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Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor.

ABSTRACT: The novel HIV-1 integrase inhibitor 1, discovered in our laboratory, exhibits potent anti-HIV activity against a diverse set of HIV-1 isolates and also against HIV-2 and SIV. In addition, this compound displays low cellular cytotoxicity and possesses a favorable in vitro drug interaction profile with respect to isozymes of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT). However, the total synthesis of this significant HIV integrase inhibitor has not been reported. This contribution describes an optimized, reproducible, multi-step, synthetic route to inhibitor 1. The yield for the separate steps averaged about 80%. The methodologies utilized in the synthesis were, among others, a palladium-catalyzed cross-coupling reaction, a crossed-Claisen condensation, and a hydrazino amide synthesis step. Successful alternative synthetic methodologies for some of the steps are also described.

SUBMITTER: Okello M

PROVIDER: S-EPMC3846259 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Approaches to the synthesis of a novel, anti-HIV active integrase inhibitor.

Okello Maurice M Nishonov Malik M Singh Pankaj P Mishra Sanjay S Mangu Naveen N Seo Byung B Gund Machhindra M Nair Vasu V

Organic & biomolecular chemistry 20131007 45

The novel HIV-1 integrase inhibitor 1, discovered in our laboratory, exhibits potent anti-HIV activity against a diverse set of HIV-1 isolates and also against HIV-2 and SIV. In addition, this compound displays low cellular cytotoxicity and possesses a favorable in vitro drug interaction profile with respect to isozymes of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT). However, the total synthesis of this significant HIV integrase inhibitor has not been reported. T ...[more]

PMID: 24100441

Similar Datasets

Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor.

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Integrase Inhibitor Prodrugs: Approaches to Enhancing the Anti-HIV Activity of ?-Diketo Acids.

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A novel anti-HIV active integrase inhibitor with a favorable in vitro cytochrome P450 and uridine 5'-diphospho-glucuronosyltransferase metabolism profile.

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Catalytically-active complex of HIV-1 integrase with a viral DNA substrate binds anti-integrase drugs.

Project description:HIV-1 integration into the host cell genome is a multistep process catalyzed by the virally-encoded integrase (IN) protein. In view of the difficulty of obtaining a stable DNA-bound IN at high concentration as required for structure determination, we selected IN-DNA complexes that form disulfide linkages between 5'-thiolated DNA and several single mutations to cysteine around the catalytic site of IN. Mild reducing conditions allowed for selection of the most thermodynamically-stable disulfide-linked species. The most stable complexes induce tetramer formation of IN, as happens during the physiological integration reaction, and are able to catalyze the strand transfer step of retroviral integration. One of these complexes also binds strand-transfer inhibitors of HIV antiviral drugs, making it uniquely valuable among the mutants of this set for understanding portions of the integration reaction. This novel complex may help define substrate interactions and delineate the mechanism of action of known integration inhibitors.

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Corrigendum: 7-Step Flow Synthesis of the HIV Integrase Inhibitor Dolutegravir.

Project description: Not available

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Identification and Optimization of a Novel HIV-1 Integrase Inhibitor.

Project description:Human immunodeficiency virus-1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS). HIV-1, like all retroviruses, stably integrates its vDNA copy into host chromatin, a process allowing for permanent infection. This essential step for HIV-1 replication is catalyzed by viral integrase (IN) and aided by cellular protein LEDGF/p75. In addition, IN is also crucial for proper virion maturation as it interacts with the viral RNA genome to ensure encapsulation of ribonucleoprotein complexes within the protective capsid core. These key functions make IN an attractive target for the development of inhibitors with various mechanisms of action. We conducted a high-throughput screen (HTS) of ∼370,000 compounds using a homogeneous time-resolved fluorescence-based assay capable of capturing diverse inhibitors targeting multifunctional IN. Our approach revealed chemical scaffolds containing diketo acid moieties similar to IN strand transfer inhibitors (INSTIs) as well as novel compounds distinct from all current IN inhibitors including INSTIs and allosteric integrase inhibitors (ALLINIs). Specifically, our HTS resulted in the discovery of compound 12, with a novel IN inhibitor scaffold amenable for chemical modification. Its more potent derivative 14e similarly inhibited catalytic activities of WT and mutant INs containing archetypical INSTI- and ALLINI-derived resistant substitutions. Further SAR-based optimization resulted in compound 22 with an antiviral EC50 of ∼58 μM and a selectivity index of >8500. Thus, our studies identified a novel small-molecule scaffold for inhibiting HIV-1 IN, which provides a promising platform for future development of potent antiviral agents to complement current HIV-1 therapies.

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Discovery of a Potent HIV Integrase Inhibitor that Leads to a Prodrug with Significant anti-HIV Activity.

Project description:Worldwide research efforts in drug discovery involving HIV integrase have produced only one compound, raltegravir, that has been approved for clinical use in HIV/AIDS. As resistance, toxicity and drug-drug interactions are recurring issues with all classes of anti-HIV drugs, the discovery of novel integrase inhibitors remains a significant scientific challenge. We have designed a lead HIV-1 strand transfer (ST) inhibitor (IC(50) 70 nM), strategically assembled on a pyridinone scaffold. A focused structure-activity investigation of this parent compound led to a significantly more potent ST inhibitor, 2 (IC(50) 6 ± 3 nM). Compound 2 exhibits good stability in pooled human liver microsomes. It also displays a notably favorable profile with respect to key human cytochrome P450 (CYP) isozymes and human UDP glucuronosyl transferases (UGTs). The prodrug of inhibitor 2, i.e., compound 10, was found to possess remarkable anti-HIV-1 activity in cell culture (EC(50) 9 ± 4 nM, CC(50) 135 ± 7 μM, therapeutic index = 15,000).

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HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants.

Project description:The currently recommended first-line therapy for HIV-1-infected patients is an integrase (IN) strand transfer inhibitor (INSTI), either dolutegravir (DTG) or bictegravir (BIC), in combination with two nucleoside reverse transcriptase inhibitors (NRTIs). Both DTG and BIC potently inhibit most INSTI-resistant IN mutants selected by the INSTIs raltegravir (RAL) and elvitegravir (EVG). BIC has not been reported to select for resistance in treatment-naive patients, and DTG has selected for a small number of resistant viruses in treatment-naive patients. However, some patients who had viruses with substitutions selected by RAL and EVG responded poorly when switched to DTG-based therapies, and there are mutants that cause a considerable decrease in the potencies of DTG and BIC in in vitro assays. The new INSTI cabotegravir (CAB), which is in late-stage clinical trials, has been shown to select for novel resistant mutants in vitro Thus, it is important to develop new and improved INSTIs that are effective against all the known resistant mutants. This led us to test our best inhibitors, in parallel with DTG, BIC, and CAB, in a single-round infection assay against a panel of the new CAB-resistant mutants. Of the INSTIs we tested, BIC and our compound 4d had the broadest efficacy. Both were superior to DTG, as evidenced by the data obtained with the IN mutant T66I/L74M/E138K/S147G/Q148R/S230N, which was selected by CAB using an EVG-resistant lab strain. These results support the preclinical development of compound 4d and provide information that can be used in the design of additional INSTIs that will be effective against a broad spectrum of resistant mutants.

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Allosteric inhibitor development targeting HIV-1 integrase.

Project description:HIV-1 integrase (IN) is one of three essential enzymes for viral replication, and is a focus of ardent antiretroviral drug discovery and development efforts. Diligent research has led to the development of the strand-transfer-specific chemical class of IN inhibitors, with two compounds from this group, raltegravir and elvitegravir, advancing the farthest in the US Food and Drug Administration (FDA) approval process for any IN inhibitor discovered thus far. Raltegravir, developed by Merck & Co., has been approved by the FDA for HIV-1 therapy, whereas elvitegravir, developed by Gilead Sciences and Japan Tobacco, has reached phase III clinical trials. Although this is an undoubted success for the HIV-1 IN drug discovery field, the emergence of HIV-1 IN strand-transfer-specific drug-resistant viral strains upon clinical use of these compounds is expected. Furthermore, the problem of strand-transfer-specific IN drug resistance will be exacerbated by the development of cross-resistant viral strains due to an overlapping binding orientation at the IN active site and an equivalent inhibitory mechanism for the two compounds. This inevitability will result in no available IN-targeted therapeutic options for HIV-1 treatment-experienced patients. The development of allosterically targeted IN inhibitors presents an extremely advantageous approach for the discovery of compounds effective against IN strand-transfer drug-resistant viral strains, and would likely show synergy with all available FDA-approved antiretroviral HIV-1 therapeutics, including the IN strand-transfer-specific compounds. Herein we review the concept of allosteric IN inhibition, and the small molecules that have been investigated to bind non-active-site regions to inhibit IN function.

| S-EPMC3115487 | biostudies-literature

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