Synthesis and evaluation of bile acid amides of $$\alpha $$-cyanostilbenes as anticancer agents

A series of amino-substituted \(\alpha \)-cyanostilbene derivatives and their bile acid (cholic and deoxycholic acid) amides were designed and synthesized. A comparative study on the anticancer and antibacterial activity evaluation on the synthesized analogs was carried against the human osteosarcoma (HOS) cancer cell line, and two gram ?ve (E. coli and S. typhi) and two gram \(+\)ve (B. subtilis and S. aureus) bacterial strains. All the cholic acid \(\alpha \)-cyanostilbene amides showed an \(\hbox {IC}_{50}\) in the range 2–13 \(\upmu \hbox {M}\) against human osteosarcoma cells (HOS) with the most active analog (6g) possessing an \(\hbox {IC}_{50}\) of \(2\,\upmu \hbox {M}\). One of the amino-substituted \(\alpha \)-cyanostilbene, 4e, was found to possess an \(\hbox {IC}_{50}\) of \(3\,\upmu \hbox {M}\). An increase in the number of cells at the sub-\(\hbox {G}_{1}\) phase of the cell was observed in the in vitro cell cycle analysis of two most active compounds in the series (4e, 6g) suggesting a clear indication toward induction of apoptotic cascade. With respect to antibacterial screening, amino-substituted \(\alpha \)-cyanostilbenes were found to be more active than their corresponding bile acid amides. The synthesized compounds were also subjected to in silico study to predict their physiochemical properties and drug-likeness score.     

Conventional and microwave-assisted synthesis of new indole-tethered benzimidazole-based 1,2,3-triazoles and evaluation of their antimycobacterial,antioxidant and antimicrobial activities

A new series of triheterocycles containing indole–benzimidazole-based 1,2,3-triazole hybrids have been synthesized in good yields via a microwave-assisted click reaction. All the compounds were characterized by IR, \(^{1}\hbox {H}\) NMR, \(^{13}\hbox {C}\) NMR and mass spectroscopy and were evaluated for their in vitro antitubercular activity against the Mycobacterium tuberculosis H37Rv strain. Compounds 4b, 4h and 4i displayed highly potent antitubercular activity with MIC 3.125–6.25 \(\upmu \hbox {g}/\hbox {mL}\). The antioxidant potential was evaluated using 2,2-diphenyl-1-picryl hydrazine and \(\hbox {H}_{2}\hbox {O}_{2}\) radical scavenging activity, and compounds 4e,4f and 4g showed excellent radical scavenging activity with \(\hbox {IC}_{50}\) values in the range of 08.50–10.05 \(\upmu \hbox {g}/\hbox {mL}\). Furthermore, the compounds were evaluated for antimicrobial activity against numerous bacterial and fungal strains, and compounds 4b, 4c and 4h were found to be the most promising potential antimicrobial molecules with MIC 3.125–6.25 \(\upmu \hbox {g}/\hbox {mL}\).     

Synthesis of first ever 4-quinolone-3-carboxylic acid-appended spirooxindole-pyrrolidine derivatives and their biological applications

A series of 4-quinolone-3-carboxylic acid-containing spirooxindole-pyrrolidine derivatives was synthesized via multicomponent 1,3-dipolar cycloaddition reactions of azomethine ylides with new (E)-4-oxo-6-(3-phenyl-acryloyl)-1,4-dihydroquinoline-3-carboxylic acids in good yields with high regioselectivity. The cycloadducts were characterized by analytical and spectral data including \(^{1}\hbox {H}\), \(^{13}\hbox {C}\), 2D NMR and mass spectroscopy. The structure of one of the compounds (8a) was investigated theoretically by computational techniques. DFT studies support the proposed mechanism for this cycloaddition reaction. Furthermore, antibacterial activities of the new compounds were evaluated against Gram-positive and Gram-negative bacterial strains. Compounds 8f, 8m and 8p showed potent inhibition activities against selected bacteria. The in vitro cytotoxicity of spirooxindole derivatives (8a–r) was evaluated against MCF-7 breast cancer cell line. Among the various compounds tested, compound 8f \((\hbox {IC}_{50} = 18.35~\upmu \hbox {M})\) showed significant cytotoxic activity compared to the standard drug doxorubicin \((\hbox {IC}_{50 }= 15.00~\upmu \hbox {M})\).     

Synthesis of novel 7-aryl and 7-spiropyrazolo[4′,3′:5,6]pyrido[2,3-<Emphasis Type="BoldItalic">d</Emphasis>]pyrimidine derivatives and their study as AChE inhibitors

An efficient route for the synthesis of novel 7-aryl and 7-spiropyrazolo[4\(^{\prime }\),3\(^{\prime }\):5,6]pyrido[2,3-d]pyrimidine derivatives is described. These compounds were obtained by a cyclocondensation reaction between pyrazolopyridinediamines 4 and aldehydes 5 or cyclic ketones 6 in the presence of acetic acid as catalyst. This procedure provides the desired compounds in good yields under a simple two-step methodology. The obtained compounds were evaluated as AChE inhibitors and showed weak AChe inhibition with \(\hbox {IC}_{50} = 115{-}470 \, \upmu \hbox {M}\).     

Design,synthesis, in silico and biological evaluation of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)hydrazine carboxamides

A series of novel 2-(4-(4-substituted piperazin-1-yl)benzylidene)hydrazinecarboxamide derivatives has been successfully designed and synthesized to evaluate their potential as carbonic anhydrase (CA) inhibitors. The inhibitory potential of synthesized compounds against human CAI and CAII was evaluated. Compounds 3a–n exhibited \(\hbox {IC}_{50}\) values between \(1.89{-}415.1\,\upmu \hbox {M}\) against CAI and \(0.62{-}66.9\,\upmu \hbox {M}\) against CAII. Compound 3g was the most active inhibitor, with an \(\hbox {IC}_{50}\) value of \(0.62\,\upmu \hbox {M}\) against CAII. Molecular docking studies of compound 3g with CAII showed this compound fits nicely in the active site of CAII and it interacts with the zinc ion (\(\hbox {Zn}^{2+}\)) along with three histidine residues in the active site. Molecular dynamics simulation studies of compound 3g complexed with CAII also showed essential interactions which were maintained up to 40 ns of simulation. In vivo sub-acute toxicity study using 3g (300 mg/kg) was found non-toxic in adult Wistar rats.     

Synthesis,in vitro $$\alpha $$-glucosidase inhibitory activity,and in silico study of ( E)-thiosemicarbazones and ( E)-2-(2-(arylmethylene)hydrazinyl)-4-arylthiazole derivatives

This study is focused on the identification of thiazole-based inhibitors for the \(\alpha \)-glucosidase enzyme. For that purpose, (E)-2-(2-(arylmethylene)hydrazinyl)-4-arylthiazole derivatives were synthesized in two steps and characterized by various spectroscopic techniques. All derivatives and intermediates were evaluated for their in vitro \(\alpha \)-glucosidase inhibitory activity. Thiosemicarbazones 20 and 35, and cyclized thiazole derivatives 2, 5–11, 13, 15, 21–24, 27–31, and 36–37 showed significant inhibitory potential in the range of \(\hbox {IC}_{50}=6.2\pm 0.19\)–\(43.6\pm 0.23~\upmu \hbox {M}\) as compared to standard acarbose (\(\hbox {IC}_{50}=37.7\pm 0.19~\upmu \hbox {M}\)). A molecular modeling study was carried out to understand the binding interactions of compounds with the active site of enzyme.     

Synthesis and preliminary biological evaluations of (+)-isocampholenic acid-derived amides

The synthesis of two novel (+)-isocampholenic acid-derived amines has been realized starting from commercially available (1S)-(+)-10-camphorsulfonic acid. The novel amines as well as (+)-isocampholenic acid have been used as building blocks in the construction of a library of amides using various aliphatic, aromatic, and amino acid-derived coupling partners using BPC and CDI as activating agents. Amide derivatives have been assayed against several enzymes that hold potential for the development of new drugs to battle bacterial infections and Alzheimer’s disease. Compounds 20c and 20e showed promising selective sub-micromolar inhibition of human butyrylcholinesterase \((h\hbox {BChE})\) (\(\hbox {IC}_{50}\) values \(0.80\,\pm 0.05\) and \(0.25\,\pm 0.02\,{\upmu }\hbox {M}\), respectively).     

Synthesis and three-dimensional quantitative structure-activity relationship study of quinazoline derivatives containing a 1,3,4-oxadiazole moiety as efficient inhibitors against <Emphasis Type="BoldItalic">Xanthomonas axonopodis pv. citri</Emphasis>

A series of quinazoline derivatives containing a 1,3,4-oxadiazole moiety were synthesized and evaluated for their antibacterial activities against Xanthomonas axonopodis pv. citri (Xac) and Ralstonia solanacearum (Rs). Antibacterial bioassays indicated that most of target compounds exhibited significant antibacterial activities against Xac and Rs in vitro. Strikingly, compounds 6d–6i, 6m–6r and 6u–6x showed antibacterial activity against Xac, with \(\hbox {EC}_{50}\) values ranging from 14.42 to 38.91 \(\upmu \)g/mL, which are better than that of bismerthiazol (39.86 \(\upmu \)g/mL). Based on the antibacterial activity against Xac, comparative molecular filed analysis and comparative molecular similarity index analysis models were generated to investigate the structure-activity relationship of title compounds against Xac. The analytical results indicated that the above models exhibited good predictive accuracy and could be used as practical tools for guiding the design and synthesis of more potent quinazoline derivatives containing a 1,3,4-oxadiazole moiety.     

Synthesis of substituted 2<Emphasis Type="Italic">H</Emphasis>-chromenes by a three-component reaction as potential antioxidants

A series of alkoxy-substituted 2H-chromenes were synthesized by a one-pot three-component reaction using salicylaldehydes, acetyl acetone and alcohol as reactant and medium with tetra-n-butylammonium fluoride (TBAF) as catalyst. Simple reaction conditions, short reaction time and overall good yield of products make this synthetic strategy an efficient one to synthesize 2H-chromene molecules. All the synthesized compounds were evaluated for antioxidant activities. Among all the new compounds, 5j and 5k showed good inhibition \((70.41\, \pm \, 0.14\) and \(64.71\, \pm \, 1.02\%\)) at 100 \(\upmu \hbox {g/mL}\) concentrations.     

Synthesis of new quinazolin-2,4-diones as anti-<Emphasis Type="Italic">Leishmania mexicana</Emphasis> agents

The quinazolin-2,4-dione moiety is found in many compounds with important biological activities making it a target for its synthesis. In this work, a one-pot three-step synthesis of new quinazolin-2,4-diones from phthalic anhydrides and their activity against Leishmania mexicana are described. The new quinazolin-2,4-diones were isolated with yields in the range of 32–70 %. All compounds displayed lower cytotoxicity in RAW 264.7 macrophage over miltefosine. Compound 6,7-dichloro-3-phenylquinazoline-2,4(1H,3H)-dione (6e) displayed an attractive profile which includes anti-Leishmania mexicana activity (\(\hbox {IC}_{50} = 6.05\) \(\upmu \)M), much lower cytotoxic activity (\(\hbox {CC}_{50} = 111\) \(\upmu \)M) and a high selective index (\(\text {SI} = 18.35\)) proving to be superior to miltefosine.     

Design and one-pot synthesis of 2-thiazolylhydrazone derivatives as influenza neuraminidase inhibitors

Two series of novel 2-thiazolylhydrazone derivatives were designed and synthesized via one-pot reaction of benzaldehyde derivatives, \(\alpha \)-haloketones and thiosemicarbazide. The structures of compounds 1 and 2 were characterized by \(^{1}\hbox {H}\) NMR and \(^{13}\hbox {C}\) NMR, and compound 1g was further confirmed by X-ray crystallography. All of the target compounds were evaluated for their NA inhibitory activity against influenza viral neuraminidase (H1N1) in vitro, and the results showed that many compounds exhibited moderate to strong inhibitory activities against influenza viral neuraminidase (H1N1). Among them, compounds 1p, 1q and 2c showed the most potent inhibitory activities with \(\hbox {IC}_{50}\) values ranging from 10.50 to \(13.75\, \upmu \hbox {g}/\hbox {mL}\). Our structure–activity relationship analysis indicated that 2-thiazolylhydrazone is an effective scaffold for NA inhibitors and that introducing an ethoxycarbonyl group to the 5-position of thiazole ring could enhance inhibitory potency. Molecular docking was performed on the most active compounds 1p and 2c to provide more insight into their mechanism of interaction.     

Synthesis and antifungal activity of dehydroabietic acid-based 1,3,4-thiadiazole-thiazolidinone compounds

In an attempt to search for new natural products-based antifungal agents, a series of novel dehydroabietic acid derivatives bearing a 1,3,4-thiadiazole-thiazolidinone moiety were designed and synthesized. The primary bioassay used showed that at a concentration of \(50\,\upmu \hbox {g}/\hbox {mL}\), the target compounds 3c, 3f, and 3n exhibited excellent antifungal activity (91.3 % inhibition) against Gibberella zeae, which was equivalent to the commercial antifungal drug azoxystrobin (positive control).     

Synthesis,insecticidal activities and structure–activity relationship study of dual chiral sulfilimines

To investigate the “methyl” impact on bioactivity of sulfiliminyl dicarboxamides, a total of 16 novel N-cyano and N-trifluoroacetyl sulfiliminyl dicarboxamides containing m-heptafluoroisopropylated aromatic amino moiety were studied. Two series of sulfiliminyl substituents were designed, synthesized and evaluated against oriental armyworm (Pseudaletia separata Walker) for their insecticidal activities. Their chemical structures were established by corresponding \(^{1}\hbox {H}\) NMR, HRMS and optical polarimetry. Bioassay results revealed that some of the title compounds showed potent insecticidal activities against oriental armyworm. Notably, compounds IIa, IIIa, IVa exhibited 100% activity at \(1\, \hbox {mg}\,\hbox {L}^{-1}\), in particular, IIa showed a comparable control efficacy to that of the commercial product flubendiamide. The SAR of these N-cyano sulfiliminyl isomers can be summarized as follows (Sc, Ss) \(\ge \) (Sc, Rs), while the N-trifluoroacetyl sulfiliminyl isomers is (Sc, Rs) \(\ge \) (Sc, Ss). Comparative molecular field analysis indicated that an electropositive substituent, \(\hbox {CH}_{3}\) group in the benzene ring was very important for the improvement in biological activity. These results could hold promise for novel chiral sulfiliminyl RyR regulators.     

Synthesis,characterization and molecular docking studies of thiouracil derivatives as potent thymidylate synthase inhibitors and potential anticancer agents

Thymidylate synthase (TS), one of folate-dependent enzymes, is a key and well-recognized target for anticancer agents. In this study, a series of 6-aryl-5-cyano thiouracil derivatives were designed and synthesized in accordance with essential pharmacophoric features of known TS inhibitors. Nineteen compounds were screened in vitro for their anti-proliferative activities toward HePG-2, MCF-7, HCT-116, and PC-3 cell lines. Compounds \(\mathbf{21}_{\mathbf{c}}\), \(\mathbf{21}_{\mathbf{d}}\), and 24 exhibited high anti-proliferative activity, comparable to that of 5-fluorouracil. Additionally, ten compounds with potent anti-proliferative activities were further evaluated for their ability to inhibit TS enzyme. Six compounds (\(\mathbf{21}_{\mathbf{b}}\), \(\mathbf{21}_{\mathbf{c}}\), \(\mathbf{21}_{\mathbf{d}}\), 22, 23 and 24) demonstrated potent dose-related TS inhibition with \(\hbox {IC}_{50}\) values ranging from 1.57 to \(3.89\,\upmu \hbox {M}\). The in vitro TS activity results were consistent with those of the cytotoxicity assay where the most potent anti-proliferative compounds of the series showed good TS inhibitory activity comparable to that of 5-fluorouracil. Furthermore, molecular docking studies were carried out to investigate the binding pattern of the designed compounds with the prospective target, TS (PDB-code: 1JU6).     

Antioxidative and antiproliferative activities of novel pyrido[1,2-<Emphasis Type="Italic">a</Emphasis>]benzimidazoles

A series of pyrido[1,2-a]benzimidazoles has been designed, and novel examples are synthesized and evaluated for their potential antiproliferative activity against four human tumour cell lines—cervical (HeLa), colorectal (SW620), breast (MCF-7) and hepatocellular carcinoma (HepG2). In addition, their antioxidative potency has been evaluated by in vitro spectrophotometric assays. Preliminary structure–activity relationships among the synthesized compounds are discussed. Evaluation of their antioxidative capacity has shown that two compounds (25 and 26) possess promising reducing characteristics and free radical scavenging activity. Selective antiproliferative effect in the single-digit micromolar range was observed for compound 25 on MCF-7 \((\hbox {IC}_{50} = 6\,{\upmu }\hbox {M})\) and HeLa \((\hbox {IC}_{50} = 8\,{\upmu }\hbox {M})\) cell lines, comparable to the standards 5-fluorouracil and cisplatin. The combination of the radical scavenging activity and antiproliferative activity of compound 25 positions this compound as a potential lead candidate for further optimization.     

The strong decays of <Emphasis Type="Italic">X</Emphasis>(3940) and <Emphasis Type="Italic">X</Emphasis>(4160)

The new mesons X(3940) and X(4160) have been found by Belle Collaboration in the processes \(e^+e^-\rightarrow J/\psi D^{(*)}{\bar{D}}^{(*)}\). Considering X(3940) and X(4160) as \(\eta _c(3S)\) and \(\eta _c(4S)\) states, the two-body open charm OZI-allowed strong decay of \(\eta _c(3S)\) and \(\eta _c(4S)\) are studied by the improved Bethe–Salpeter method combined with the \(^3P_0\) model. The strong decay width of \(\eta _c(3S)\) is \(\Gamma _{\eta _c(3S)}=(33.5^{+18.4}_{-15.3})\) MeV, which is close to the result of X(3940); therefore, \(\eta _c(3S)\) is a good candidate of X(3940). The strong decay width of \(\eta _c(4S)\) is \(\Gamma _{\eta _c(4S)}=(69.9^{+22.4}_{-21.1})\) MeV, considering the errors of the results, it is close to the lower limit of X(4160). But the ratio of the decay width \(\frac{\Gamma (D{\bar{D}}^*)}{\Gamma (D^*{\bar{D}}^*)}\) of \(\eta _c(4S)\) is larger than the experimental data of X(4160). According to the above analysis, \(\eta _c(4S)\) is not the candidate of X(4160), and more investigations of X(4160) is needed.     

Method of uniform effective field in structure-dynamic approach of nanoionics

In the structure-dynamic approach of nanoionics, the method of a uniform effective field \( {F}_{\mathrm{eff}}^{j,k} \) of a crystallographic planeX ^j has been substantiated for solid electrolyte nanostructures. The \( {F}_{\mathrm{eff}}^{j,k} \)is defined as an approximation of a non-uniform field \( {F}_{\mathrm{dis}}^j \)of X ^j with a discrete- random distribution of excess point charges. The parameters of \( {F}_{\mathrm{eff}}^{j,k} \)are calculated by correction of the uniform Gauss field \( {F}_{\mathrm{G}}^j \) of X ^j . The change in an average frequency of ionic jumps X ^k ?→?X ^k?+?1 between adjacent planes of nanostructure is determined by the sum of field additives to the barrier heights η _k , _k?+?1, and for \( {F}_{\mathrm{G}}^j \) and \( {F}_{\mathrm{dis}}^j \), these sums are the same decimal order of magnitude. For nanostructures with length ~4 nm, the application of \( {F}_{\mathrm{G}}^j \) (as \( {F}_{\mathrm{eff}}^{j,k} \)) gives the accuracy ~20 % in calculations of ion transport characteristics. The computer explorations of the “universal” dynamic response (Reσ ^??∝?ω ⁿ ) show an approximately the same power n < ≈1 for\( {F}_{\mathrm{G}}^j \) and \( {F}_{\mathrm{eff}}^{j,k} \).     

Anatomy of $B^{0}_{s,d} \to J/\psi f_{0}(980)$

The \(B^{0}_{s}\to J/\psi f_{0}(980)\) decay offers an interesting experimental alternative to the well-known \(B^{0}_{s}\to J/\psi \phi\) channel for the search of CP-violating New-Physics contributions to \(B^{0}_{s}\)–\(\bar{B}^{0}_{s}\) mixing. As the hadronic structure of the f ₀(980) has not yet been settled, we take a critical look at the implications for the relevant observables and address recent experimental data. It turns out that the effective lifetime of \(B^{0}_{s}\to J/\psi f_{0}(980)\) and its mixing-induced CP asymmetry S are quite robust with respect to hadronic effects and thereby allow us to search for a large CP-violating \(B^{0}_{s}\)–\(\bar{B}^{0}_{s}\) mixing phase ? _s , which is tiny in the Standard Model. However, should small CP violation, i.e. in the range ?0.1?S?0, be found in \(B^{0}_{s}\to J/\psi f_{0}(980)\), it will be crucial to constrain hadronic corrections in order to distinguish possible New-Physics effects from the Standard Model. We point out that \(B^{0}_{d}\to J/\psi f_{0}(980)\), which has not yet been measured, is a key channel in this respect and discuss the physics potential of this decay.     

Simple and efficient synthesis of $$5'$$-aryl-$$5'$$-deoxyguanosine analogs by azide-alkyne click reaction and their antileishmanial activities

A series of non-hydrolysable \(5'\)-aryl substituted GDP analogs has been synthesized by reacting \(5'\)-azido-\(5'\)-deoxyguanosine with different aryl- and benzyloxy-alkynes. Cu(I) nanoparticles in water were found to be the most efficient catalyst, producing the desired \(5'\)-arylguanosines with good yields. The synthesized compounds were screened for in vitro antileishmanial activity against Leishmania donovani axenic amastigotes and intramacrophage amastigotes stages. The 4-(3-nitrobenzyl)-1,2,3-triazole \(5'\)-substituted guanosine analog was found to be the most active in the series with an IC\(_{50}\) of \(8.6\,\upmu \hbox {M}\) on axenic amastigotes. Despite a rather low in vitro antileishmanial activity on the intramacrophage amastigotes, the absence of cytotoxicity on RAW 264.7 macrophages justifies further pharmacomodulations making this antileishmanial series promising.     

On Blow-up Profile of Ground States of Boson Stars with External Potential

We study minimizers of the pseudo-relativistic Hartree functional \({\mathcal {E}}_{a}(u):=\Vert (-\varDelta +m^{2})^{1/4}u\Vert _{L^{2}}^{2}+\int _{{\mathbb {R}}^{3}}V(x)|u(x)|^{2}\mathrm{d}x-\frac{a}{2}\int _{{\mathbb {R}}^{3}}(\left| \cdot \right| ^{-1}\star |u|^{2})(x)|u(x)|^{2}\mathrm{d}x\) under the mass constraint \(\int _{{\mathbb {R}}^3}|u(x)|^2\mathrm{d}x=1\). Here \(m>0\) is the mass of particles and \(V\ge 0\) is an external potential. We prove that minimizers exist if and only if a satisfies \(0\le a<a^{*}\), and there is no minimizer if \(a\ge a^*\), where \(a^*\) is called the Chandrasekhar limit. When a approaches \(a^*\) from below, the blow-up behavior of minimizers is derived under some general external potentials V. Here we consider three cases of V: trapping potential, i.e. \(V\in L_{\mathrm{loc}}^{\infty }({\mathbb {R}}^3)\) satisfies \(\lim _{|x|\rightarrow \infty }V(x)=\infty \); periodic potential, i.e. \(V\in C({\mathbb {R}}^3)\) satisfies \(V(x+z)=V(x)\) for all \(z\in \mathbb {Z}^3\); and ring-shaped potential, e.g. \( V(x)=||x|-1|^p\) for some \(p>0\).