Evaluation of novel 2-(quinoline-2-ylthio)acetamide derivatives linked to diphenyl-imidazole as α-glucosidase inhibitors: Insights from in silico, in vitro, and in vivo studies on their anti-diabetic properties.

The inhibition of the α-glucosidase enzyme is crucial for targeting type 2 diabetes mellitus (DM). This study introduces a series of synthetic analogs based on thiomethylacetamide-quinoline derivatives linked to diphenyl-imidazole as highly potential α-glucosidase inhibitors. Twenty derivatives were synthesized and screened in vitro against α-glucosidase, revealing IC50 values ranging from 0.18 ± 0.00 to 2.10 ± 0.07 µM, in comparison to the positive control, acarbose. Among these derivatives, compound 10c (IC50 = 0.180 µM) demonstrated the highest potency and revealed a competitive inhibitory mechanism in kinetic studies (Ki = 0.15 µM). Docking and molecular dynamic evaluations elucidated the binding mode of 10c with the active site residues of the α-glucosidase enzyme. Moreover, in vivo assessments on a rat model of DM affirmed the anti-diabetic efficacy of 10c, evidenced by reduced fasting and overall blood glucose levels. The histopathological evaluation enhanced pancreatic islet architecture and hepatocytes in liver sections. In conclusion, novel 2-(quinoline-2-ylthio)acetamide derivatives as potent α-glucosidase inhibitors were developed. Compound 10c emerged as a promising candidate for diabetes management, warranting further investigation for potential clinical applications and mechanistic insights.

Inhibition of cancer cells by Quinoline-Based compounds: A review with mechanistic insights.

This article includes a thorough examination of the inhibitory potential of quinoline-based drugs on cancer cells, as well as an explanation of their modes of action. Quinoline derivatives, due to their various chemical structures and biological activity, have emerged as interesting candidates in the search for new anticancer drugs. The review paper delves into the numerous effects of quinoline-based chemicals in cancer progression, including apoptosis induction, cell cycle modification, and interference with tumor-growth signaling pathways. Mechanistic insights on quinoline derivative interactions with biological targets enlightens their therapeutic potential. However, obstacles such as poor bioavailability, possible off-target effects, and resistance mechanisms make it difficult to get these molecules from benchside to bedside. Addressing these difficulties might be critical for realizing the full therapeutic potential of quinoline-based drugs in cancer treatment.

New Library of Iodo-Quinoline Derivatives Obtained by an Alternative Synthetic Pathway and Their Antimicrobial Activity.

6-Iodo-substituted carboxy-quinolines were obtained using a one-pot, three-component method with trifluoroacetic acid as a catalyst under acidic conditions. Iodo-aniline, pyruvic acid and 22 phenyl-substituted aldehydes (we varied the type and number of radicals) or O-heterocycles, resulting in different electronic effects, were the starting components. This approach offers advantages such as rapid response times, cost-effective catalysts, high product yields and efficient purification procedures. A comprehensive investigation was conducted to examine the impact of aldehyde structure on the synthesis pathway. A library of compounds was obtained and characterized by FT-IR, MS, 1H NMR and 13C NMR spectroscopy and single-ray crystal diffractometry. Their antimicrobial activity against S. epidermidis, K. pneumonie and C. parapsilosis was tested in vitro. The effect of iodo-quinoline derivatives on microbial adhesion, the initial stage of microbial biofilm development, was also investigated. This study suggests that carboxy-quinoline derivatives bearing an iodine atom are interesting scaffolds for the development of novel antimicrobial agents.

Development, preclinical evaluation and preliminary dosimetry profiling of SB03178, a first-of-its-kind benzo[h]quinoline-based fibroblast activation protein-α-targeted radiotheranostic for cancer imaging and therapy.

Fibroblast activation protein-α (FAP) is a marker of cancer-associated fibroblasts (CAFs) that constitute a significant portion of most carcinomas. Since it plays a critical role in tumor growth and metastasis, its timely detection to identify tumor lesions in early developmental stages using targeted radiopharmaceuticals has gained significant impetus. In the present work, two novel FAP-targeted precursors SB03178 and SB04033 comprising of an atypical benzo[h]quinoline construct were synthesized and either chelated to diagnostic radionuclide gallium-68 or therapeutic radionuclide lutetium-177, with ≥90% radiochemical purities and 22-76% decay-corrected radiochemical yields. natGa-labeled complexes displayed dose-dependent FAP inhibition, with binding potency of natGa-SB03178 being ∼17 times higher than natGa-SB04033. To evaluate their pharmacokinetic profiles, PET imaging and ex vivo biodistribution analyses were executed in FAP-overexpressing HEK293T:hFAP tumor-bearing mice. While both tracers displayed clear tumor visualization that was primarily FAP-arbitrated, with negligible uptake in most peripheral tissues, [68Ga]Ga-SB03178 demonstrated higher tumor uptake and superior tumor-to-background contrast ratios than [68Ga]Ga-SB04033. 177Lu-labeled SB03178 was subjected to tumor retention studies, mouse dosimetry profiling and mouse-to-human dose extrapolations also using the HEK293T:hFAP tumor model. [177Lu]Lu-SB03178 exhibited a combination of high and sustained tumor uptake, with excellent tumor-to-critical organ uptake ratios resulting in a high radiation absorbed dose to the tumor and a low estimated whole-body dose to humans. Our preliminary findings are considerably encouraging to support clinical development of [68Ga]Ga-/[177Lu]Lu-SB03178 theranostic pair for use in a vast majority of FAP-overexpressing neoplasms, particularly carcinomas.

Pyrimido[5,4-c]quinolines: Synthesis from 3,4-Di-functionallized Quinoline, Reactivity and Biological Activities.

Quinoline and pyrimidine moieties are ubiquitous components in both natural and synthetic compounds, showcasing diverse applications. The fusion of these well-known structures into hybrid molecules has garnered attention due to their intriguing biological properties. Particularly in the field of medicinal chemistry, numerous studies in the last decade have focused on pyrimido[5,4-c]quinoline ring systems (PyQs5,4-c). This review elucidates the synthesis of PyQs5,4-c and their derivatives using 3,4-difunctionalized quinoline as a key starting material. The preparation of PyQs5,4-c involves a series of chemical transformations, including the Friedländer, Ullmann and Biginelli reaction, Vilsmeier-Haack formylation, Suzuki coupling, and a one-pot three-component reaction. These synthetic routes not only offer access to diverse PyQs5,4-c derivatives.

Discovery of new piperaquine hybrid analogs linked by triazolopyrimidine and pyrazolopyrimidine scaffolds with antiplasmodial and transmission blocking activities.

The World Health Organization (WHO) estimated that there were 247 million malaria cases in 2021 worldwide, representing an increase in 2 million cases compared to 2020. The urgent need for the development of new antimalarials is underscored by specific criteria, including the requirement of new modes of action that avoid cross-drug resistance, the ability to provide single-dose cures, and efficacy against both assexual and sexual blood stages. Motivated by the promising results obtained from our research group with [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine derivatives, we selected these molecular scaffolds as the foundation for designing two new series of piperaquine analogs as potential antimalarial candidates. The initial series of hybrids was designed by substituting one quinolinic ring of piperaquine with the 1,2,4-triazolo[1,5-a]pyrimidine or pyrazolo[1,5-a]pyrimidine nucleus. To connect the heterocyclic systems, spacers with 3, 4, or 7 methylene carbons were introduced at the 4 position of the quinoline. In the second series, we used piperazine as a spacer to link the 1,2,4-triazolo[1,5-a]pyrimidine or pyrazolo[1,5-a]pyrimidine group to the quinoline core, effectively merging both pharmacophoric groups via a rigid spacer. Our research efforts yielded promising compounds characterized by low cytotoxicity and selectivity indices exceeding 1570. These compounds displayed potent in vitro inhibitory activity in the low nanomolar range against the erythrocytic form of the parasite, encompassing both susceptible and resistant strains. Notably, these compounds did not show cross-resistance with either chloroquine or established P. falciparum inhibitors. Even though they share a pyrazolo- or triazolo-pyrimidine core, enzymatic inhibition assays revealed that these compounds had minimal inhibitory effects on PfDHODH, indicating a distinct mode of action unrelated to targeting this enzyme. We further assessed the compounds' potential to interfere with gametocyte and ookinete infectivity using mature P. falciparum gametocytes cultured in vitro. Four compounds demonstrated significant gametocyte inhibition ranging from 58 % to 86 %, suggesting potential transmission blocking activity. Finally, we evaluated the druggability of these new compounds using in silico methods, and the results indicated that these analogs had favorable physicochemical and ADME (absorption, distribution, metabolism, and excretion) properties. In summary, our research has successfully identified and characterized new piperaquine analogs based on [1,2,4]triazolo[1,5-a]pyrimidine and pyrazolo[1,5-a]pyrimidine scaffolds and has demonstrated their potential as promising candidates for the development of antimalarial drugs with distinct mechanisms of action, considerable selectivity, and P. falciparum transmission blocking activity.

Aryl-quinoline-4-carbonyl hydrazone bearing different 2-methoxyphenoxyacetamides as potent α-glucosidase inhibitors; molecular dynamics, kinetic and structure-activity relationship studies.

Regarding the important role of α-glucosidase enzyme in the management of type 2 diabetes mellitus, the current study was established to design and synthesize aryl-quinoline-4-carbonyl hydrazone bearing different 2-methoxyphenoxyacetamide (11a-o) and the structure of all derivatives was confirmed through various techniques including IR, 1H-NMR, 13C-NMR and elemental analysis. Next, the α-glucosidase inhibitory potentials of all derivatives were evaluated, and all compounds displayed potent inhibition with IC50 values in the range of 26.0 ± 0.8-459.8 ± 1.5 µM as compared to acarbose used as control, except 11f and 11l. Additionally, in silico-induced fit docking and molecular dynamics studies were performed to further investigate the interaction, orientation, and conformation of the newly synthesized compounds over the active site of α-glucosidase.

Synthesis, in vitro potency of inhibition, enzyme kinetics and in silico studies of quinoline-based α-glucosidase inhibitors.

Diabetes mellitus is a multifactorial global health disorder that is rising at an alarming rate. One effective therapeutic approach for controlling hyperglycemia associated with type-2 diabetes is to target α-glucosidase, which catalyzes starch hydrolysis in the intestine. In an attempt to find potential α-glucosidase inhibitors, a series of twenty new quinoline linked benzothiazole hybrids (8a-t) were synthesized in good yields from suitable reaction procedures and their chemical structures were analyzed by 1HNMR, 13CNMR, IR, and ESI-MS analysis. The synthesized derivatives further screened for their activity against α-glucosidase. Among them, compounds 8b, 8h, 8n and 8o exhibited remarkable α-glucosidase inhibitory activity with IC50 values ranging from 38.2 ± 0.3 to 79.9 ± 1.2 µM compared with standard drug acarbose (IC50 = 750.0 ± 2.0 µM). Enzyme kinetic studies of the most active compound (8h) indicated a non-competitive inhibition with Ki value of 38.2 µM. Moreover, the homology modeling, molecular docking and molecular dynamics simulation studies were conducted to reveal key interactions between the most active compound 8h and the targeted enzyme. These results are complementary to the experimental observations. In order to predict the druggability of the novel derivatives, the pharmacokinetic properties were also applied. These findings could be useful for the design and development of new α-glucosidase inhibitors.

Additional PfCRT mutations driven by selective pressure for improved fitness can result in the loss of piperaquine resistance and altered Plasmodium falciparum physiology.

IMPORTANCE: Our study leverages gene editing techniques in Plasmodium falciparum asexual blood stage parasites to profile novel mutations in mutant PfCRT, an important mediator of piperaquine resistance, which developed in Southeast Asian field isolates or in parasites cultured for long periods of time. We provide evidence that increased parasite fitness of these lines is the primary driver for the emergence of these PfCRT variants. These mutations differentially impact parasite susceptibility to piperaquine and chloroquine, highlighting the multifaceted effects of single point mutations in this transporter. Molecular features of drug resistance and parasite physiology were examined in depth using proteoliposome-based drug uptake studies and peptidomics, respectively. Energy minimization calculations, showing how these novel mutations might impact the PfCRT structure, suggested a small but significant effect on drug interactions. This study reveals the subtle interplay between antimalarial resistance, parasite fitness, PfCRT structure, and intracellular peptide availability in PfCRT-mediated parasite responses to changing drug selective pressures.

Quinoline-based thiazolyl-hydrazones target cancer cells through autophagy inhibition.

Heterocyclic pharmacophores such as thiazole and quinoline rings have a significant role in medicinal chemistry. They are considered privileged structures since they constitute several Food and Drug Administration (FDA)-approved drugs for cancer treatment. Herein, we report the synthesis, in silico evaluation of the ADMET profiles, and in vitro investigation of the anticancer activity of a series of novel thiazolyl-hydrazones based on the 8-quinoline (1a-c), 2-quinoline (2a-c), and 8-hydroxy-2-quinolyl moiety (3a-c). The panel of several human cancer cell lines and the nontumorigenic human embryonic kidney cell line HEK-293 were used to evaluate the compound-mediated in vitro anticancer activities, leading to [2-(2-(quinolyl-8-ol-2-ylmethylene)hydrazinyl)]-4-(4-methoxyphenyl)-1,3-thiazole (3c) as the most promising compound. The study revealed that 3c blocks the cell-cycle progression of a human colon cancer cell line (HCT-116) in the S phase and induces DNA double-strand breaks. Also, our findings demonstrate that 3c accumulates in lysosomes, ultimately leading to the cell death of the hepatocellular carcinoma cell line (Hep-G2) and HCT-116 cells, by the mechanism of autophagy inhibition.

Antibacterial Activity of Quinoline-Based Derivatives against Methicillin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa: Design, Synthesis, DFT and Molecular Dynamic Simulations.

Bacterial virulence becomes a significant challenge for clinical treatments, particularly those characterized as Multi-Drug-Resistant (MDR) strains. Therefore, the preparation of new compounds with active moieties could be a successful approach for eradication of MDR strains. For this purpose, newly synthesized quinoline compounds were prepared and tested for their antimicrobial activity against Methicillin-Resistant Staphylococcus Aureus (MRSA) and Pseudomonas Aeruginosa (PA). Among the synthesized derivatives, compounds 1-(quinolin-2-ylamino)pyrrolidine-2,5-dione (8) and 2-(2-((5-methylfuran-2-yl)methylene)hydrazinyl)quinoline (12) were shown to possess the highest antimicrobial activity with the minimum inhibitory concentration with the values of 5±2.2 and10±1.5 µg/mL towards Pseudomonas aeruginosa without any activity towards MRSA. Interestingly, compounds 2-(2-((1H-indol-3-yl)methylene)hydrazinyl)quinoline (13) and 2-(4-bromophenyl)-3-(quinolin-2-ylamino)thiazolidin-4-one (16c) showed significant inhibition activity against Staphylococcus aureus MRSA and Pseudomonas aeruginosa. Compound 13 (with indole moiety) particularly displayed excellent bactericidal activity with low MIC values 20±3.3 and 10±1.5 µg/mL against Staphylococcus aureus MRSA and Pseudomonas aeruginosa, respectively. Effects molecular modelling was used to determine the mode of action for the antimicrobial effect. The stability of complexes formed by docking and target-ligand pairing was evaluated using molecular dynamics simulations. The compounds were also tested for binding affinity to the target protein using MM-PBSA. Density-functional theory (DFT) calculations were also used to investigate the electrochemical properties of various compounds.

Carbon-to-nitrogen single-atom transmutation of azaarenes.

When searching for the ideal molecule to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom1. Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines2, but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis3. Here, we report a transformation that enables the direct conversion of a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines. Oxidative restructuring of the parent azaarene gives a ring-opened intermediate bearing electrophilic sites primed for ring reclosure and expulsion of a carbon-based leaving group. Such a 'sticky end' approach subverts existing atom insertion-deletion approaches and as a result avoids skeleton-rotation and substituent-perturbation pitfalls common in stepwise skeletal editing. We show a broad scope of quinolines and related azaarenes, all of which can be converted into the corresponding quinazolines by replacement of the C3 carbon with a nitrogen atom. Mechanistic experiments support the critical role of the activated intermediate and indicate a more general strategy for the development of C-to-N transmutation reactions.

Fused Tetrahydroquinolines Are Interfering with Your Assay.

Tricyclic tetrahydroquinolines (THQs) have been repeatedly reported as hits across a diverse range of high-throughput screening (HTS) campaigns. The activities of these compounds, however, are likely due to reactive byproducts that interfere with the assay. As a lesser studied class of pan-assay interference compounds, the mechanism by which fused THQs react with protein targets remains largely unknown. During HTS follow-up, we characterized the behavior and stability of several fused tricyclic THQs. We synthesized key analogues to pinpoint the cyclopentene ring double bond as a source of reactivity of fused THQs. We found that these compounds degrade in solution under standard laboratory conditions in days. Importantly, these observations make it likely that fused THQs, which are ubiquitously found within small molecule screening libraries, are unlikely the intact parent compounds. We urge deprioritization of tricylic THQ hits in HTS follow-up and caution against the investment of resources to follow-up on these problematic compounds.

Novel 1,2,3-Triazole-Containing Quinoline-Benzimidazole Hybrids: Synthesis, Antiproliferative Activity, In Silico ADME Predictions, and Docking.

The newly synthesized quinoline-benzimidazole hybrids containing two types of triazole-methyl-phenoxy linkers were characterized via NMR and elemental analysis. Additional derivatization was achieved by introducing bromine at the C-2 position of the phenoxy core. These novel hybrids were tested for their effects on the growth of the non-tumor cell line MRC-5 (human fetal lung fibroblasts), leukemia and lymphoma cell lines: Hut78, THP-1 and HL-60, and carcinoma cell lines: HeLa and CaCo-2. The results obtained, presented as the concentration that achieves 50% inhibition of cell growth (IC50 value), show that the compounds tested affect tumor cell growth differently depending on the cell line and the dose applied (IC50 ranged from 0.2 to >100 µM). The quinoline-benzimidazole hybrids tested, including 7-chloro-4-(4-{[4-(5-methoxy-1H-1,3-benzo[d]imidazol-2-yl)phenoxy]methyl}-1H-1,2,3-triazol-1-yl)quinoline 9c, 2-(3-bromo-4-{[1-(7-chloroquinolin-4-yl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 10e, 2-{4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 14e and 2-{3-bromo-4-[(1-{2-[(7-chloroquinolin-4-yl)amino]ethyl}-1H-1,2,3-triazol-4-yl)methoxy]phenyl}-N-propyl-1H-benzo[d]imidazol-5-carboximidamide trihydrochloride 15e, arrested the cell cycle of lymphoma (HuT78) cells. The calculated ADMET properties showed that the synthesized compounds violated at most two of Lipinski's rules, making them potential drug candidates, but mainly for parenteral use due to low gastrointestinal absorption. The quinoline-benzimidazole hybrid 14e, which was shown to be a potent and selective inhibitor of lymphoma cell line growth, obtained the highest binding energy (-140.44 kcal/mol), by docking to the TAO2 kinase domain (PDB: 2GCD).

Arylidene and amino spacer-linked rhodanine-quinoline hybrids as upgraded antimicrobial agents.

Antibiotic resistance associated with various microorganisms such as Gram-positive, Gram-negative, fungal strains, and multidrug-resistant tuberculosis increases the risk of healthcare survival. Preliminary therapeutics becoming ineffective that might lead to noteworthy mortality presents a crucial challenge for the scientific community. Hence, there is an urgent need to develop hybrid compounds as antimicrobial agents by combining two or more bioactive heterocyclic moieties into a single molecular framework with fewer side effects and a unique mode of action. This review highlights the recent advances (2013-2023) in the pharmacology of rhodanine-linked quinoline hybrids as more effective antimicrobial agents. In the drug development process, linker hybrids acquire the top position due to their excellent π-stacking and Van der Waals interaction with the DNA active sites of pathogens. A molecular hybridization strategy has been optimized, indicating that combining these two bioactive moieties with an arylidene and an amino spacer linker increases the antimicrobial potential and reduces drug resistance. Moreover, the structure-activity relationship study is discussed to express the role of various functional groups in improving and decrementing antimicrobial activities for rational drug design. Also, a linker approach may accelerate the development of dynamic antimicrobial agents through molecular hybridization.

Recruitment of hexahydroquinoline as anticancer scaffold targeting inhibition of wild and mutants EGFR (EGFRWT, EGFRT790M, and EGFRL858R).

Hexahydroquinoline (HHQ) scaffold was constructed and recruited for development of new series of anticancer agents. Thirty-two new compounds were synthesised where x-ray crystallography was performed to confirm enantiomerism. Thirteen compounds showed moderate to good activity against NCI 60 cancer cell lines, with GI % mean up to 74% for 10c. Expending erlotinib as a reference drug, target compounds were verified for their inhibiting activities against EGFRWT, EGFRT790M, and EGFRL858R where compound 10d was the best inhibitor with IC50 = 0.097, 0.280, and 0.051 µM, respectively, compared to erlotinib (IC50 = 0.082 µM, 0.342 µM, and 0.055 µM, respectively). Safety profile was validated using normal human lung (IMR-90) cells. 10c and 10d disrupted cell cycle at pre-G1 and G2/M phases in lung cancer, HOP-92, and cell line. Molecular docking study was achieved to understand the potential binding interactions and affinities in the active sites of three versions of EGFRs.

New 32 hexahydroquinoline (HHQ) analogues 6a­i, 8a­m, 10a­d, and 12a­f having the same features of EGFR inhibitors were synthesised in racemic mixtures.The antiproliferative activities were assessed towards 60 cancer cell lines which were efficiently inhibited by compound 10c.Compound 10d remarkably inhibited EGFR^WT, EGFR^T790M, and EGFR^L858R.Cell cycle analysis and Annexin V-based flow cytometry in the HOP-92 lung cancer cells were performed.The safety profile of compounds 10c and 10d was validated using normal human lung (IMR-90) cells.Molecular docking studies revealed that the S-isomers exhibited higher affinity than R-isomers to active sites.

Quinoline Hydrazone Derivatives as New Antibacterials against Multidrug Resistant Strains.

To develop novel antimicrobial agents a series of 2(4)-hydrazone derivatives of quinoline were designed, synthesized and tested. QSAR models of the antibacterial activity of quinoline derivatives were developed by the OCHEM web platform using different machine learning methods. A virtual set of quinoline derivatives was verified with a previously published classification model of anti-E. coli activity and screened using the regression model of anti-S. aureus activity. Selected and synthesized 2(4)-hydrazone derivatives of quinoline exhibited antibacterial activity against the standard and antibiotic-resistant S. aureus and E. coli strains in the range from 15 to 30 mm by the diameter of growth inhibition zones. Molecular docking showed the complex formation of the studied compounds into the catalytic domain of dihydrofolate reductase with an estimated binding affinity from -8.4 to -9.4 kcal/mol.

Synthesis of 4-(Phenylchalcogenyl)tetrazolo[1,5-a]quinolines by Bicyclization of 2-Azidobenzaldehydes with Phenylchalcogenylacetonitrile.

A general methodology to access valuable 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinolines was developed by the reaction of 2-azidobenzaldehyde with phenylchalcogenylacetonitriles (sulfur and selenium) in the presence of potassium carbonate (20 mol%) as a catalyst. The reactions were conducted using a mixture of dimethylsulfoxide and water (7:3) as solvent at 80 °C for 4 h. This new methodology presents a good functional group tolerance to electron-deficient and electron-rich substituents, affording a total of twelve different 4-(phenylchalcogenyl)tetrazolo[1,5-a]quinolines selectively in moderate to excellent yields. The structure of the synthesized 4-(phenylselanyl)tetrazolo[1,5-a]quinoline was confirmed by X-ray analysis.

Tetrahydrobenzo[h]quinoline derivatives as a novel chemotype for dual antileishmanial-antimalarial activity graced with antitubercular activity: Design, synthesis and biological evaluation.

Derivatives with tetrahydrobenzo[h]quinoline chemotype were synthesized via one-pot reactions and evaluated for their antileishmanial, antimalarial and antitubercular activities. Based on a structure-guided approach, they were designed to possess antileishmanial activity through antifolate mechanism, via targeting Leishmania major pteridine reductase 1 (Lm-PTR1). The in vitro antipromastigote and antiamastigote activity are promising for all candidates and superior to the reference miltefosine, in a low or sub micromolar range of activity. Their antifolate mechanism was confirmed via the ability of folic and folinic acids to reverse the antileishmanial activity of these compounds, comparably to Lm-PTR1 inhibitor trimethoprim. Molecular dynamics simulations confirmed a stable and high potential binding of the most active candidates against leishmanial PTR1. For the antimalarial activity, most of the compounds exhibited promising antiplasmodial effect against P. berghei with suppression percentage of up to 97.78%. The most active compounds were further screened in vitro against the chloroquine resistant strain P. falciparum, (RKL9) and showed IC50 value range of 0.0198-0.096 µM, compared to IC50 value of 0.19420 µM for chloroquine sulphate. Molecular docking of the most active compounds against the wild-type and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Some candidates showed good antitubercular activity against sensitive Mycobacterium tuberculosis in a low micromolar range of MIC, compared to 0.875 µM of isoniazid. The top active ones were further tested against a multidrug-resistant strain (MDR) and extensively drug-resistant strain (XDR) of Mycobacterium tuberculosis. Interestingly, the in vitro cytotoxicity test of the best candidates displayed high selectivity indices emphasizing their safety on mammalian cells. Generally, this work introduces a fruitful matrix for new dual acting antileishmanial-antimalarial chemotype graced with antitubercular activity. This would help in tackling drug-resistance issues in treating some Neglected Tropical Diseases.

Sequence-Specific Dual DNA Binding Modes and Cytotoxicities of N-6-Functionalized Norcryptotackieine Alkaloids.

Norcryptotackieine (1a) belongs to the indoloquinoline class of alkaloids isolated from Cryptolepis sanguinolenta, a plant species that has been traditionally used as an antimalarial agent. Additional structural modifications of 1a can potentially enhance its therapeutic potency. Indoloquinolines such as cryptolepine, neocryptolepine, isocryptolepine, and neoisocryptolepine show restricted clinical applications owing to their cytotoxicity deriving from interactions with DNA. Here, we examined the effect of substitutions at the N-6 position of norcryptotackieine on the cytotoxicity, as well as structure-activity relationship studies pertaining to sequence specific DNA-binding affinities. The representative compound 6d binds DNA in a nonintercalative/pseudointercalative fashion, in addition to nonspecific stacking on DNA, in a sequence selective manner. The DNA-binding studies clearly establish the mechanism of DNA binding by N-6-substituted norcryptotackieines and neocryptolepine. The synthesized norcryptotackieines 6c,d and known indoloquinolines were screened on different cell lines (HEK293, OVCAR3, SKOV3, B16F10, and HeLa) to assess their cytotoxicity. Norcryptotackieine 6d (IC50 value of 3.1 µM) showed 2-fold less potency when compared to the natural indoloquinoline cryptolepine 1c (IC50 value of 1.64 µM) in OVCAR3 (ovarian adenocarcinoma) cell lines.