Nitrogen-Enriched Biguanidine-Functionalized Cobalt Ferrite Nanoparticles as a Heterogeneous Base Catalyst for Knoevenagel Condensation under Solvent-Free Conditions.

Designing efficient, economical heterogeneous catalysts for the Knoevenagel condensation reaction is highly significant owing to the importance of reaction products in industries as well as pharmaceutics. Herein, we have designed and synthesized biguanidine-functionalized basic magnetically retrievable cobalt ferrite nanoparticles (CFNPs) for the synthesis of Knoevenagel condensation products using benzaldehydes and active methylene compounds (malononitrile/ethyl cyanoacetate/cyanoacetamide). Several advanced techniques, such as Fourier transform infrared (FT-IR), thermogravimetric analysis (TGA), powder X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and vibration sample magnetometry (VSM), were utilized to precisely characterize the catalyst. The robust features of the current approach involve outstanding catalytic performance, solvent-free reaction conditions, ease of catalyst retrievability, easy workup procedure, large substrate tolerance, high turnover frequency (TOF) values (up to 486.88 h-1), values of green chemistry metrics such as E-factor (0.15), reaction mass efficiency (RME) value (87.07%), carbon efficiency (93.4%), and atom economy (AE) value (88.10%) close to their ideal values, and recyclability up to eight runs without a considerable reduction in activity, boosting the appeal of this approach from a commercial and ecological point of view.

N-sulfonylpiperidinedispiro-1,2,4,5-tetraoxanes exhibit potent in vitro antiplasmodial activity and in vivo efficacy in mice infected with P. berghei ANKA.

The artemisinin resistance has posed a serious threat against malaria elimination lately. Past few years have seen important development of several peroxide based medicinal compounds and their derivatives such as trioxanes and tetraoxanes. Here, we report a rapid, one-pot method for synthesizing a new series of N-sulfonylpiperidine dispiro-1,2,4,5-tetraoxane analogs with diverse substitution on the tetraoxane ring i.e., various substituted alkyl and aryl sulfonyl chlorides, as well as cyclic, acyclic and aryl substituted ketones. All the synthesized tetraoxanes were characterized by spectroscopic (1H NMR,13C NMR), and spectrometric (High-resolution mass spectrometry) techniques and quantify by High Performance Liquid Chromatography (HPLC) analysis. The structure of compound 19 was confirmed by single crystal XRD. From the overall preliminary in vitro data, analogs 14, 16, 19, 20, 24, 41, and 44 exhibited potential IC50 values in the nanomolar range between 4.7 ± 0.3 to 12.9 ± 1.1 nM against P. falciparum (Pf3D7) strains of human malaria parasite. Furthermore, these selective analogs were evaluated in vivo for their antimalarial potential against P. berghei and results revealed that analogue 24 rapidly kills the infected cell at asexual erythrocytic stage, with activity comparable to positive control chloroquine.

Recent advances in the synthesis of thienoindole analogs and their diverse applications.

Thiophene-fused heterocyclic organosulfur systems, especially the thieno[3,2-b]indole moiety have attracted significant attention because they show a wide spectrum of biological activities such as antituberculosis, antitumor, antifungal, antibacterial, and human 5-HT5A receptor binding inhibition. Moreover, they also find applications in material chemistry and chemical engineering. Thus, due to their intriguing properties and applications, researchers are continually attempting to create more effective and environment-friendly methods for their preparation. In this review, we present a complete assessment of the current advances in the field of thieno[3,2-b]indole synthesis.

Advancement of chimeric hybrid drugs to cure malaria infection: An overview with special emphasis on endoperoxide pharmacophores.

Emergence and spread of Plasmodium falciparum resistant to artemisinin-based combination therapy has led to a situation of haste in the scientific and pharmaceutical communities. Sincere efforts are redirected towards finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. Extensive research yielded the concept of "Chimeric Bitherapy (CB)" which involves the linking of two molecules with individual pharmacological activity and exhibit dual mode of action into a single hybrid molecule. Current research in this field seems to endorse hybrid molecules as the next-generation antimalarial drugs and are more effective compared to the multi-component drugs because of the lower occurrence of drug-drug adverse effects. This review is an attempt to congregate complete survey on endoperoxide based hybrid antiplasmodial molecules that will give glimpse on the future directions for successful development and discovery of useful antimalarial hybrid drugs.

Interaction between the Antimalarial Drug Dispiro-Tetraoxanes and Human Serum Albumin: A Combined Study with Spectroscopic Methods and Computational Studies.

Dispiro-tetraoxanes, a class of fully synthetic peroxides which can be used as an antiplasmodial remedy for multiple drug-resistant strains of Plasmodium falciparum, were selected for the interaction study with human serum albumin (HSA). The insight into the interaction of the two chemically synthesized, most potent antimalarial tetraoxane analogues (TO1 and TO2) and HSA has been scrutinized using distinct spectroscopic techniques such as. UV-visible absorption, fluorescence, time-resolved fluorescence, and circular dichroism (CD). Fluorescence quenching experiments divulged the static mode of quenching and binding constants obtained (∼104) indicated the moderate affinity of the analogues to HSA. CD confirmed the conformational changes in the serum albumin upon interaction with these analogues. Molecular docking validated the empirical results as these two analogues bind through hydrophobic interactions and hydrogen bonding with HSA. Present work first defined the binding mechanism of dispiro-tetraoxanes with HSA and thus provides a fresh insight into the drug transportation and metabolism. The present study could direct toward designing more potent tetraoxane analogues for their use in the biomedical field.

Green and Mechanochemical One-Pot Multicomponent Synthesis of Bioactive 2-amino-4H-benzo[b]pyrans via Highly Efficient Amine-Functionalized SiO2@Fe3O4 Nanoparticles.

An ecofriendly, magnetically retrievable amine-functionalized SiO2@Fe3O4 catalyst was successfully synthesized and affirmed by several physicochemical characterization tools, such as scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FT-IR), vibrating sample magnetometry (VSM), energy-dispersive X-ray spectroscopy (EDX), and powder X-ray diffraction. Thereafter, the catalytic performance of this environmentally benign NH2@SiO2@Fe3O4 catalyst was investigated in the one-pot multicomponent synthesis of 2-amino-4H-benzo[b]pyran derivatives. The reaction was simply achieved by grinding of various substituted aromatic aldehydes, dimedone, and malononitrile at room temperature under solvent and waste-free conditions with excellent yields and high purity. Moreover, the developed catalyst not only possesses immense potential to accelerate the synthesis of bioactive pyran derivatives but also exhibits several remarkable attributes like broad functional group tolerance, durability, improved yield, reusability, and recyclability. Besides, various other fascinating advantages of this protocol are milder reaction conditions, cost effectiveness, short reaction time, and simple work up procedures.

Interaction of coumarin triazole analogs to serum albumins: Spectroscopic analysis and molecular docking studies.

The interaction of triazole substituted 4-methyl-7-hydroxycoumarin derivatives (CUM1-4) with serum albumin (bovine serum albumin [BSA] and human serum albumin [HSA]) have been studied employing ultraviolet-visible (UV-Vis), fluorescence, circular dichroism (CD) spectroscopy, and molecular docking methods at physiological pH 7.4. The fluorescence quenching occurred with increasing concentration of CUMs, and the binding constant of CUM derivatives with BSA and HSA obtained from fluorescence quenching experiment was found to be ~ 104 L mol-1 . CD study showed conformational changes in the secondary structure of serum albumin upon titration of CUMs. The observed experimental results were further validated by theoretical studies involving density functional theory (DFT) and molecular docking.

Efficient N-formylation of primary aromatic amines using novel solid acid magnetic nanocatalyst.

Sulfonic acid functionalized over biguanidine fabricated silica-coated heterogeneous magnetic nanoparticles (NP@SO3H) have been synthesized, well characterized and explored for the first time, as an efficient and recyclable catalyst for N-formylation of primary amines under mild reaction conditions. Exploiting the magnetic nature of Fe3O4, the prepared catalyst was readily recovered from the reaction mixture via an external magnet. The catalyst can be reused for up to six cycles without any substantial loss of catalytic activity. The cost effectiveness, simple methodology, wide substrate tolerance, excellent yield and easy work-up are the additional advantages of present catalytic system.

In vitro synergistic interaction of potent 4-aminoquinolines in combination with dihydroartemisinin against chloroquine-resistant Plasmodium falciparum.

High-grade chloroquine (CQ) resistance has been reported in malaria endemic geographical regions such as Papua New Guinea, northern Papua, and eastern and western provinces of Indonesia, along with low-level resistance in Vietnam, South Korea, Turkey, Burma, South America, and Madagascar. Studies on CQ drug resistance have revealed the association of P. falciparum chloroquine resistance transporter protein. Thus, we are in dire need of alternate chemotherapeutic agents which in combination with artemisinin (or its analogues) are efficacious against chloroquine-resistant strains. Such combinations may thwart the emergence of drug resistant strains, along with reducing the malaria burden. Hypothesizing that newer 4-aminoquinolines, earlier reported by our group, could be part of a combination therapy to efficiently treat malaria, we sought to evaluate these compounds, viz. 1m, 1o, 2c, and 2j against the erythrocytic stages of Plasmodium falciparum, strain 3D7 (chloroquine-sensitive) and strain Dd2 (chloroquine-resistant), in combination with dihydroartemisinin (DHA). Results revealed substantially synergistic interactions between the combination partners, which could be further established by their potential to inhibit hemozoin formation with increased efficiency when combined, as compared to the compounds assessed individually. Furthermore, aminoquinolines and DHA show distinct stage-specific profiles. Our results stand in strong support of the potential of these aminoquinoline derivatives to serve as partner drugs in antimalarial combinations to treat multiple-drug-resistant Plasmodium strains.

Insights into the interaction of potent antimicrobial chalcone triazole analogs with human serum albumin: spectroscopy and molecular docking approaches.

Mechanistic insights into the interaction of five previously chemically synthesized triazole-linked chalcone analogs (CTs) with human serum albumin (HSA) were sought using various spectroscopic techniques (UV-visible absorption, fluorescence, and circular dichroism) and molecular docking. The fluorescence quenching experiments performed at three different temperatures (288, 298 and 308 K) revealed the static mode of quenching and the binding constants (K b ∼ 106-9) obtained indicated the strong affinity of these analogs for HSA. Furthermore, significant changes in the secondary structure of HSA in the presence of these analogs were also confirmed by far UV-CD spectroscopy. The thermodynamic properties such as the enthalpy change (ΔH°), Gibbs free energy change (ΔG°) and entropy change (ΔS°) revealed that the binding process was spontaneous and exothermic. Theoretical studies, viz., DFT and molecular docking corroborated the experimental results as these five analogs could bind with HSA through hydrogen bonding and hydrophobic interactions. The present study provides useful information regarding the interaction mechanism of these analogs with HSA, which can provide a new avenue to design more potent chalcone triazole analogs for use in the biomedical field.

In vitro antiplasmodial efficacy of synthetic coumarin-triazole analogs.

Twenty two diverse coumarin-triazole derivatives were synthesized by alkylation of 7-hydroxy-4-methyl-coumarin followed by click chemistry at 7-position. These compounds were evaluated for their in vitro antiplasmodial activity against chloroquine sensitive strain of Plasmodium falciparum (3D7). Compound 9 (7-[1-(2, 4-dimethoxy-phenyl)-1H- [1-3] triazol-4-ylmethoxy]-4-methyl-chromen-2-one) was found most active with IC50 value 0.763 ±â€¯0.0124 µg/mL. Further, the structure of compound 20 was characterized by single crystal X-ray diffraction. In view of impressive results, we considered it worthwhile to validate the results of in vitro antiplasmodial activity by assessing whether these compounds are capable of hampering the catalytic activity of DNA gyrase, thus preventing its supercoiling function.

Are Antimalarial Hybrid Molecules a Close Reality or a Distant Dream?

Emergence of drug-resistant Plasmodium falciparum strains has led to a situation of haste in the scientific and pharmaceutical communities. Hence, all their efforts are redirected toward finding alternative chemotherapeutic agents that are capable of combating multidrug-resistant parasite strains. In light of this situation, scientists have come up with the concept of hybridization of two or more active pharmacophores into a single chemical entity, resulting in "antimalarial hybrids." The approach has been applied widely for generation of lead compounds against deadly diseases such as cancer and AIDS, with a proven potential for use as novel drugs, but is comparatively new in the sphere of antimalarial drug discovery. A sudden surge has been evidenced in the number of studies on the design and synthesis of hybrids for treating malaria and may be regarded as proof of their potential advantages over artemisinin-based combination therapy (ACT). However, it is evident from recent studies that most of the potential advantages of antimalarial hybrids, such as lower toxicity, better pharmacokinetics, and easier formulation, have yet to be realized. A number of questions left unaddressed at present need to be answered before this approach can progress to the late stages of clinical development and prove their worth in the clinic. To the best of our knowledge, this compilation is the first attempt to shed light on the shortcomings that are surfacing as more and more studies on molecular hybridization of the active pharmacophores of known antimalarials are being published.

4-Aminoquinoline derivatives: Synthesis, in vitro and in vivo antiplasmodial activity against chloroquine-resistant parasites.

Synthetic quinoline derivatives continue to be considered as candidates for new drug discovery if they act against CQ-resistant strains of malaria even after the widespread emergence of resistance to CQ. In this study, we explored the activities of two series of new 4-aminoquinoline derivatives and found them to be effective against Plasmodium falciparum under in vitro conditions. Further, we selected four most active derivatives 1m, 1o, 2c and 2j and evaluated their antimalarial potential against Plasmodium berghei in vivo. These 4-aminoquinolines cured BALB/c mice infected with P. berghei. The ED50 values were calculated to be 2.062, 2.231, 1.431, 1.623 and 1.18 mg/kg of body weight for each of the compounds 1m, 1o, 2c, 2j and amodiaquine, respectively. Total doses of 500 mg/kg of body weight were well received. The study suggests that these new 4-aminoquinolines should be used for structure activity relationship to find lead molecules for treating multidrug-resistant Plasmodium falciparum and Plasmodium vivax.

In vitro synergistic effect of fluoroquinolone analogues in combination with artemisinin against Plasmodium falciparum; their antiplasmodial action in rodent malaria model.

BACKGROUND: Emergence of drug-resistant parasite strains has surfaced as a major obstacle in attempts to ameliorate malaria. Current treatment regimen of malaria relies on the concept of artemisinin-based combination therapy (ACT). METHODS: Fluoroquinolone analogues, compounds 10, 12 and 18 were investigated for their anti-malarial interaction in combination with artemisinin in vitro, against Plasmodium falciparum 3D7 strain, employing fixed-ratio combination isobologram method. In addition, the efficacy of these compounds was evaluated intraperitoneally in BALB/c mice infected with chloroquine-resistant Plasmodium berghei ANKA strain in the Peters' four-day suppressive test. RESULTS: Promising results were obtained in the form of synergistic or additive interactions. Compounds 10 and 12 were found to have highly synergistic interactions with artemisinin. Antiplasmodial effect was further verified by the convincing ED50 values of these compounds, which ranged between 2.31 and 3.09 (mg/kg BW). CONCLUSIONS: In vivo studies substantiated the potential of the fluoroquinolone derivatives to be developed as synergistic partners for anti-malarial drug combinations.

Surface confined heteroleptic copper(II)-polypyridyl complexes for photonuclease activity.

Heteroleptic copper(II)-polypyridyl complexes with extended π-conjugated, aromatic terminal units were immobilized on glass/Si substrates to intercalate DNA and cleave it upon photoexposure. Photonuclease activity is shown to be high, well reproducible and non-destructible towards the assembled complexes.

Design, synthesis and antimicrobial activity of novel benzothiazole analogs.

In an attempt to design and synthesize a new class of antimicrobials, dialkyne substituted 2-aminobenzothiazole was reacted with various substituted aryl azides to generate a small library of 20 compounds (3a-t) by click chemistry. Structures of the newly synthesized compounds were established on the basis of spectral data. These compounds were screened for their antibacterial activity against Gram+ bacteria (Staphylococcus aureus and Enterococcus faecalis), Gram- bacteria (Salmonella typhi, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Shigella boydii) and antifungal activity against Candida tropicalis, Candida albicans, Candida krusei, Cryptococcus neoformans) as well as molds (Aspergillus niger, Aspergillus fumigatus). The compound 3e showed maximum potency against all Gram+/gram- bacterial strains with MIC value 3.12 µg/ml, which is two fold more active as compared to standard drug ciprofloxacin (MIC 6.25 µg/ml). However, all compounds were found ineffective against S. boydii (clinical isolate). Further, only one compound 3n was found to be the most active against all fungal strains with MIC value in the range of 1.56 µg/ml-12.5 µg/ml while the remaining compounds showed moderate to weak antifungal activity.

Synthesis and in vitro antiplasmodial activities of fluoroquinolone analogs.

Fluoroquinolone analogs were synthesized by simple alkylation followed by click chemistry and evaluated for their antimalarial in vitro against chloroquine sensitive strain of Plasmodium falciparum while ciprofloxacin was used as standard. Our results showed that the compound 12 was found most active with IC(50) value of 1.33 µg/mL while ciprofloxacin showed IC(50) = 8.81 µg/mL. Therefore, screening of either known or unknown quinolone/fluoroquinolone analogs are worthwhile to find more potent antimalarial drugs which might prove useful in the treatment of mild or severe malaria in human either alone or in combination with existing antimalarial drugs.

Antimalarial activity of newly synthesized chalcone derivatives in vitro.

Twenty-seven novel chalcone derivatives were synthesized using Claisen-Schmidt condensation and their antimalarial activity against asexual blood stages of Plasmodium falciparum was determined. Antiplasmodial IC(50) (half-maximal inhibitory concentration) activity of a compound against malaria parasites in vitro provides a good first screen for identifying the antimalarial potential of the compound. The most active compound was 1-(4-benzimidazol-1-yl-phenyl)-3-(2, 4-dimethoxy-phenyl)-propen-1-one with IC(50) of 1.1 µg/mL, while that of the natural phytochemical, licochalcone A is 1.43 µg/mL. The presence of methoxy groups at position 2 and 4 in chalcone derivatives appeared to be favorable for antimalarial activity as compared to other methoxy-substituted chalcones. Furthermore, 3, 4, 5-trimethoxy groups on chalcone derivative probably cause steric hindrance in binding to the active site of cysteine protease enzyme, explaining the relative lower inhibitory activity.

2-(4-Chloro-phen-yl)chromen-4-one.

The title compound, C(15)H(9)ClO(2), is a synthetic flavonoid obtained by the cyclization of 3-(4-chloro-phen-yl)-1-(2-hy-droxy-phen-yl)prop-2-en-1-one. The 4-chloro-phenyl ring is twisted at an angle of 11.54° with respect to the chromen-4-one skeleton. In the crystal, pairs of mol-ecules are inter-connected by weak Cl⋯Cl inter-actions [3.3089 (10) Å] forming dimmers which are further peripherally connected through inter-molecular C-H⋯O hydrogen bonds.

1-Prop-2-ynyl-1H-benzimidazol-2-amine.

In the title compound, C(10)H(9)N(3), the benzimidazol-2-amine and CH(2)-C CH units are not coplanar, with a dihedral angle of 60.36° between their mean planes. The crystal structure is stabilized by inter-molecular N-H⋯N hydrogen bonding and π-π inter-actions [centroid-centroid distances 3.677 (1) and 3.580 (1) Å], assembling the mol-ecules into a supra-molecular structure with a three-dimensional network.