ability for high-precision antifungal treatment was validated by invivo models. The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model. Overall, this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

طريقة جديدة في تحضير مشتقات 3- ثنائي امين من الاميدازوبنزوثايازول مع دراسة فعاليتها الحيوية

In this research, new derivatives of bicyclic fused rings containing bridgehead nitrogen atom imidazo/benzothiazole were prepared from 2-aminobenzothiazole with 2-bromo-1-(4-bromophenyl)ethan-1-one to form compound A1. Then, through the Mannich reaction, compound A2 was prepared from compound A1 with formaldehyde and 4-aminoacetophenone. Schiff bases A3-A6 were prepared from condensation reaction between compound A2 with different amines. Finally, the reduction reaction was accomplished by using NaBH4 to reduce the imine group to forming new compounds A7-A10. These compounds were characterized by FTIR, 1HNMR, and 13CNMR. The prepared compounds showed biological activity against some microorganisms.

Synthesis of Novel Porphyrin Derivatives and Investigate their Application in Sensitized Solar Cells

Solar energy has significant advantages compared to conventional sources such as coal and natural gas, including no emissions, no need for fuel, and the potential for installation in a wide range of locations with access to sunlight. In this investigation, heterocyclic derivatives were synthesized from several porphyrin derivatives (4,4',4",4"'-(porphyrin-5,10,15,20-tetrayl) tetra benzoic acid) compound (3), obtained by reaction Pyrrole with 4-formyl benzoic acid. Subsequently, porphyrin derivative-component amides 5a, 5b, and 5c were produced by reacting compound (3) with amine derivatives at a 1:4 molar ratio. These derivatives exhibited varying sensitivities for utilization in solar cells, with compound 5a displaying the highest power conversion efficiency (PCE) at 1.37%, as determined by measuring the short circuit current (Jsc), open-circuit voltage (Voc), and fill factor (FF) (Jsc = 2.24 mA cm-2, Voc = 0.80 mV, FF = 76.5%). Meanwhile, compound 5c exhibited the lowest PCE at 0.94% (Jsc = 1.55 mA cm-2, Voc = 0.750 mV, FF = 76.4%).

Novel promising benzoxazole/benzothiazole-derived immunomodulatory agents: Design, synthesis, anticancer evaluation, and in silico ADMET analysis.

Eleven novel benzoxazole/benzothiazole-based thalidomide analogs were designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against HepG-2, HCT-116, PC3, and MCF-7 cells. Generally, the open analogs with semicarbazide and thiosemicarbazide moieties (10, 13a-c, 14, and 17a,b) exhibited higher cytotoxic activities than derivatives with closed glutarimide moiety (8a-d). In particular, compound 13a (IC50 = 6.14, 5.79, 10.26, and 4.71 µM against HepG-2, HCT-116, PC3, and MCF-7, respectively) and 14 (IC50 = 7.93, 8.23, 12.37, and 5.43 µM, respectively) exhibited the highest anticancer activities against the four tested cell lines. The most active compounds 13a and 14 were further evaluated for their in vitro immunomodulatory activities on tumor necrosis factor-alpha (TNF-α), caspase-8 (CASP8), vascular endothelial growth factor (VEGF), and nuclear factor kappa-B p65 (NF-κB p65) in HCT-116 cells. Compounds 13a and 14 showed a remarkable and significant reduction in TNF-α. Furthermore, they showed significant elevation in CASP8 levels. Also, they significantly inhibited VEGF. In addition, compound 13a showed significant decreases in the level of NF-κB p65 while compound 14 demonstrated an insignificant decrease with respect to thalidomide. Moreover, our derivatives exhibited good in silico absorption, distribution, metabolism, elimination, toxicity (ADMET) profiles.

Reversal of subtype-selectivity and function by the introduction of a para-benzamidyl substituent to N-cyclopropylmethyl nornepenthone

The discovery and development of novel μ-opioid receptor (MOR) antagonists is a significant area to combat Opioid Use Disorder (OUD). In this work, a series of para-substituted N-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized and pharmacologically assayed. Compound 6a was identified as a selective MOR antagonist both in vitro and in vivo. Its molecular basis was elucidated using molecular docking and MD simulations. A subpocket on the extracellular side of the TM2 domain of MOR, in particular the residue Y2.64, was proposed to be responsible for the reversal of subtype selectivity and functional reversal of this compound.

Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights

Annually, millions of new cancer cases are reported, leading to millions of deaths worldwide. Among the newly reported cases, breast and colon cancers prevail as the most frequently detected variations. To effectively counteract this rapid increase, the development of innovative therapies is crucial. Small molecules possessing pyridine and urea moieties have been reported in many of the currently available anticancer agents, especially VEGFR2 inhibitors. With this in mind, a rational design approach was employed to create hybrid small molecules combining urea and pyridine. These synthesized compounds underwent in vitro testing against breast and colon cancer cell lines, revealing potent submicromolar anticancer activity. Compound 8a, specifically, exhibited an impressive GI50 value of 0.06 μM against the MCF7 cancer cell line, while compound 8h displayed the highest cytotoxic activity against the HCT116 cell line, with a GI50 of 0.33 ± 0.042 μM. Notably, compounds 8a, 8h, and 8i demonstrated excellent safety profiles when tested on normal cells. Molecular docking, dynamic studies, and free energy calculations were employed to validate the affinity of these compounds as VEGFR2 inhibitors.

Iron mediated reductive cyclization/oxidation for the generation of chemically diverse scaffolds: An approach in drug discovery

Chemically diverse scaffolds represent a main source of biologically important starting points in drug discovery. Herein, we report the development of such diverse scaffolds from nitroarene/ nitro(hetero)arenes using a key synthetic strategy. In a pilot-scale study, the synthesis of 10 diverse scaffolds was achieved. The 1,7-phenanthroline, thiazolo[5,4-f]quinoline, 2,3-dihydro-1H-pyrrolo[2,3-g]quinoline, pyrrolo[3,2-f]quinoline, 1H-[1,4]oxazino[3,2-g]quinolin-2(3H)-one, [1,2,5]oxadiazolo[3,4-h]quinoline, 7H-pyrido[2,3-c]carbazole, 3H-pyrazolo[4,3-f]quinoline, pyrido[3,2-f]quinoxaline were obtained from nitro hetero arenes in ethanol using iron-acetic acid treatment followed by reaction under oxygen atmosphere. This diverse library is compliant with the rule of five for drug-likeness. The mapping of chemical space represented by these scaffolds revealed a significant contribution to the underrepresented chemical diversity. Crucial to the development of this approach was the mapping of biological space covered by these scaffolds which revealed neurotropic and prophylactic anti-inflammatory activities. In vitro, neuro-biological assays revealed that compounds 14a and 15a showed excellent neurotropic potential and neurite growth compared to controls. Further, anti-inflammatory assays (in vitro and in vivo models) exhibited that Compound 16 showed significant anti-inflammatory activity by attenuating the LPS-induced TNF-α and CD68 levels by modulating the NFkB pathway. In addition, treatment with compound 16 significantly ameliorated the LPS-induced sepsis conditions, and pathological abnormalities (in lung and liver tissues) and improved the survival of the rats compared to LPS control. Owing to their chemical diversity along with bioactivities, it is envisaged that new quality pre-clinical candidates will be generated in the above therapeutic areas using identified leads.

5-Nitro-3-(2-(4-phenylthiazol-2-yl)hydrazineylidene)indolin-2-one derivatives inhibit HIV-1 replication by a multitarget mechanism of action.

In the effort to identify and develop new HIV-1 inhibitors endowed with innovative mechanisms, we focused our attention on the possibility to target more than one viral encoded enzymatic function with a single molecule. In this respect, we have previously identified by virtual screening a new indolinone-based scaffold for dual allosteric inhibitors targeting both reverse transcriptase-associated functions: polymerase and RNase H. Pursuing with the structural optimization of these dual inhibitors, we synthesized a series of 35 new 3-[2-(4-aryl-1,3-thiazol-2-ylidene)hydrazin-1-ylidene]1-indol-2-one and 3-[3-methyl-4-arylthiazol-2-ylidene)hydrazine-1-ylidene)indolin-2-one derivatives, which maintain their dual inhibitory activity in the low micromolar range. Interestingly, compounds 1a, 3a, 10a, and 9b are able to block HIV-1 replication with EC50 < 20 µM. Mechanism of action studies showed that such compounds could block HIV-1 integrase. In particular, compound 10a is the most promising for further multitarget compound development.

Design and synthesis of pyrrolo[2,3-d]pyrimidine linked hybrids as α-amylase inhibitors: molecular docking, MD simulation, ADMET and antidiabetic screening.

Novel pyrrolo[2,3-d]pyrimidine-based analogues were designed, synthesized, and evaluated for their ability to inhibit the α-amylase enzyme in order to treat diabetes. In vitro antidiabetic analysis demonstrated excellent antidiabetic action for compounds 5b, 6c, 7a, and 7b, with IC50 values in the 0.252-0.281mM range. At a 200μg/mL concentration, the exceptional percent inhibition values for compounds 5a, 5b, 5d, and 6a varied from 97.79 ± 2.86% to 85.56 ± 4.13% overperforming the standard (acarbose). Molecular docking of all compounds performed with Bacillus paralicheniformis α-amylase enzyme. The most active compounds via in vitro and non-toxic via in silico ADMET and molecular docking analysis, hybrids 6c, 7a, and 7b displayed binding affinity from - 8.2 and - 8.5kcal/mol. Molecular dynamic simulations of most active compound 5b and 7a investigated into the active sites of the Bacillus paralicheniformis α-amylase enzyme for a 100-ns indicating the stability of hybrid-protein complex. Consistent RGyr values for the two complexes under study further suggest that the system's proteins are closely packed in the dynamic state. Synthesized analogs' in vitro biological assessments, ADMET, molecular docking, and MD modelling reveal that 5b, 6c, 7a, and 7b hybrid analogs may be employed in the development of future antidiabetic drugs.

New 2-aminobenzothiazole derivatives: Design, synthesis, anti-inflammatory and ulcerogenicity evaluation

Two series of twenty diversely substituted benzothiazole amides were designed and synthesized aiming to obtain derivatives with potential anti-inflammatory activity and decreased GIT ulceroginicity. All the synthesized compounds were in-vivo screened for their anti-inflammatory activity using carrageenan induced rat hind paw edema model. Results revealed that compounds 3h and 6a were the most potent ones with remarkable GIT tolerability compared to indomethacin (ED50 = 0.012, 0.016 and 0.015 mmol/kg, respectively). Moreover, compounds 3h and 6a ulcerogenic investigation proved ulcer index= 0 at the first 2 doses (0.01, 0.02 mmol/kg) and surpassing the third dose (0.03 mmol/kg) for 6a only, respectively. In vitro COX-1/COX-2 isozyme selectivity testing revealed the best selectivity index for compound 6a (SI= 3.10) among the investigated compounds compared to celecoxib (SI= 11.89), which was further confirmed with the molecular docking study.

Excited state dynamics of 1,2,4-triazolyl-thio-pentane-2,4-dione system and their conversion to biologically active novel triazole-S-pyrazole hybrids

The current study focuses on designing and synthesis of novel 1,2,4-triazole appended pyrazoles linked to each other through sulphur atom. Herein we report the condensation of nicotinic hydrazide and isonicotinic hydrazide with aryl isothiocyanate derivatives to obtain carbothioamides which are cyclised to yield 4-aryl-5-(pyridinyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives under alkaline conditions. Further, condensation of thiones with 3-chloro-pentane-2,4-dione generated novel 1,2,4-triazolyl-thio-pentane-2,4-dione system which was studied for keto-enol tautomerism with the help of spectral data (FT-IR, NMR and Mass). Low energy barrier between three different tautomers (chelated enol, keto, non-chelated enol) resulted in transformation of chelated enol ⇌ non-chelated enol ⇌ keto form upon UV-irradiation. Solvent effects on excited state intramolecular proton transfer (ESIPT) in dione 5a have been studied and the experimental findings were documented with TD-DFT studies. The generated 1,3-diketones were treated with hydrazine hydrate to obtain triazolyl-S-pyrazole hybrids 6. Structure of the synthesized compounds was identified on the basis of spectroscopic data. Single crystal X-ray diffraction (SC-XRD) studies of the representative compound 6a predicts the strong intermolecular hydrogen bonding interaction between N2H2 of pyrazole ring of one molecule and N4 of triazole ring (N2H2…N4) of the other molecule which accounts for the crystal stability. Moreover, triazolyl-S-pyrazole hybrids were also assessed for their antibacterial activities and some derivatives have shown promising activity against E. coli.

Rational Design and Identification of Novel Thiosemicarbazide Derivatives as Laccase Inhibitors.

Laccase is a key enzyme in the fungal 1,8-dihydroxynaphthalene(DHN) melanin biosynthesis pathway, which is a potential target for the control of pathogenic fungi. In our previous work, a2 was found with higher inhibition activity against laccase and antifungal activity than laccase inhibitor PMDD-5Y. The introduction of hydrogen-bonded receptors in amino part was found to be beneficial in improving laccase inhibitory activity by target-based-biological rational design. In this work, the hydrogen-bonded receptors morpholine and piperazine were introduced for structure optimization to enhancing biological activity. Enzyme activity tests indicated that all target compounds had inhibitory activity against laccase, and some compounds exhibited better activity against laccase than a2, it was further verified the introduction of hydrogen-bonded receptors in the amino portion could enhance the laccase inhibitory activity of target compounds. Most compounds showed excellent antifungal activities in vitro. Compound m14 displayed good activity against Magnaporthe. oryzae both in vitro and in vivo. The SEM analysis showed that the mycelium of M. oryzae treated with m14 were destroyed. Molecular docking revealed the binding mode between laccase and target compounds. Thirty-eight compounds were synthesized and showed good inhibitory activity against laccase, the introduction of morpholine and piperazine in amino part was beneficial to improve antifungal activity and laccase activity. Further validation of laccase as a potential target for rice blast control, while m14 can be used as a candidate compound for the control of rice blast. This article is protected by copyright. All rights reserved.

Exploring Pyrrolo-Fused Heterocycles as Promising Anticancer Agents: An Integrated Synthetic, Biological, and Computational Approach.

Five new series of pyrrolo-fused heterocycles were designed through a scaffold hybridization strategy as analogs of the well-known microtubule inhibitor phenstatin. Compounds were synthesized using the 1,3-dipolar cycloaddition of cycloimmonium N-ylides to ethyl propiolate as a key step. Selected compounds were then evaluated for anticancer activity and ability to inhibit tubulin polymerization in vitro. Notably, pyrrolo[1,2-a]quinoline 10a was active on most tested cell lines, performing better than control phenstatin in several cases, most notably on renal cancer cell line A498 (GI50 27 nM), while inhibiting tubulin polymerization in vitro. In addition, this compound was predicted to have a promising ADMET profile. The molecular details of the interaction between compound 10a and tubulin were investigated through in silico docking experiments, followed by molecular dynamics simulations and configurational entropy calculations. Of note, we found that some of the initially predicted interactions from docking experiments were not stable during molecular dynamics simulations, but that configurational entropy loss was similar in all three cases. Our results suggest that for compound 10a, docking experiments alone are not sufficient for the adequate description of interaction details in terms of target binding, which makes subsequent scaffold optimization more difficult and ultimately hinders drug design. Taken together, these results could help shape novel potent antiproliferative compounds with pyrrolo-fused heterocyclic cores, especially from an in silico methodological perspective.