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Herein we present the design and the synthesis of novel substituted coumarin– benzimidazole/benzothiazole hybrids bearing a cyclic amidino group on the benzazole core as biologically active agents. All prepared compounds were evaluated for their in vitro antiviral and antioxidative activity as well as for their in vitro antiproliferative activity against a panel of several human cancer cell lines. Coumarin– benzimidazole hybrid 10 (EC50 9.0–43.8 μM) displayed the most promising broad spectrum antiviral activity, while two other coumarin– benzimidazole hybrids 13 and 14 showed the highest antioxidative capacity in the ABTS assay, superior to the reference standard BHT (IC50 0.17 and 0.11 mM, respectively). Computational analysis supported these results and demonstrated that these hybrids benefit from the high C–H hydrogen atom releasing tendency of the cationic amidine unit, and the pronounced ease with which they can liberate an electron, promoted by the electron- donating diethylamine group on the coumarin core. The coumarin ring substitution at position 7 with a N, N-diethylamino group also caused a significant enhancement of the antiproliferative activity, with the most active compounds being derivatives with a 2-imidazolinyl amidine group 13 (IC50 0.3– 1.9 μM) and benzothiazole derivative with a hexacyclic amidine group 18 (IC50 1.3–2.0 μM).

INTRODUCTION: The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are hexanucleotide repeats in chromosome 9 open reading frame 72 (C9orf72). These repeats produce dipeptide repeat proteins with poly(PR) being the most toxic one. METHODS: We performed a kinome-wide CRISPR/Cas9 knock-out screen in human induced pluripotent stem cell (iPSC) -derived cortical neurons to identify modifiers of poly(PR) toxicity, and validated the role of candidate modifiers using in vitro, in vivo, and ex-vivo studies. RESULTS: Knock-down of NIMA-related kinase 6 (NEK6) prevented neuronal toxicity caused by poly(PR). Knock-down of nek6 also ameliorated the poly(PR)-induced axonopathy in zebrafish and NEK6 was aberrantly expressed in C9orf72 patients. Suppression of NEK6 expression and NEK6 activity inhibition rescued axonal transport defects in cortical neurons from C9orf72 patient iPSCs, at least partially by reversing p53-related DNA damage. DISCUSSION: We identified NEK6, which regulates poly(PR)-mediated p53-related DNA damage, as a novel therapeutic target for C9orf72 FTD/ALS. ispartof: ALZHEIMERS & DEMENTIA vol:19 issue:4 pages:1245-1259 ispartof: location:United States status: published

Purpose: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports different cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibiting XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in phase-II/IIb clinical trials when dosed 1 to 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily. Here, we investigate and validate the drug–target interaction of KPT-8602 and explore its activity against acute lymphoblastic leukemia (ALL).Experimental Design: We examined the effect of KPT-8602 on XPO1 function and XPO1-cargo as well as on a panel of leukemia cell lines. Mutant XPO1 leukemia cells were designed to validate KPT-8602′s drug-target interaction. In vivo, anti-ALL activity was measured in a mouse ALL model and patient-derived ALL xenograft models.Results: KPT-8602 induced caspase-dependent apoptosis in a panel of leukemic cell lines in vitro. Using CRISPR/Cas9 genome editing, we demonstrated the specificity of KPT-8602 for cysteine 528 in the cargo-binding groove of XPO1 and validated the drug target interaction. In vivo, KPT-8602 showed potent anti-leukemia activity in a mouse ALL model as well as in patient-derived T- and B-ALL xenograft models without affecting normal hematopoiesis.Conclusions: KPT-8602 is highly specific for XPO1 inhibition and demonstrates potent anti-leukemic activity supporting clinical application of the second-generation SINE compound for the treatment of ALL. Clin Cancer Res; 23(10); 2528–41. ©2016 AACR.

Purpose:Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease urgently requiring new treatments. Overexpression of the protein transporter exportin-1 (XPO1) leads to mislocalization of tumor-suppressor proteins (TSP) and their inactivation. Earlier, we showed that blocking XPO1 by CRISPR/Cas9 validated Selective Inhibitor of Nuclear Export (SINE) compounds (selinexor and analogs) restores the antitumor activity of multiple TSPs leading to suppression of PDAC in vitro and in orthotopic models.Experimental Design:We evaluate the synergy between SINE compounds and standard-of-care treatments in preclinical models and in a PDAC Phase Ib trial.Results:SINE compounds synergize with gemcitabine (GEM) and nanoparticle albumin–bound (nab)-paclitaxel leading to suppression of PDAC cellular growth and cancer stem cell (CSC) spheroids disintegration. Label-free quantitative proteome profiling with nuclear and cytoplasmic enrichment showed superior enhancement in nuclear protein fraction in combination treatment. Selinexor inhibited the growth of PDAC CSC and two patient-derived (PDX) subcutaneous xenografts. Selinexor–GEM–nab-paclitaxel blocked PDX and orthotopic tumor growth. In a phase 1b study (NCT02178436), 9 patients were exposed to selinexor (60 mg oral) with GEM (1,000 mg/m2 i.v.) and nab-paclitaxel (125 mg/m2 i.v.) on days 1, 8, and 15 of 28-day cycle. Two patients showed partial response, and 2 had stable disease. An outstanding, durable objective response was observed in one of the responders with progression-free survival of 16 months and overall survival of 22 months.Conclusions:Our preclinical and ongoing clinical study lends support to the use of selinexor–GEM–nab-paclitaxel as an effective therapy for metastatic PDAC.

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Supplementary Table 1 - EC50 values for KPT-8602 and KPT-330 in different leukemia cells Supplementary Table 2 - EC50 values for KPT-8602 in wild-type versus XPO1C528S mutant cell lines Figure S1 - High content images of HeLa cells stably expressing the NLS-AcGFP-NES reporter treated with different concentrations KPT-330 or KPT-8602 Figure S2 - Effect of KPT-8602 treatment on normal peripheral blood cells of NSG mice

An enzymatic method has been successfully established enabling the generation of partially base-modified RNA (previously named RZA) constructs, in which all G residues were replaced by isomorphic fluorescent thienoguanosine (thG) analogs, as well as fully modified RZA featuring thG, 5-bromocytosine, 7-deazaadenine and 5-chlorouracil. The transcriptional efficiency of emissive fully modified RZA was found to benefit from the use of various T7 RNA polymerase variants. Moreover, dthG could be incorporated into PCR products by Taq DNA polymerase together with the other three base-modified nucleotides. Notably, the obtained RNA products containing thG as well as thG together with 5-bromocytosine could function as effectively as natural sgRNAs in an in vitro CRISPR-Cas9 cleavage assay. N1-Methylpseudouridine was also demonstrated to be a faithful non-canonical substitute of uridine to direct Cas9 nuclease cleavage when incorporated in sgRNA. The Cas9 inactivation by 7-deazapurines indicated the importance of the 7-nitrogen atom of purines in both sgRNA and PAM site for achieving efficient Cas9 cleavage. Additional aspects of this study are discussed in relation to the significance of sgRNA-protein and PAM--protein interactions that were not highlighted by the Cas9-sgRNA-DNA complex crystal structure. These findings could expand the impact and therapeutic value of CRISPR-Cas9 and other RNA-based technologies.With the advent of CRISPR-Cas9 gene editing, we now have to hand a simple two-component system amendable to silencing and knock-in editing effectively any gene. Yet we must not forget that the implications of immunotoxicity along with the poor stability and specificity of canonical nucleic acids hold enormous challenges for in vivo applications, especially in gene therapy. Our study endorses the feasibility of the enzymatic approach to incorporate nucleobase modifications into the CRISPR-Cas9 system unveiling the tolerance of Cas9 to N1-methylpseudouridine (m1Ψ)- and emissive thienoguanosine (thG)-modified sgRNA as well as thus far uncharted structural requirements for ensuring proper PAM recognition.

A series of cyano- and amidino-substituted imidazo[4,5-b]pyridines were synthesized using standard methods of organic synthesis, and their biological activity was evaluated. Biological evaluation included in vitro assessment of antiproliferative effects on a diverse selection of human cancer cell lines, antibacterial activity against chosen Gram-positive and Gram-negative bacterial strains, and antiviral activity on a broad panel of DNA and RNA viruses. The most pronounced antiproliferative activity was observed for compound 10, which contained an unsubstituted amidino group, and compound 14, which contained a 2-imidazolinyl amidino group; both displayed selective and strong activity in sub-micromolar inhibitory concentration range against colon carcinoma (IC50 0.4 and 0.7 μM, respectively). All tested compounds lacked antibacterial activity, with the exception of compound 14, which showed moderate activity against E. coli (MIC 32 μM). Bromo-substituted derivative 7, which contained an unsubstituted phenyl ring (EC50 21 μM), and para-cyano-substituted derivative 17 (EC50 58 μM) showed selective but moderate activity against respiratory syncytial virus (RSV). ispartof: MOLECULES vol:28 issue:1 ispartof: location:Switzerland status: published

Vallve, Maria Lourdes Farre. Fundacao Oswaldo Cruz. Instituto Goncalo Moniz. Salvador, BA, Brasil. 1KU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, B-3000 Leuven, Belgium. 2KU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, B-3000 Leuven, Belgium. 3Karyopharm Therapeutics, Newton, MA, USA. 4Instituto de Pesquisa Goncalo Moniz, Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil. 5HUPES, Federal University of Bahia (UFBA), Salvador-Bahia, Brazil. 6Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan

In synthetic biology, small molecules are commonly used for altering gene expression through the (in)activation of gene switches. Current switches, however, have a narrow species range, are non-titratable, or use non-inert inducers which evoke important side effects. Universal gene switches (XRs) that have dynamic ranges without interference with the host cell physiology will overcome these limitations. Ideal starting points for developing such XRs are the steroid receptors (SRs). The SRs are frequently applied as regulator domain or gene switch in organisms in which they are not naturally expressed, like microbes and plants. Several SRs, such as the estrogen receptor alpha (ERα), have been redesigned to respond to synthetic effectors but these variants require inducer amounts that are detrimental to the host or affect endogenous SRs. By combining in silico modelling with directed evolution in the yeast Saccharomyces cerevisiae, we developed a platform and strategy for evolving SRs towards a chemical of choice. Validation of this method was achieved by first evolving the ERα to employ tamoxifen as an agonist, yielding the preTERRA variant. Subsequently, activation by estradiol was removed, rendering a tamoxifen receptor (TERRA). We show that TERRA gets activated by subtoxic tamoxifen amounts while remaining insensitive for physiological estradiol levels. Further evaluation demonstrated TERRA to be transferable to mammalian cells. Ongoing research aims at converting the TERRA receptor into a regulatory domain for controlling nuclear translocation of Cre recombinases and Cas9 proteins in both cell lines and mouse models. The same platform was employed for adapting ERα towards the plasticizer Bisphenol A. This yielded an ERα variant that is no longer inducible by estradiol but is responsive to lower concentrations of Bisphenol in yeast. The transferal to cell lines will provide us with an additional regulatory domain. The ability to engineer any SR towards a synthetic ligand of choice not only expands the synthetic biology toolbox but can find applications in landscaping SR-related drug resistance and ligand-inducibility. Presentation: Saturday, June 11, 2022 1:48 p.m. - 1:53 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Taking the previously reported compound BH-7d as the lead, we designed and synthesized a series of piperidinyl-substituted [1,2,4]triazolo[1,5-a]pyrimidines, and their anti-HIV activities as well as cytotoxicities were evaluated. Several compounds exhibited moderate anti-HIV (IIIB) potency, among which 2b was the most active one (EC50 = 4.29 μM). Structure-activity relationships derived from the antiretroviral results were analyzed. Additionally, most compounds demonstrated reduced cytotoxicity (CC50 > 200 μM) compared with those of BH-7d and etravirine. Molecular docking study further revealed the binding conformation of 2b in the binding pocket of HIV-1 reverse transcriptase. ispartof: CHEMICAL BIOLOGY & DRUG DESIGN vol:97 issue:1 pages:67-76 ispartof: location:England status: published

Several key functions of the androgen receptor (AR) such as hormone recognition and co-regulator recruitment converge in the ligand binding domain (LBD). Loss- or gain-of-function of the AR contributes to pathologies such as the androgen insensitivity syndrome and prostate cancer. Here, we describe a gain-of-function mutation of the surface-exposed threonine at position 850, located at the amino-terminus of Helix 10 (H10) in the AR LBD. Since T850 phosphorylation was reported to affect AR function, we created the phosphomimetic mutation T850D. The AR T850D variant has a 1.5- to 2-fold increased transcriptional activity with no effect on ligand affinity. In the androgen responsive LNCaP cell line grown in medium with low androgen levels, we observed a growth advantage for cells in which the endogenous AR was replaced by AR T850D. Despite the distance to the AF2 site, the AR T850D LBD displayed an increased affinity for coactivator peptides as well as the 23FQNLF27 motif of AR itself. Molecular Dynamics simulations confirm allosteric transmission of the T850D mutation towards the AF2 site via extended hydrogen bond formation between coactivator peptide and AF2 site. This mechanistic study thus confirms the gain-of-function character of T850D and T850 phosphorylation for AR activity and reveals details of the allosteric communications within the LBD. ispartof: International Journal Of Molecular Sciences vol:23 issue:3 ispartof: location:Switzerland status: Published online

Exportin 1 (XPO1/CRM1) is a key nuclear transport receptor (karyopherin) responsible for the export of different cargo proteins out of the cell’s nucleus into the cytoplasm. Its correct function is essential for cellular homeostasis, however normal XPO1 function is often disrupted in malignant cells. XPO1 is overexpressed in solid and hematological tumors and higher XPO1 expression is often associated with poorer prognosis. XPO1-regulated cargo proteins include tumor suppressor proteins and cell cycle regulators that can be involved in tumorigenesis. For example, aberrant XPO1 function may lead to cytoplasmic mislocalization of tumor suppressor proteins which results in their functional inactivation and hence may cause tumorigenesis. Inhibition of XPO1 function will restore their proper subcellular localization and function and cause tumor regression. Although XPO1 has a central role in cellular homeostasis, it is a good target for cancer therapy, as illustrated by the clinical success of the selective inhibitor of nuclear export (SINE) selinexor. Selinexor is the first and currently the only XPO1 inhibitor clinically approved. It is applied for the treatment of patients with multiple myeloma after at least one prior treatment, and for the treatment of diffuse large B cell lymphoma. Selinexor covalently binds to XPO1. The second generation SINE eltanexor is also a covalent XPO1 inhibitor but has only minimal brain penetration and consequently lower toxicity in preclinical studies. Here, we describe a novel chemical class of reversible XPO1 inhibitors with high brain penetration but with good tolerability allowing frequent dosing in preclinical models. The lead compound, FR-027, potently inhibits XPO1 function (EC50 69 ± 10 nM) and shows potent cancer cell growth inhibition in vitro of both hematological and solid cancer cell lines (EC50 50-950 nM). FR-027 is a reversible inhibitor of XPO1 and unlike many other XPO1 inhibitors it does not induce XPO1 protein degradation; this may contribute to an increased tolerability. Indeed, while it shows high brain penetration, FR-027 allows frequent dosing in mice with good tolerability (body weight). It is orally bioavailable and demonstrates strong anti-leukemic efficacy in an aggressive MOLT-4 xenograft model. Importantly, it shows potent efficacy in both an orthotopic U87 MG brain tumor xenograft model and a metastatic syngeneic ID8-fLuc ovarian cancer model with significant survival benefit as monotherapy. Altogether, these results demonstrate that FR-027 is a novel, reversible XPO1 inhibitor with important molecular and pharmacological characteristics that warrant further clinical development. Citation Format: Janne Van Hauwenhuyse, Felien Reniers, Leentje Persoons, Sam Noppen, Eline Boel, Els Vanstreels, Ann Vankerckhoven, Bert Kwanten, An Coosemans, Guy Van den Mooter, Wim Dehaen, Dirk Daelemans. A novel reversible inhibitor of XPO1 with potent efficacy in multiple preclinical mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1652.

Selinexor (KPT-330), a small-molecule inhibitor of exportin-1 (XPO1, CRM1) with potent anticancer activity, has recently been granted FDA approval for treatment of relapsed/refractory multiple myeloma and diffuse large B-cell lymphoma (DLBCL), with a number of additional indications currently under clinical investigation. Since selinexor has often demonstrated synergy when used in combination with other drugs, notably bortezomib and dexamethasone, a more comprehensive approach to uncover new beneficial interactions would be of great value. Moreover, stratifying patients, personalizing therapeutics and improving clinical outcomes requires a better understanding of the genetic vulnerabilities and resistance mechanisms underlying drug response. Here, we used CRISPR-Cas9 loss-of-function chemogenetic screening to identify drug-gene interactions with selinexor in chronic myeloid leukemia, multiple myeloma and DLBCL cell lines. We identified the TGFβ-SMAD4 pathway as an important mediator of resistance to selinexor in multiple myeloma cells. Moreover, higher activity of this pathway correlated with prolonged progression-free survival in multiple myeloma patients treated with selinexor, indicating that the TGFβ-SMAD4 pathway is a potential biomarker predictive of therapeutic outcome. In addition, we identified ASB8 (ankyrin repeat and SOCS box containing 8) as a shared modulator of selinexor sensitivity across all tested cancer types, with both ASB8 knockout and overexpression resulting in selinexor hypersensitivity. Mechanistically, we showed that ASB8 promotes selinexor-induced proteasomal degradation of XPO1. This study provides insight into the genetic factors that influence response to selinexor treatment and could support both the development of predictive biomarkers as well as new drug combinations. ispartof: BIOMEDICINE & PHARMACOTHERAPY vol:160 ispartof: location:France status: published

Target deconvolution of new bioactive agents identified from phenotypic screens remains a challenging task. The discovery of mutations that confer resistance to such agents is regarded as the gold standard proof of target identification. Here, we describe a method that exploits the error-prone repair of CRISPR-induced DNA double-strand breaks to enhance mutagenesis and increase the incidence of drug resistance mutations in essential genes. As each DNA double-strand break is introduced at a targeted genomic site predefined by the presence of a protospacer adjacent motif (PAM) and a particular CRISPR single guide RNA (sgRNA), the genetic location of drug resistance mutations can be easily uncovered through targeted sequencing of CRISPR sgRNAs. Moreover, the method allows for the identification of not only the drug target gene, but also the drug-binding domain within the target gene.

Target deconvolution of new bioactive agents identified from phenotypic screens remains a challenging task. The discovery of mutations that confer resistance to such agents is regarded as the gold standard proof of target identification. Here, we describe a method that exploits the error-prone repair of CRISPR-induced DNA double-strand breaks to enhance mutagenesis and increase the incidence of drug resistance mutations in essential genes. As each DNA double-strand break is introduced at a targeted genomic site predefined by the presence of a protospacer adjacent motif (PAM) and a particular CRISPR single guide RNA (sgRNA), the genetic location of drug resistance mutations can be easily uncovered through targeted sequencing of CRISPR sgRNAs. Moreover, the method allows for the identification of not only the drug target gene, but also the drug-binding domain within the target gene.

Two series of new pyridyl-bearing fused bicyclic analogues designed to target the dual-tolerant regions of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket were synthesized and evaluated for their anti-HIV activities. Several compounds, such as 6, 14, 15, 21, 30, and 33, were found to be potent inhibitors against the wild-type (WT) HIV-1 strain or multiple NNRTI-resistant strains at low nanomolar levels. Detailed structure-activity relationships were obtained by utilizing the variation of moieties within the corresponding pharmacophores. In vitro metabolic stability profiles and some drug-like properties of selected compounds were assessed, furnishing the preliminary structure-metabolic stability relationships. Furthermore, molecular modeling studies elucidated the binding modes of compounds 6, 15, 21, and 30 in the binding pocket of WT, E138K, K103N, or Y181C HIV-1 RTs. These promising compounds can be used as lead compounds and warrant further structural optimization to yield more active HIV-1 inhibitors.

Two novel series of human immunodeficiency virus-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) bearing a thiophene[3,2-d]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated activity against the wild-type (WT) HIV-1 strain in MT-4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV-1. Compound 7 (EC50 = 0.014, 0.031 μM) achieved the most potent activity against the two mutants, being more effective than that of nevirapine (NVP, EC50 = 7.572, 0.190 μM) and comparable to that of etravirine (ETV, EC50 = 0.004, 0.014 μM). Molecular docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization.

A novel series of acetamide-substituted derivatives and two prodrugs of doravirine were designed and synthesized as potent HIV-1 NNRTIs by employing the structure-based drug design strategy. In MT-4 cell-based assays using the MTT method, it was found that most of the new compounds exhibited moderate to excellent inhibitory potency against the wild-type (WT) HIV-1 strain with a minimum EC50 value of 54.8 nM. Among them, the two most potent compounds 8i (EC50 = 59.5 nM) and 8k (EC50 = 54.8 nM) displayed robust activity against WT HIV-1 with double-digit nanomolar EC50 values, being superior to lamivudine (3TC, EC50 = 12.8 μM) and comparable to doravirine (EC50 = 13 nM). Besides, 8i and 8k shown moderate activity against the double RT mutant (K103N + Y181C) HIV-1 RES056 strain. The HIV-1 RT inhibition assay further validated the binding target. Molecular simulation of the representative compounds was employed to provide insight on their structure-activity relationships (SARs) and direct future design efforts. Finally, the aqueous solubility and chemical stability of the prodrugs 9 and 10 were investigated in detail.

A convenient strategy for molecular editing of available ent-kauranic natural scaffolds has been developed based on radical mediated C-C bond formation. Iodine atom transfer radical addition (ATRA) followed by rapid ionic elimination and radical azidoalkylation were investigated. Both reactions involve radical addition to the exo-methylenic double bond of the parent substrate. Easy transformations of the obtained adducts lead to extended diterpenes of broad structural diversity and artificial diterpene-alkaloid hybrids possessing lactam and pyrrolidine pharmacophores. The cytotoxicity of selected diterpenic derivatives was examined by in vitro testing on several tumor cell lines. The terpene-alkaloid hybrids containing N-heterocycles with unprecedented spiro-junction have shown relevant cytotoxicity and promising selectivity indexes. These results represent a solid basis for following research on the synthesis of such derivatives based on available natural product templates. ispartof: MOLECULES vol:26 issue:15 ispartof: location:Switzerland status: published

Graphic abstract A new series of ( ±)-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl)(phenyl)methanones were efficiently synthesized starting from 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol 1, acetyl acetone 2, various aromatic and heterocyclic aldehydes 3 and phenacyl bromides 4. All the newly synthesized compounds were tested for their antiviral and antitumoral activity. It was shown that subtle structural variations on the phenyl moiety allowed to tune biological properties toward antiviral or antitumoral activity. Mode-of-action studies revealed that the antitumoral activity was due to inhibition of tubulin polymerization. Supplementary Information The online version contains supplementary material available at 10.1007/s11030-021-10258-8.

Graphical abstract In the present study, we report the design and synthesis of novel amide-type hybrid molecules based on anthranilic acid and quinoline or β-carboline heterocyclic scaffolds. Three types of biological screenings were performed: (i) in vitro antiproliferative screening against a panel of solid tumor and leukemia cell lines, (ii) antiviral screening against several RNA viruses, and (iii) anti-quorum sensing screening using gram-negative Chromobacterium violaceum as the reporter strain. Antiproliferative screening revealed a high activity of several compounds. Anthranilamides 12 and 13 with chloroquine core and halogenated anthranilic acid were the most active agents toward diverse cancer cell lines such as glioblastoma, pancreatic adenocarcinoma, colorectal carcinoma, lung carcinoma, acute lymphoblastic, acute myeloid, chronic myeloid leukemia, and non-Hodgkin lymphoma, but also against noncancerous cell lines. Boc-protected analogs 2 and 3 showed moderate activities against the tested cancer cells without toxic effects against noncancerous cells. A nonhalogenated quinoline derivative 10 with N-benzylanthranilic acid residue was equally active as 12 and 13 and selective toward tumor cells. Chloroquine and quinoline anthranilamides 10–13 exerted pronounced antiviral effect against human coronaviruses 229E and OC43, whereas 12 and 13 against coronavirus OC43 (EC50 values in low micromolar range; selectivity indices from 4.6 to > 10.4). Anthranilamides 14 and 16 with PQ core inhibited HIV-1 with EC50 values of 9.3 and 14.1 µM, respectively. Compound 13 displayed significant anti-quorum/biofilm effect against the quorum sensing reporter strain (IC50 of 3.7 μM) with no apparent bactericidal effect. Supplementary Information The online version contains supplementary material available at 10.1007/s11030-021-10347-8.