To ascertain the structure–activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the ...1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously observed for OZ439 versus OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides.
In three phase 3 placebo-controlled trials, the oral selective JAK inhibitor upadacitinib was effective as induction and maintenance therapy in patients with moderate-to-severe Crohn’s disease.
Cancer has been cursed for human beings for long time. Millions people lost their lives due to cancer. Despite of the several anticancer drugs available, cancer cannot be cured; especially at the ...late stages without showing any side effect. Heterocyclic compounds exhibit exciting medicinal properties including anticancer. Some market selling heterocyclic anticancer drugs include 5-flourouracil, methortrexate, doxorubicin, daunorubicin, etc. Besides, some natural products such as vinblastine and vincristine are also used as anticancer drugs. Overall, heterocyclic moeities have always been core parts in the expansion of anticancer drugs. This article describes the importance of heterocyclic nuclei in the development of anticancer drugs. Besides, the attempts have been made to discuss both naturally occurring and synthetic heterocyclic compounds as anticancer agents. In addition, some market selling anticancer heterocyclic compounds have been described. Moreover, the efforts have been made to discuss the mechanisms of actions and recent advances in heterocyclic compounds as anticancer agents. The current challenges and future prospectives of heterocyclic compounds have also been discussed. Finally, the suggestions for syntheses of effective, selective, fast and human friendly anticancer agents are discussed into the different sections.
A series of novel furo2,3-bpyridine-2-carboxamide 4a–h/pyrido3′,2′:4,5furo3,2-d pyrimidin-4(3H)-one 5a–p, furo 2,3-b pyridine-2-carbohydrazide Schiff’s base 7a–h and pyrido 3′,2′:4,5 furo3,2-d ...pyrimidin-4(3H)-one derivatives 8a–h were prepared. All the final products 4a–h, 5a–p, 7a–h and 8a–h were screened against four human cancer cell lines (HeLa, COLO205, HepG2 and MCF7) and one normal cell line (HEK293). Compounds 4e, 4f, 4g, 5h, 7c, 7d, 7e and 7f showed significant anticancer activity against all the cell lines at micro molar concentration and found to be non-toxic to normal cell line. Further studied for HeLa, COLO205 and MCF-7 using CoMFA and CoMSIA. Models obtained from 3D-QSAR studies provided a strong basis for future rational design of more active and selective HeLa, COLO205 and MCF-7 cell line inhibitors.
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•Novel hetero ring fused pyridine derivatives.•All products screened against four human cancer cell lines and one normal cell line.•Compounds 4e, 4f, 4g, 5h, 7c, 7d, 7e and 7f showed promising anticancer activity.•All compounds found to be non-toxic to normal cell line.
A series of novel furo2,3-bpyridine-2-carboxamide 4a–h/pyrido3′,2′:4,5furo3,2-d pyrimidin-4(3H)-one derivatives 5a–p were prepared from pyridin 2(1H) one 1 via selective O-alkylation with α-bromoethylester followed by cyclization, then reaction with different aliphatic primary amines to obtain 4 and further reaction with triethyl orthoacetate/triethyl orthoformate. Also prepared novel furo2,3-bpyridine-2-carbohydrazide Schiff’s bases 7a–h and pyrido 3′,2′:4,5furo3,2-dpyrimidin-4(3H)-one derivatives 8a–h starting from furo2,3-bpyridine carboxylate derivatives 3 by reaction with hydrazine hydrate to form 6 and reaction with diverse substituted aldehydes and cyclization. Products 4a–h, 5a–p, 7a–h and 8a–h were screened against four human cancer cell lines (HeLa, COLO205, Hep G2 and MCF 7) and one normal cell line (HEK 293). Compounds 4e, 4f, 4g, 5h, 7c, 7d, 7e and 7f showed significant anticancer activity against all the cell lines at micro molar concentration and found to be non-toxic to normal cell line. Studies for HeLa, COLO205 and MCF-7 using CoMFA and CoMSIA. Models from 3D-QSAR provided a strong basis for future rational design of more active and selective HeLa, COLO205 and MCF-7 cell line inhibitors.
A small library of 1H-benzo4,5imidazo1,2-c1,3oxazin-1-one derivatives was prepared in good to excellent yields, involving a Agsub.2COsub.3/TFA-catalyzed intramolecular oxacyclization of ...N-Boc-2-alkynylbenzimidazole substrates. In all experiments, the 6-endo-dig cyclization was exclusively achieved since the possible 5-exo-dig heterocycle was not observed, indicating the high regioselectivity of this process. The scope and limitations of the silver catalyzed 6-endo-dig cyclization of N-Boc-2-alkynylbenzimidazoles as substrates, bearing various substituents, were investigated. While ZnClsub.2 has shown limits for alkynes with an aromatic substituent, Agsub.2COsub.3/TFA demonstrated its effectiveness and compatibility regardless of the nature of the starting alkyne (aliphatic, aromatic or heteroaromatic), providing a practical regioselective access to structurally diverse 1H-benzo4,5imidazo1,2-c1,3oxazin-1-ones in good yields. Moreover, the rationalization of oxacyclization selectivity in favor of 6-endo-dig over 5-exo-dig was explained by a complementary computational study.
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•Different targets have been indicated for antiviral N-heterocyclic compounds.•Investigation of structure-activity relationship (SAR).•5- or 6-ring N-heterocycles represent valuable ...scaffold for broad spectrum antiviral activity.•The review summarizes the existing knowledge about the antiviral activity of some N-heterocyclic compounds.•Evaluating drug efficacy, specificity and toxicity may help to develop an optimal treatment regime for further studies.
N-heterocycles are important, not only because of their abundance, but above all because of their chemical, biological and technical significance. They play an important role in biological investigation such as anticancer, antiinflammatory, antibacterial, antiviral, anti-tumor, antidiabetic, etc. In this study, we focused on examining synthesized some 5- or 6-ring N-heterocyclic compounds that showed the antiviral activity in last 5 years, and investigation of these compounds structure-activity relationship studies. This review will be useful to scientists in research fields of organic synthesis, medicinal chemistry, and pharmacology.
In our ongoing search for highly active hybrid molecules exceeding their parent compounds in anticancer, antimalaria as well as antiviral activity and being an alternative to the standard drugs, we ...present the synthesis and biological investigations of 2nd generation 1,2,4-trioxane-ferrocene hybrids. In vitro tests against the CCRF-CEM leukemia cell line revealed di-1,2,4-trioxane-ferrocene hybrid 7 as the most active compound (IC50 of 0.01 μM). Regarding the activity against the multidrug resistant subline CEM/ADR5000, 1,2,4-trioxane-ferrocene hybrid 5 showed a remarkable activity (IC50 of 0.53 μM). Contrary to the antimalaria activity of hybrids 4–8 against Plasmodium falciparum 3D7 strain with slightly higher IC50 values (between 7.2 and 30.2 nM) than that of their parent compound DHA, hybrids 5–7 possessed very promising activity (IC50 values lower than 0.5 μM) against human cytomegalovirus (HCMV). The application of 1,2,4-trioxane-ferrocene hybrids against HCMV is unprecedented and demonstrated here for the first time.
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•2nd generation 1,2,4-trioxane-ferrocene-based hybrids were synthesized.•The IC50 0.01 μM against CCRF-CEM leukemia cells was achieved.•Unprecedented application of 1,2,4-trioxane-ferrocene hybrids against HCMV was presented.•Hybrids 5–7 showed highest activity (IC50 up to 0.11 μM) against HCMV.•The IC50 value of the most active hybrid against Plasmodium falciparum 3D7 was 7.2 nM.
An efficient one-pot synthesis of isoquinolines and heterocycle-fused pyridines by three-component reaction of aryl ketones, hydroxylamine, and alkynes is developed. The reaction involves ...condensation of aryl ketones and hydroxylamine, rhodium(III)-catalyzed C–H bond activation of the in situ generated aryl ketone oximes, and cyclization with internal alkynes. This protocol enables rapid assembly of multisubstituted isoquinolines as well as γ-carbolines, furo2,3-cpyridines, thieno2,3-cpyridines, and benzofuro2,3-cpyridines from readily available substrates.
In our arduous efforts to develop new potent HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), novel piperidine-linked 1,2,4triazolo1,5-apyrimidine derivatives were designed, ...synthesized and evaluated for their antiviral activities in MT-4 cell cultures. Biological results showed that all of the title compounds displayed moderate to excellent activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 8.1 nM to 2284 nM in a cell-based assay. Among them, the most promising analog 7d possessed an EC50 value of 8.1 nM against wt HIV-1, which was much more potent than the reference drugs DDI, 3 TC, NVP and DLV. Additionally, 7d demonstrated weak activity against the double mutant HIV-1 strain (K103N + Y181C), and was more efficient than NVP in a RT inhibition assay. Besides, some measured and calculated physicochemical properties of 7d, like log P and water solubility, as well as the structure–activity relationships (SARs) analysis have been discussed in detail. Furthermore, the binding mode of the active compound 7d was rationalized by molecular simulation studies.
A series of novel piperidine-linked 1,2,4triazolo1,5-apyrimidine derivatives were synthesized and identified as inhibitors of HIV-1 wild-type and K103N + Y181C double mutant strains in this paper. Display omitted
•Novel 1,2,4triazolo1,5-apyrimidines were identified as potent HIV-1 inhibitors.•7d exhibited anti-HIV-1 activity with EC50 values of 8.1 nM (wt) and 13 μM (RES056).•Log P and water solubility of 7d were measured.•Preliminary SARs and molecular simulation of these new analogs were detailed.
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