7‐Chloro‐4‐quinolinyl Hydrazones: A Promising and Potent Class of Antileishmanial Compounds

In this work, we report the antileishmanial evaluation of twenty 7‐chloro‐4‐quinolinyl hydrazone derivatives ( 1 – 20 ). Firstly, the compounds were tested against promastigotes of four different Leishmania species. After that, all derivatives were assayed against L. braziliensis amastigotes and murine macrophages. Furthermore, it was investigated whether the antiamastigote L. braziliensis effect of the compounds could be associated with nitric oxide production. Compounds 6 and 7 showed a strong leishmanicidal activity against intracellular parasite with IC₅₀ in nanogram levels (30 and 20 ng/mL, respectively). Appreciable activity of three compounds tested can be considered an important finding for the rational design of new leads for antileishmanial compounds.     

Design,synthesis and antitrypanosomatid activities of 3,5‐diaryl‐isoxazole analogues based on neolignans veraguensin,grandisin and machilin G

Using bioisosterism as a medicinal chemistry tool, 16 3,5‐diaryl‐isoxazole analogues of the tetrahydrofuran neolignans veraguensin, grandisin and machilin G were synthesized via 1,3‐dipolar cycloaddition reactions, with yields from 43% to 90%. Antitrypanosomatid activities were evaluated against Trypanosoma cruzi, Leishmania (L.) amazonensis and Leishmania (V.) braziliensis. All compounds were selective for the Leishmania genus and inactive against T. cruzi. Isoxazole analogues showed a standard activity on both promastigotes of L. amazonensis and L. braziliensis. The most active compounds were 15 , 16 and 19 with IC₅₀ values of 2.0, 3.3 and 9.5 μM against L. amazonensis and IC₅₀ values of 1.2, 2.1 and 6.4 μM on L. braziliensis, respectively. All compounds were noncytotoxic, showing lower cytotoxicity (>250 μM) than pentamidine (78.9 μM). Regarding the structure–activity relationship (SAR), the methylenedioxy group was essential to antileishmanial activity against promastigotes. Replacement of the tetrahydrofuran nucleus by an isoxazole core improved the antileishmanial activity.     

Identification of dehydroxy isoquine and isotebuquine as promising antileishmanial agents

Traditional antimalarial drugs based on 4‐aminoquinolines have exhibited good antiproliferative activities against Leishmania parasites; however, their clinical use is currently limited. To identify new 4‐aminoquinolines to combat American cutaneous leishmaniasis, we carried out a full in vitro evaluation of a series of dehydroxy isoquines and isotebuquines against two Leishmania parasites such as Leishmania braziliensis and Leishmania mexicana. First, the antiproliferative activity of the quinolines was studied against the promastigote forms of L. braziliensis and L. mexicana parasites, finding that five of them exhibited good antileishmanial responses with micromolar IC₅₀ values ranging from 3.84 to 10 μM. A structure‐activity relationship analysis gave evidence that a piperidine or a morpholine attached as N‐alkyamino terminal substituent as well as the inclusion of an extra phenyl ring attached at the aniline ring of the isotebuquine core constitute important pharmacophores to generate the most active derivatives, with antileishmanial responses by far superior to those found for the reference drug, glucantime. All compounds showed a relatively low toxicity on human dermis fibroblasts, with CC₅₀ ranging from 69 to >250 μM. The five most active compounds displayed moderate to good antileishmanial activity against the intracellular amastigote form of L. braziliensis, compared to the reference drug. In particular, compound 2j was identified as the most potent agent against antimony‐resistant amastigotes of L. braziliensis with acceptable biological response and selectivity, emerging as a promising candidate for further in vivo antileishmanial evaluation. Diverse mechanism‐of‐action studies and molecular docking simulations were performed for the most active 4‐aminoquinoline.     

Design,synthesis, and in vitro biological evaluation of novel thiazolopyrimidine derivatives as antileishmanial compounds

A series of thiazolopyrimidine derivatives was designed and synthesized as a Leishmania major pteridine reductase 1 (LmPTR1) enzyme inhibitor. Their LmPTR1 inhibitor activities were evaluated using the enzyme produced by Escherichia coli in a recombinant way. The antileishmanial activity of the selected compounds was tested in vitro against Leishmania sp. Additionally, the compounds were evaluated for cytotoxic activity against the murine macrophage cell line RAW 264.7. According to the results, four compounds displayed not only a potent in vitro antileishmanial activity against promastigote forms but also low cytotoxicity. Among them, compound L16 exhibited an antileishmanial activity for both the promastigote and amastigote forms of L. tropica, with IC₅₀ values of 7.5 and 2.69 µM, respectively. In addition, molecular docking studies and molecular dynamics simulations were also carried out in this study. In light of these findings, the compounds provide a new potential scaffold for antileishmanial drug discovery.     

Discovery of novel pyrrolopyrimidine/pyrazolopyrimidine derivatives bearing 1,2,3‐triazole moiety as c‐Met kinase inhibitors

Six series of pyrrolo[2,3‐d]pyrimidine and pyrazolo[3,4‐d]pyrimidine derivatives bearing 1,2,3‐triazole moiety were designed and synthesized, and some bio‐evaluation was also carried out. As a result, four points can be summarized: Firstly, some of compounds exhibited excellent cytotoxicity activity and selectivity with the IC₅₀ values in single‐digit μm level. In particular, the most promising compound 16d showed equal activity to lead compound foretinib against A549, HepG2, and MCF‐7 cell lines, with the IC₅₀ values of 4.79 ± 0.82, 2.03 ± 0.39, and 2.90 ± 0.43 μm , respectively. Secondly, the SARs and docking studies indicated that the in vitro antitumor activity of pyrrolo[2,3‐d]pyrimidine derivatives bearing 1,2,3‐triazole moiety was superior to the pyrazolo[3,4‐d]pyrimidine derivatives bearing 1,2,3‐triazole moiety. Thirdly, three selected compounds ( 16d , 18d , and 20d ) were further evaluated for inhibitory activity against the c‐Met kinase, and the 16d could inhibit the c‐Met kinase selectively by experiments of enzyme‐based selectivity. What is more, 16d could induce apoptosis of HepG2 cells and inhibitor the cell cycle of HepG2 on G2/M phase by acridine orange staining and cell cycle experiments, respectively.     

Synthesis,Cytotoxicity and In Vitro Antileishmanial Activity of Naphthothiazoles

The leishmaniasis is a spectral disease caused by the protozoan Leishmania spp., which threatens millions of people worldwide. Current treatments exhibit high toxicity, and there is no vaccine available. The need for new lead compounds with leishmanicidal activity is urgent. Considering that many lead leishmanicidal compounds contain a quinoidal scaffold and the thiazole heterocyclic ring is found in a number of antimicrobial drugs, we proposed a hybridization approach to generate a diverse set of semi‐synthetic heterocycles with antileishmanial activity. We found that almost all synthesized compounds demonstrated potent activity against promastigotes of Leishmania (Viannia) braziliensis and reduced the survival index of Leishmania amastigotes in mammalian macrophages. Furthermore, the compounds were not cytotoxic to macrophages at fivefold higher concentrations than the EC₅₀ for promastigotes. All molecules fulfilled Lipinski's Rule of Five, which predicts efficient orally absorption and permeation through biological membranes, the in silico pharmacokinetic profile confirmed these characteristics. The potent and selective activity of semi‐synthetic naphthothiazoles against promastigotes and amastigotes reveals that the 2‐amino‐naphthothiazole ring may represent a scaffold for the design of compounds with leishmanicidal properties and encourage the development of drug formulation and new compounds for further studies in vivo.     

Synthesis and biological evaluation of novel imidazopyrimidin‐3‐amines as anticancer agents

Groebke–Blackburn–Bienayme reaction has been utilized for the synthesis of new imidazo[1,2‐a]pyrimidine derivatives as novel anticancer agents. The cytotoxic activities of compounds were evaluated against human cancer cell lines including MCF‐7, T‐47D, and MDA‐MB‐231, compared with etoposide as the standard drug. Among the tested compounds, hydroxy‐ and/or methoxy‐phenyl derivatives ( 6a–c and 6k ) with IC₅₀ values of 6.72–14.36 μm were more potent than etoposide against all cell lines. The acridine orange/ethidium bromide double staining and DNA fragmentation studies demonstrated that the cytotoxic effect of 3‐hydroxy‐4‐methoxyphenyl derivative 6c is associated with apoptosis in cancer cells.     

Design,Synthesis, and Biological Evaluation of 1,4‐dihydropyridine Derivatives as Potent Antitubercular Agents

A series of novel 1,4‐dihydropyridine‐3,5‐dicarbamoyl derivatives bearing an imidazole nucleus at C‐4 position were synthesized in excellent yields via multicomponent Hantzsch reaction. The newly synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, and mass spectroscopy. The synthesized compounds 3a‐p were screened for antitubercular activity. Among all the screened compounds, compounds 3j and 3m showed most prominent activity against Mycobacterium tuberculosis with minimum inhibitory concentration of 0.02 μg/mL and SI > 500, making it more potent than first‐line antitubercular drug isoniazid. In addition, these compounds displayed relatively low cytotoxicity.     

Design,Synthesis, and Biological Evaluation of 1‐(thiophen‐2‐yl)‐9H‐pyrido[3,4‐b]indole Derivatives as Anti‐HIV‐1 Agents

A novel series of 1‐(thiophen‐2‐yl)‐9H‐pyrido [3,4‐b]indole derivatives were synthesized using DL‐tryptophan as starting material. All the compounds were characterized by spectral analysis such as ¹H NMR, Mass, IR, elemental analysis and evaluated for inhibitory potency against HIV‐1 replication. Among the reported analogues, compound 7g exhibited significant anti‐HIV activity with EC₅₀ 0.53 μm and selectivity index 483; compounds 7e , 7i , and 7o displayed moderate activity with EC₅₀ 3.8, 3.8, and 2.8 μm and selectivity index >105, >105, and 3.85, respectively. Interestingly, compound 7g inhibited p24 antigen expression in acute HIV‐1_IIIB infected cell line C8166 with EC₅₀ 1.1 μm . In this study, we also reported the Lipinski rule of 5 parameters, predicted toxicity profile, drug‐likeness, and drug score of the synthesized analogues.     

Design,synthesis and in vitro antiplasmodial activity of some bisquinolines against chloroquine‐resistant strain

A series of novel bisquinoline compounds comprising N¹‐(7‐chloroquinolin‐4‐yl) ethane‐1,2‐diamine and 7‐chloro‐N‐(2‐(piperazin‐1‐yl)ethyl)quinolin‐4‐amine connected with 7‐chloro‐4‐aminoquinoline containing various amino acids is described. We have bio‐evaluated the compounds against both chloroquine‐sensitive (3D7) and chloroquine‐resistant (K1) strains of Plasmodium falciparum in vitro. Among the series, compounds 4 and 7 exhibited 1.8‐ and 10.6‐fold superior activity as compared to chloroquine (CQ; IC₅₀ = 0.255 ± 0.049 μm ) against the K1 strain with IC₅₀ values 0.137 ± 0.014 and 0.026 ± 0.007 μm , respectively. Furthermore, compound 7 also displayed promising activity against the 3D7 strain (IC₅₀ = 0.024 ± 0.003 μm ) of P. falciparum when compared to CQ. All the compounds in the series displayed resistance factor between 0.57 and 4.71 as against 51 for CQ. These results suggest that bisquinolines can be explored for further development as new antimalarial agents active against chloroquine‐resistant P. falciparum.     

Synthesis,Antibacterial Activities,and 3D‐QSAR of Sulfone Derivatives Containing 1, 3, 4‐Oxadiazole Moiety

A series of sulfone derivatives containing 1, 3, 4‐oxadiazole moiety were prepared and evaluated for their antibacterial activities by the turbidimeter test. Most compounds inhibited growth of Ralstonia solanacearum (R. solanacearum) from tomato and tobacco bacterial wilt with high potency, among which compounds 5a and 5b exhibited the most potent inhibition against R. solanacearum from tomato and tobacco bacterial wilts with EC₅₀ values of 19.77 and 8.29 μg/mL, respectively. Our results also demonstrated that 5a, 5b , and a number of other compounds were more potent than commercial bactericides Kocide 3000 and Thiodiazole Copper, which inhibited R. solanacearum from tomato bacterial wilt with EC₅₀ values of 93.59 and 99.80 μg/mL and tobacco bacterial wilt with EC₅₀ values of 45.91 and 216.70 μg/mL, respectively. The structure–activity relationship (SAR) of compounds was studied using three‐dimensional quantitative structure–activity relationship (3D‐QSAR) models created by comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) based on compound bioactivities against tomato and tobacco bacterial wilts. The 3D‐QSAR models effectively predicted the correlation between inhibitory activity and steric–electrostatic properties of compounds.     

Effect of isoxazole derivatives of tetrahydrofuran neolignans on intracellular amastigotes of Leishmania (Leishmania) amazonensis: A structure–activity relationship comparative study with triazole‐neolignan‐based compounds

Isoxazole analogues derived from the neolignans veraguensin, grandisin, and machilin G were previously synthesized with different substitution patterns through the bioisosterism strategy. These compounds were tested on intracellular amastigotes of Leishmania (Leishmania) amazonensis; the derivatives proved to be active against intracellular amastigotes, with IC₅₀ values ranging from 0.4 to 25 μM. The most active analogues were 4′ , 14′ , 15′, and 18′ , with IC₅₀ values of 0.9, 0.4, 0.7, and 1.4 μM, respectively, showing high selectivity indexes (SI = 277.0; 625.0; 178.5 and 357.1). Overall, the isoxazole analogues did not induce nitric oxide (NO) production by infected cells; there was no evidence that NO influences the antileishmanial mechanism of action, except for compound 4′ . Trimethoxy groups as substituents seemed to be critical for antileishmanial activity. The SAR study demonstrated that the isoxazole compounds were more active than 1,2,3‐triazole compounds with the same substitution pattterns, demonstrating the importance of the bioisosterism strategy in drug design.     

1,3‐Bis(aryloxy)propan‐2‐ols as potential antileishmanial agents

We describe herein the synthesis and antileishmanial activity of 1,3‐bis(aryloxy)propan‐2‐ols. Five compounds ( 2 , 3 , 13 , 17 , and 18 ) exhibited an effective antileishmanial activity against stationary promastigote forms of Leishmania amazonensis (IC₅₀ < 15.0 μm ), and an influence of compound lipophilicity on activity was suggested. Most of the compounds were poorly selective, as they showed toxicity toward murine macrophages, except 17 and 18 , which presented good selective indexes (SI ≥ 10.0). The five more active compounds ( 2 , 3 , 13 , 17 , and 18 ) were selected for the treatment of infected macrophages, and all of them were able to reduce the number of internalized parasites by more than 80%, as well as the number of infected macrophages by more than 70% in at least one of the tested concentrations. Altogether, these results demonstrate the potential of these compounds as new hits of antileishmanial agents and open future possibilities for them to be tested in in vivo studies.     

Synthesis and Biological Evaluation of Tricyclic Guanidine Analogues of Batzelladine K for Antimalarial,Antileishmanial, Antibacterial,Antifungal, and Anti‐HIV Activities

Fifty analogues of batzelladine K were synthesized and evaluated for in vitro antimalarial (Plasmodium falciparum), antileishmanial (Leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (HIV‐1) activities. Analogues 14h and 20l exhibited potential antimalarial activity against chloroquine‐sensitive D6 strain with IC₅₀ 1.25 and 0.88 μm and chloroquine‐resistant W2 strain with IC₅₀ 1.64 and 1.07 μm , respectively. Analogues 12c and 14c having nonyl substitution showed the most potent antileishmanial activity with IC₅₀ 2.39 and 2.78 μm and IC₉₀ 11.27 and 12.76 μm , respectively. Three analogues 12c , 14c, and 14i were the most active against various pathogenic bacteria and fungi with IC₅₀ < 3.02 μm and MIC/MBC/MFC <6 μm . Analogue 20l having pentyl and methyl substituents on tricycle showed promising activities against all pathogens. However, none was found active against HIV‐1. Our study demonstrated that the tricyclic guanidine compounds provide new structural class for broad spectrum activity.     

Discovery of benzimidazole‐based Leishmania mexicana cysteine protease CPB2.8ΔCTE inhibitors as potential therapeutics for leishmaniasis

Chemotherapy is currently the only effective approach to treat all forms of leishmaniasis. However, its effectiveness is severely limited due to high toxicity, long treatment length, drug resistance, or inadequate mode of administration. As a consequence, there is a need to identify new molecular scaffolds and targets as potential therapeutics for the treatment of this disease. We report a small series of 1,2‐substituted‐1H‐benzo[d]imidazole derivatives ( 9a–d ) showing affinity in the submicromolar range (K_i = 0.15–0.69 μM) toward Leishmania mexicanaCPB2.8ΔCTE, one of the more promising targets for antileishmanial drug design. The compounds confirmed activity in vitro against intracellular amastigotes of Leishmania infantum with the best result being obtained with derivative 9d (IC₅₀ = 6.8 μM), although with some degree of cytotoxicity (CC₅₀ = 8.0 μM on PMM and CC₅₀ = 32.0 μM on MCR‐5). In silico molecular docking studies and ADME‐Tox properties prediction were performed to validate the hypothesis of the interaction with the intended target and to assess the drug‐likeness of these derivatives.     

Synthesis,activity, and molecular modeling studies of 1,2,3‐triazole derivatives from natural phenylpropanoids as new trypanocidal agents

The search for compounds with new structural scaffolds is an important tool to the discovery of new drugs against Chagas disease. We report herein the synthesis of 1,2,3‐triazoles obtained from eugenol and di‐hydroeugenol and their in vitro and in vivo trypanocidal activity. These derivatives were obtained by a three‐step objective route and were suitably characterized by ¹H and ¹³C nuclear magnetic resonance spectroscopy and high‐resolution mass spectrometry. Two compounds ( 9 and 10 ) showed activity against epimastigote forms of Trypanosoma cruzi (Y strain) in the range 42.8–88.4 μM and were weakly toxic to cardiomyoblast cells (H9c2 cells). The triazole 10 was the most active derivative and could reduce more than 50% of parasitemia after a 100‐mg/kg oral treatment of mice infected with T. cruzi. Molecular docking studies suggested this compound could act as a trypanocidal agent by inhibiting cruzain, an essential enzyme for T. cruzi metabolism, usually inhibited by triazole compounds.     

Discovery of Synthetic Leishmania Inhibitors by Screening of a 2‐Arylbenzothiophene Library

Tamoxifen has been shown to be active in vitro against Leishmania and effective in the treatment for leishmaniasis in murine models. Through the screening of a compound library of estrogen receptor modulator analogs, we identified the major characteristics required for antileishmanial activity. To overcome the difficulties presented by tamoxifen's propensity for E/Z isomerization, we used the 2‐arylbenzothiophene compound BTP as a more stable alternative. Directed screening of a small compound library based on BTP led to active compounds against Leishmania. Subsequent structure–activity data for the synthetic 2‐arylbenzothiophenes evaluated in this study indicate that optimal antileishmanial potency is dependent on the presence of two basic side chains. In addition, the primary structural features required for estrogen receptor binding, the phenols, are not required for inhibiting parasitic growth. Significantly, the most active antileishmanial benzothiophenes lack the pharmacophore for estrogen receptor activity and therefore address potential concerns about the undesirable effects of using selective estrogen receptor modulators in women and children with leishmaniasis. Three compounds selected from the screening have shown consistent activity against all species and stages of Leishmania in vitro although improvements in selectivity are needed. These compounds represent viable starting points for further optimization as antileishmanial agents.     

Synthesis,in vitro evaluation and molecular docking studies of novel coumarin‐isatin derivatives as α‐glucosidase inhibitors

This study synthesized a series of novel coumarin‐isatin derivatives and evaluated them for α‐glucosidase inhibitory activity. The majority of the screened compounds exhibited excellent inhibition activities with IC₅₀ values of 2.56 ± 0.08–268.79 ± 3.04 μm , when compared to acarbose. Among the newly derivatives, compound 5p was found to be the most active compound in the library of coumarin‐isatin derivatives. Furthermore, enzyme kinetic studies showed that compound 5p is a non‐competitive inhibitor with a K_i of 2.14 μm . Molecular docking analysis revealed the existence of hydrophobic and hydrogen interactions between compound 5p and the active site of α‐glucosidase. Our results indicate that coumarin‐isatin derivatives as a new class of α‐glucosidase inhibitors.