Serendipitous Identification of Azine Anticancer Agents Using a Privileged Scaffold Morphing Strategy.

The use of privileged scaffolds as a starting point for the construction of libraries of bioactive compounds is a widely used strategy in drug discovery and development. Scaffold decoration, morphing and hopping are additional techniques that enable the modification of the chosen privileged framework and better explore the chemical space around it. In this study, two series of highly functionalized pyrimidine and pyridine derivatives were synthesized using a scaffold morphing approach consisting of triazine compounds obtained previously as antiviral agents. Newly synthesized azines were evaluated against lymphoma, hepatocarcinoma, and colon epithelial carcinoma cells, showing in five cases acceptable to good anticancer activity associated with low cytotoxicity on healthy fibroblasts. Finally, ADME in vitro studies were conducted on the best derivatives of the two series showing good passive permeability and resistance to metabolic degradation.

Design, Synthesis, and Biological Evaluation of Novel Coumarin Analogs Targeted against SARS-CoV-2.

SARS-CoV, an RNA virus, is contagious and displays a remarkable degree of adaptability, resulting in intricate disease presentations marked by frequent genetic mutations that can ultimately give rise to drug resistance. Targeting its viral replication cycle could be a potential therapeutic option to counter its viral growth in the human body leading to the severe infectious stage. The Mpro of SARS-CoV-2 is a promising target for therapeutic development as it is crucial for viral transcription and replication. The derivatives of ß-diketone and coumarin have already been reported for their antiviral potential and, thus, are considered as a potential scaffold in the current study for the computational design of potential analogs for targeting the viral replication of SARS-CoV-2. In our study, we used novel diketone-hinged coumarin derivatives against the SARS-CoV-2 MPro to develop a broad-spectrum antiviral agent targeting SARS-CoV-2. Through an analysis of pharmacokinetics and docking studies, we identified a list of the top 10 compounds that demonstrated effectiveness in inhibiting the SARS-CoV-2 MPro virus. On the basis of the pharmacokinetics and docking analyses, the top 5 novel coumarin analogs were synthesized and characterized. The thermodynamic stability of compounds KS82 and KS94 was confirmed by their molecular dynamics, and the stability of the simulated system indicated their inhibitory nature. Molecules KS82 and KS94 were further evaluated for their anti-viral potential using Vero E6 cells followed by RT-PCR assay against SARS-CoV-2. The test compound KS82 was the most active with the potential to inhibit SARS-CoV-2 replication in Vero E6 cells. These data indicate that KS82 prevents the attack of the virus and emerges as the primary candidate with promising antiviral properties.

Discovery of a series of benzopyrimidodiazepinone TNK2 inhibitors via scaffold morphing.

The protein kinase TNK2 (ACK1) is an emerging drug target for a variety of indications, in particular for cancer where it plays a key role transmitting cell survival, growth and proliferative signals via modification of multiple downstream effectors by unique tyrosine phosphorylation events. Scaffold morphing based on our previous TNK2 inhibitor XMD8-87 identified urea 17 from which we developed the potent and selective compound 32. A co-crystal structure was obtained showing 32 interacting primarily with the main chain atoms of an alanine residue of the hinge region. Additional H-bonds exist between the urea NHs and the Thr205 and Asp270 residues.

Discovery of 2-oxopiperazine dengue inhibitors by scaffold morphing of a phenotypic high-throughput screening hit.

A series of 2-oxopiperazine derivatives were designed from the pyrrolopiperazinone cell-based screening hit 4 as a dengue virus inhibitor. Systematic investigation of the structure-activity relationship (SAR) around the piperazinone ring led to the identification of compound (S)-29, which exhibited potent anti-dengue activity in the cell-based assay across all four dengue serotypes with EC50<0.1µM. Cross-resistant analysis confirmed that the virus NS4B protein remained the target of the new oxopiperazine analogs obtained via scaffold morphing from the HTS hit 4.

Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described.

Structure guided optimization of a fragment hit to imidazopyridine inhibitors of PI3K.

PI3 kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kα overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5-heteroaryl imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties.

Design and synthesis of amino-substituted N-arylpiperidinyl-based inhibitors of the (immuno)proteasome.

The constitutive proteasome and the immunoproteasome represent validated targets for pharmacological intervention in the context of various diseases, such as cancer, inflammation, and autoimmune diseases. The development of novel chemical scaffolds of non-peptidic nature, capable of inhibiting different catalytically active subunits of both isoforms, is a viable approach against these diseases. Such compounds are also useful as leads for the development of biochemical probes that enable the studies of the roles of both isoforms in various biological contexts. Here, we present a ligand-based computational design of (immuno)proteasome inhibitors, which resulted in the amino-substituted N-arylpiperidine-based compounds that can inhibit different subunits of the (immuno)proteasome in the low micromolar range. The compounds represent a useful starting point for further structure-activity relationship studies that will, hopefully, lead to non-peptidic compounds that could be used in pharmacological and biochemical studies of both proteasomes.

Functionalized sulfonyl anthranilic acid derivatives inhibit replication of all the four dengue serotypes.

Dengue virus (DENV), a mosquito-borne flavivirus, continues to be a major public health threat in many countries and no approved antiviral therapeutics are available yet. In this work, we designed and synthesized a series of sulfonyl anthranilic acid (SAA) derivatives using a ligand-based scaffold morphing approach of the 2,1-benzothiazine 2,2-dioxide core, previously used by us to develop DENV polymerase inhibitors resulting devoid of any cell-based antiviral activity. Several derivatives based on the new SAA chemotype exhibited potent inhibition against DENV infection in the cell-based assay but did not inhibit DENV NS5 polymerase activity in the in vitro de novo initiation and elongation assays. Notably, best compounds 26 and 39 showed EC50 values in the range of 0.54-1.36 µM against cells infected with the four dengue serotypes (DENV-1-4). Time-of-drug-addition assay revealed that analogue 26 is a post-entry replication inhibitor that appears to be specific for cells of primate origin, implicating a host target with a high barrier to resistance. In conclusion, SAA derivatives offer a valuable starting point for developing effective Dengue antiviral therapeutics.

Scaffold morphing of arbidol (umifenovir) in search of multi-targeting therapy halting the interaction of SARS-CoV-2 with ACE2 and other proteases involved in COVID-19.

The rapid emergence of novel coronavirus, SARS-coronavirus 2 (SARS-CoV-2), originated from Wuhan, China, imposed a global health emergency. Angiotensin-converting enzyme 2 (ACE2) receptor serves as an entry point for this deadly virus while the proteases like furin, transmembrane protease serine 2 (TMPRSS2) and 3 chymotrypsin-like protease (3CLpro) are involved in the further processing and replication of SARS-CoV-2. The interaction of SP with ACE2 and these proteases results in the SARS-CoV-2 invasion and fast epidemic spread. The small molecular inhibitors are reported to limit the interaction of SP with ACE2 and other proteases. Arbidol, a membrane fusion inhibitor approved for influenza virus is currently undergoing clinical trials against COVID-19. In this context, we report some analogues of arbidol designed by scaffold morphing and structure-based designing approaches with a superior therapeutic profile. The representative compounds A_BR4, A_BR9, A_BR18, A_BR22 and A_BR28 restricted the interaction of SARS-CoV-2 SP with ACE2 and host proteases furin and TMPRSS2. For 3CLPro, Compounds A_BR5, A_BR6, A_BR9 and A_BR18 exhibited high binding affinity, docking score and key residue interactions. Overall, A_BR18 and A_BR28 demonstrated multi-targeting potential against all the targets. Among these top-scoring molecules A_BR9, A_BR18, A_BR22 and A_BR28 were predicted to confer favorable ADME properties.

Design, synthesis, and biological evaluation of novel 4H-chromen-4-one derivatives as antituberculosis agents against multidrug-resistant tuberculosis.

A series of 4H-chromen-4-one derivatives obtained by scaffold morphing of the benzofuran compound, TAM16, were tested for antitubercular activity. Compound 8d was active against drug-sensitive and multidrug-resistant tuberculosis. A preliminary druggability evaluation showed that compound 8d displayed favorable mouse and human microsomal stability, low cytotoxicity, and acceptable oral bioavailability. An in vivo study indicated that compound 8d exhibited modest efficacy in an acute mouse model of TB after 3 weeks of treatment. Thus, 8d is a promising antituberculosis lead compound.

Core Replacements in a Potent Series of VEGFR-2 Inhibitors and Their Impact on Potency, Solubility, and hERG.

Anti-VEGF therapy has been a clinically validated treatment of age-related macular degeneration (AMD). We have recently reported the discovery of indole based oral VEGFR-2 inhibitors that provide sustained ocular retention and efficacy in models of wet-AMD. We disclose herein the synthesis and the biological evaluation of a series of novel core replacements as an expansion of the reported indole based VEGFR-2 inhibitor series. Addition of heteroatoms to the existing core and/or rearranging the heteroatoms around the 6-5 bicyclic ring structure produced a series of compounds that generally retained good on-target potency and an improved solubility profile. The hERG affinity was proven not be dependent on the change in lipophilicity through alteration of the core structure. A serendipitous discovery led to the identification of a new indole-pyrimidine connectivity: from 5-hydroxy to 6-hydroxyindole with potentially vast implication on the in vitro/in vivo properties of this class of compounds.

Evolution of a New Class of VEGFR-2 Inhibitors from Scaffold Morphing and Redesign.

Anti-VEGF therapy is a clinically validated treatment for age-related macular degeneration (AMD). We have recently reported the discovery of oral VEGFR-2 inhibitors that are selectively distributed to the ocular tissues. Herein we report a further development of those compounds and in particular the validation of the hypothesis that aminoheterocycles such as aminoisoxazoles and aminopyrazoles could also function as effective "hinge" binding moieties leading to a new class of KDR (kinase insert domain containing receptor) inhibitors.