Compound IId Research Articles

Synthesis and Preliminary Biological study of New Chalcone Derivatives Containing Isoxazoline Moiety

In this research work, synthesis, antimicrobial and antioxidant bioactivity of a chain of compounds having unsaturated ketones bond and isoxazoline moiety have been described. New chalcone derivatives containing isoxazoline moiety have been synthesized. Generally, Chalcones are unsaturated ketones bearing (-CO-CH=CH-) as reactive ketoethylenic group that give the bright yellow colored compounds due to this chromophore group. Firstly, chalcones (IIa-d) have been prepared by cyclocondensation (Claisen-Schmidt condensation) of triphenyl aminobenzaldehyde with different substituted acetophenone in ethyl alcohol to produce a series of chalcones compounds with bright yellow colored as a starting material,. The next step involving the novel chalcones (IIa-d) reacted with hydroxylamine hydrochloride afforded a new isoxazoline compounds (IIIa-d) in basic medium. The prepared compounds were fully characterized by melting points, FTIR, 1H-NMR spectroscopy, 13 C-NMR for some compounds and CHNS techniques. The reactions have been monitored by TLC (Thin Layer Chromatography) technique. The synthesised compound IId showed significant bioactivity against the gram-negative bacteria species. Also, the antioxidant activity of the some new synthesized compounds was evaluated and determined against the DPPH radical (1.1-diphenyl-2-picrylhydrazyl) and compared to that of a standard natural antioxidant, Ascorbic acid, compound IIb showed higher antioxidant activity by using the free radical DPPH. The outcomes of investigation enhanced the activity of new derivatives as antimicrobial reagent.

Design, synthesis, explorations of DFT, PM6, molecular docking with SAR-CoV-2 Mpro and anticancer properties of novel indolo[2,3-c]isoquinoline analogues

A novel series of indolo[2,3-c]isoquinoline derivatives, coupled with pyrazole and pyrazolo[3,4-d]pyrimidinone rings bearing substituted Cl, OCH3, CH3, and H groups II, II(a-d), were successfully synthesized, exhibiting significant biological and pharmacological relevance. Computational chemistry using the semiempirical method PM6 via MOPAC software was employed to investigate their thermochemical properties. Compound IIIb displayed a lower heat formation (ΔHf) value of 68.89873 kcal/mole, indicating enhanced stability, whereas compound IId exhibited a higher ΔHf value of 151.32004 kcal/mole, suggesting lesser stability. Density functional theory (DFT) at B3LYP/def2-TZVP def2/J was utilized for analyzing electronic structures and geometric optimization. The HOMO-LUMO energy gap (ΔEg) followed an ascending order in the pyrimidinone>pyrazole series, with IIIb possessing the lowest energy gap (ΔEg = 2.994 eV) and IIc having the highest (ΔEg = 3.433 eV). Compound IIa displayed the highest electrophilicity index (χ = 3.540 eV) and exhibited potent anti-cancer activity, as observed in derivatives II and III(a-d). Additionally, compounds IIa, IIb, and IIc demonstrated promising interactions with amino acids of the SARS-CoV-2 main protease (PDB:7e18).

Discovery of novel peptide–dehydroepiandrosterone hybrids inducing endoplasmic reticulum stress with effective in vitro and in vivo anti-melanoma activities

Steroid hybrids have emerged as a type of advantageous compound as they could offer improved pharmacological and pharmaceutical properties. Here, we report a series of novel peptide–dehydroepiandrosterone hybrids, which would effectively induce endoplasmic reticulum stress (ERS) and lead to apoptosis with outstanding in vitro and in vivo anti-melanoma effects. The lead compound IId among various steroids conjugated with peptides and pyridines showed effective in vivo activity in B16 xenograft mice: in medium- and high-dose treatment groups (60 and 80 mg/kg), compound IId would significantly inhibit the growth of tumours by 98%–99% compared to the control group, with the highest survival rate as well. Further mechanism studies showed that compound IId would damage the endoplasmic reticulum and upregulate the ERS markers C/EBP homologous protein (CHOP) and glucose-regulated protein 78 (GRP78), which could further regulate caspase and Bcl-2 family proteins and lead to cell apoptosis. The compound IId was also proven to be effective in inhibiting B16 cell migration and invasion.

Synthesis and Biological Activity Evaluation of Novel Chalcone Analogues Containing a Methylxanthine Moiety and Their N-Acyl Pyrazoline Derivatives.

On the basis of the structures of natural methylxanthines and chalcone, a series of novel chalcone analogues containing a methylxanthine moiety, Ia-Ig, and their N-acyl pyrazoline derivatives IIa-IIz and IIaa-IIaf were synthesized and identified through melting points, 1H NMR, 13C NMR, and HRMS. The single crystal of compound IId was obtained, which further illustrated the structural characteristics of the methylxanthine-acylpyrazoline compounds. The biological tests showed that some of them displayed favorable insecticidal activities toward Plutella xylostella L. and were superior to the natural methylxanthine compound caffeine while being comparable with the insecticide triflumuron (e.g., compound Ic: LC50 = 16.8508 mg/L, IIf: LC50 = 1.5721 mg/L, against P. xylostella). Of these compounds, Ic, IIf, and IIu could serve as novel insecticidal leading structures for further study. Some of the compounds showed good fungicidal activities (e.g., compound Ig: EC50 = 14.74 μg/mL, against Rhizoctonia cerealis; IIf: EC50 = 7.06 μg/mL, against Physalospora piricola; IIac: EC50 = 5.37 and 8.19 μg/mL, against Phytophthora capsici and Sclerotinia sclerotiorum, respectively); Ic, Ig, IIa, IIf, IIr, IIs, IIv, IIac, and IIaf could be novel fungicidal leading compounds for further exploration. Furthermore, most of the tested compounds exhibited apparent herbicidal activities against Brassica campestris at a concentration of 100 μg/mL; among others, compound IIa was the best one both toward Brassica campestris and Echinochloa crusgalli and deserves further investigation. The structure-activity relationships of these compounds were also summarized and discussed in detail. The contrast experiment results of compounds C-1 and C-2 showed a positive effect on the biological activity enhancement from the combination of the methylxanthine moiety with the N-dichloroacetyl phenylpyrazoline skeleton. In addition, two 3D-QSAR models with predictive capability were constructed based on the insecticidal and fungicidal activities to afford deep insight into the bioactivity profiles of these compounds. This research provides useful guidance and reference for the discovery and development of novel xanthine natural product-based pesticides.

Characterization and Investigation of Novel Benzodioxol Derivatives as Antidiabetic Agents: An In Vitro and In Vivo Study in an Animal Model.

In this study, we synthesized benzodioxol carboxamide derivatives and investigated their antidiabetic potential. The synthesized compounds (Ia-Ic and IIa-IId) underwent characterization via HRMS, 1H-, 13CAPT-NMR, and MicroED. Their efficacy against α-amylase was assessed in vitro, while MTS assays were employed to gauge cytotoxicity across cancer and normal cell lines. Additionally, the antidiabetic impact of compound IIc was evaluated in vivo using a streptozotocin-induced diabetic mice model. Notably, IIa and IIc displayed potent α-amylase inhibition (IC50 values of 0.85 and 0.68 µM, respectively) while exhibiting a negligible effect on the Hek293t normal cell line (IC50 > 150 µM), suggesting their safety. Compound IId demonstrated significant activity against four cancer cell lines (26-65 µM). In vivo experiments revealed that five doses of IIc substantially reduced mice blood glucose levels from 252.2 mg/dL to 173.8 mg/dL in contrast to the control group. The compelling in vitro anticancer efficacy of IIc and its safety for normal cells underscores the need for further in vivo assessment of this promising compound. This research highlights the potential of benzodioxol derivatives as candidates for the future development of synthetic antidiabetic drugs.

SYNTHESIS, CHARACTERIZATION, MOLECULAR DOCKING AND ANTIMICROBIAL EVALUATION OF AZO COUPLED – 3, 4- DIHYDROPYRIMIDINE-2(1H)-ONE DERIVATIVES

A series of 5-acetyl-4-[(4-substituted phenyl) diazinyl) phenyl]- 6-methyl-3, 4-dihydropyrimidine-2(1H)-one derivatives were synthesised via the coupling reaction between 4- substituted-3, 4- dihydropyrimidine-2(1H)-one and diazonium salt of p-nitro aniline. All the synthesised compounds were structurally elucidated by elemental analysis and IR, 1H NMR and Mass spectral techniques. Investigation of antibacterial and antifungal activity was done on titled compounds using disc diffusion method. Moderate inhibitory activity were displayed by compounds IIa, IId against bacterial strains such as Escherichia coli, Staphylococcus aureus and fungal strains Candida albicans, Aspergillus niger at a concentration range from 400-800µg/ml. Antimicrobial activity of the compounds may be due to the presence of electron donating substituent on phenyl ring attached at fourth position of dihydropyrimidinones. Molecular docking investigation of synthesised compounds performed with bacterial DNA gyrase B which showed that the compound IIa had the binding affinity of -8.3kcal/mol and the compound IId had the binding energy of -9.1 kcal/mol against fungal sterol-14α-demethylase which further supported the biological activity.

Non-food bioactive products for pesticides candidates (III): Agricultural properties of isoxazole esters from the plant product podophyllotoxin as botanical pesticides

Due to their structural diversity and biological characteristics, natural products appear to be received much attention as lead compounds. Podophyllotoxin, a naturally sustainable aryltetralin lignan, is isolated from the roots and rhizomes of Podophyllum hexandrum. To discover new potentially natural product-based pesticidal agents, a series of isoxazole esters were regioselectively prepared by structural modification of podophyllotoxin. Compared with their precursor podophyllotoxin, compounds IId, IIIc and IIId exhibited the potent insecticidal activity, and compounds IIb, IIc, IIIc and IIId showed the pronounced acaricidal activity; especially compounds IIIc (X = Cl, R = 4-ClC6H4) and IIId (X = Cl, R = 4-FC6H4) exhibited the most promising pesticidal activities against Mythimna separata Walker and Tetranychus cinnabarinus Boisduval.

Синтез, антидепрессивная активность и прогноз токсических рисков 3-алкокси(сульфанил)тиетан-1,1-диоксидов

Реакциями 3,5-дибром-1-(1,1-диоксотиетанил-3)-1,2,4-триазола с алкоголятами и тиоалкоголятами натрия синтезирован ряд 3-алкилокси(сульфанил)тиетан-1,1-диоксидов. В изученных дозах, эквимолярных 10 мг/кг амитриптилина, соединения IIa (2 мг/кг) и IIh (6 мг/кг) проявляли антидепрессивно-подобный эффект, соединения IId (2 мг/кг) и IIb (2 и 5,7 мг/кг) оказывали действие, предположительно, связанное с анксиолитическими свойствами. Прогнозирование токсических рисков, «drug-likeness» молекул и их физико-химических свойств в программах «Osiris DataWarrior» и «Osiris property explorer» показало, что соединения не должны оказывать негативного влияния на репродуктивную функцию и обладать онкогенными, мутагенными и раздражающими свойствами.

Synthesis, Crystal Structure, and Studies on Mechanism of D-π-A Ferrocene Derivative

Microwave-assisted solvent-free synthesis of new (D-π-A) chromogenes, 2-ferrocenyl-1,1-dicyanobuta-1,3-diene derivatives (II), have been accomplished through the condensation of 2-(1-ferrocenylethylidene)malononitrile (I) and aromatic aldehydes with sarcosine as the catalyst and identified by 1H NMR, 13C NMR and FT-IR. Compound IId was determined by X-ray crystallography (CIF file CCDC no. 1056735). The crystal belongs to monoclinic, space group P21/c. The possible reaction mechanism has been studied.

Синтез, антидепрессивная активность и прогноз <i>in silico</i> фармакокинетических и токсикологических свойств 3-замещенных тиетан-1,1-диоксидов

3-Арилокси- и 3-фенилсульфанилтиетан-1,1-диоксиды синтезированы реакциями 3,5-дибром-1-(1,1-диоксотиетанил-3)-1,2,4-триазола с фенолятами и тиофенолятом натрия. 5-Арилокси- и 5-арилсульфонил-3-бром-1-(1,1-диоксотиетанил-3)-1,2,4-триазолы синтезированы окислением 5-арилокси- и 5-фенилсульфанил-3-бром-1,2,4-триазолов, содержащих тиетановый или тиетаноксидный циклы, пероксидом водорода. Среди изученных 3-замещенных тиетан-1,1-диоксидов антидепрессивные свойства, сравнимые с имипрамином, проявило соединение IIг (2 и 20 мг/кг) в тестах подвешивания за хвост (TST) и принудительного плавания (FST), для которого спрогнозировано («Osiris Property Explorer», «Molinspiration») отсутствие токсических рисков (мутагенность, онкогенность, раздражающее действие, репродуктивная токсичность) и удовлетворительные фармакокинетические характеристики (соответствие «правилу пяти» Липинского).

Synthesis and Fungicidal Activity of N-(2,4,5-trichlorophenyl)-2-Oxo-and 2-Hydroxycycloalkylsulfonamides

A series of N-(2,4,5-trichlorophenyl)-2-Oxo- and 2-Hydroxycycloalkyl- sulfonamides (series II and III) were designed and synthesized based on the leading compound chesulfamide (code name: CAUWL-2004-L-13). Their structures were confirmed by 1H NMR, IR and elemental analysis. Compounds II and III showed excellent activities against the Botrytis cinerea both in vitro and in vivo. Mycelia growth and conidial germination assays exhibited that EC50 of compound IId were 0.64 μg mL-1 and 0.34 μg mL-1 respectively. For in vivo control of B. cinerea in cucumber seedlings, compounds IIb and IId showed better control effect than the commercial fungicides procymidone and pyrimethanil. In addition, these new compounds had broader fungicidal spectra than chlorothalonil. The fungicidal activity was affected obviously by the size of cycloalkane. All the compounds with six-, seven-, and eight-membered ring showed high fungicidal activities.

Design, Synthesis and Antiproliferative Activity of 2-Acetamidothiazole-5- carboxamide Derivatives

In order to develop a new series of dual inhibitors of SRC and ABL, and to investigate whether the pyrimidin- 4-ylamino moiety is critical for dasatinib's activity, acetyl substitution was adopted as alternate scaffold at the 2-amino group. Eighteen novel dasatinib derivatives were developed by a parallel synthesis approach and evaluated for their antiproliferative effects. Preliminary tests showed that some of the target compounds IId, IIe and IIf manifested strong antiproliferative activity against MCF-7, MDA-MB 231 and HT-29 cells. Easpecially IId proved to be the most potent compound. Structure-activity relationship studies indicate that the introduction of acetyl substitution as alternate scaffold of pyrimidin-4-ylamino reduced the activity.

Inhibitory effect of glycyrrhetinic acid derivatives on arachidonic acid-induced mouse ear oedema.

The inhibitory effects of glycyrrhetinic acid and its derivatives were examined on arachidonic acid (AA)-induced ear oedema in mice. Of the compounds, dihemiphthalate derivatives of 18 beta-olean-12-ene-3 beta, 30-diol (IId, IId'), 18 beta-olean-9(11)12-diene-3 beta, 30-diol (IIIa, IIIa') and olean-11, 13(18)-diene-3 beta, 30-diol (IVa, IVa') showed a strong inhibition of ear oedema on both tropical (ID50, 1.9, 2.8 and 1.7 mg/ear, respectively) and oral (ID50, 90, 130 and 88 mg kg-1, respectively) administration. Topical ID50 values were approximately the same potency as nordihydroguaiaretic acid (ID50, 2.1 mg/ear). Given topically these compounds were also capable of inhibiting PGE2 and LTC4 formation at an early stage of AA-induced ear oedema. However, glycyrrhetinic acid (Ia) and deoxoglycyrrhetol (IIa), the fundamental skeletons of the derivatives, showed no detectable inhibition of oedema at a dose of 1 mg/ear (topical) or 200 mg kg-1 (oral). The most effective time for the topical administration of the compound IId against ear oedema was 0-30 min before AA application; this is different from dexamethasone which requires a time lag for reaction. The results suggest that the inhibitory effect of the hemiphthalate compounds (IId, IId', IIIa, IIIa', IVa and IVa') is a direct action, and does not involve the anti-inflammatory action of steroids mediated by the secondary formation of a reactive protein.

Synthesis and Fungicidal Activities of 4,5-Dihydro-7H-pyrano[3,4-c]isoxazole Derivatives.

4,5-Dihydro-7H-pyrano[3,4-c]isoxazoles (II and III) with an o-chlorophenyl or p-chlorophenyl group at C-7 were synthesized and the effect of substitution at C-3 of II and III on fungicidal activity was investigated in vivo. When the substituent at C-3 of II and III was CH2Br, CH=NOMe, CH=NOEt or CH=NO-allyl, the fungicidal effect was significant and selectively high on wheat leaf rust and barley powdery mildew at 250 ppm. Compound IId with the CH2Br substituent at C-7 showed high fungicidal activity against rice blast, providing more than 90% control of the disease at 2 ppm.

Potential neuroleptics of the orthopramide series; Synthesis of N-(3-(tert.amino)propyl)-5-sulfamoyl-2-methoxybenzamides

Heating ethyl 5-sulfamoyl-2-methoxybenzoate with a series of twelve 3-(tert.amino)propylamines (IIIa-IIIl) afforded the title compounds IIa-IIl which were transformed to salts and subjected to pharmacological screening as potential neuroleptics of the sulpiride series. Only compounds IId (hydrogen oxalate, VUFB-15 453) and IIg (methanesulfonate, VUFB-15 397) showed indications of the desired psychotropic activity.

On the Active Site of α-Chymotrypsin: CYCLIZED AND NONCYCLIZED SUBSTRATES WITH TETRASUBSTITUTED α CARBON ATOMS

Abstract Cyclized α-tetrasubstituted substrates, 1-keto-3-methyl-3-carbomethoxytetrahydroisoquinoline, designated as Compound II-C, and methyl 3-methyl-3,4-dihydroisocoumarin-3-carboxylate, designated as Compound II-D, are hydrolyzed by α-chymotrypsin readily and highly stereospecifically in the R-D sense, kcat/Km = 1.8/0.0054 = 330 m-1 sec-1 and 2.7/0.0083 = 320 m-1 sec-1, respectively. The results indicate that d-cyclized substrates associate with the enzyme with the hetero ring at the α-hydrogen position, (h); the α-tetrasubstituted cyclized compounds place the α-methyl group at the l-α-acetamido site. Compounds II-C and II-D are less reactive by factors of 60 and 70 than the corresponding α-trisubstituted cyclized substrates. Factors of 9 and 20, respectively, may arise from the effect of the α-methyl group on the nonenzymic hydrolytic reactivity. The remaining factors are due to minor effects of the methyl group on Km. Noncyclized α-tetrasubstituted substrates, methyl N-acetyl-α-methyl-phenylalaninate, designated as Compound I-C, and methyl α-methyl-α-acetoxy-β-phenylpropionate, designated as Compound I-E, are inert to α-chymotrypsin, largely because they may place neither α substituent readily at h. However RS methyl α-methyl-β-phenyllactate, designated as Compound I-D, is a noncyclized α-tetrasubstituted compound which is hydrolyzed by α-chymotrypsin, kcat/ Km = 0.47/0.014 = 35 m-1 sec-1. It is hydrolyzed preferentially in the R-D sense like the cyclized compounds because, of the two α substituents, the α-hydroxyl is better accommodated at h. Interaction at the h part of the active site is with methionine 192. Absolute configurations of α-tetrasubstituted cyclized compounds are assigned by the proposed orientation in the active site and by optical rotatory dispersion correlations. Configurations of I-D and II-D are correlated by stereospecific conversion of I-D to II-D.