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

Okello, Maurice; Nishonov, Malik; Singh, Pankaj Kumar; Mishra, S. K.; Mangu, Naveen K.; Seo, Byung; Gund, Machhindra; Nair, Vasu

doi:10.1039/c3ob41728j

Cited by 9 publications

(5 citation statements)

References 20 publications

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“…Nair et al reported on the discovery of a novel anti-HIV active INI possessing low toxicity and inhibition EC 50 value of 19-35 nM depending on the HIV subtype [14,15]. The multistep synthesis (Scheme 2) started with readily available pyridine and benzene derivatives and comprised lithiation of 5-bromo-2-methoxypyridine (4) followed by reaction with 2,6-difluorobenzaldehyde.…”

Section: Monocyclic Pyridinesmentioning

confidence: 99%

“…Reactions of the latter with alkoxyaminopyridines 21 in the presence of EDC hydrochloride and 1-hydroxy-7-azabenzotriazole Dual inhibitors of HIV reverse transcriptase and integrase were synthesized on the basis of pyridine-containing reverse transcriptase inhibitor Delavirdine [19]. The synthesis was accomplished starting with reactions of diversely substituted acetylindole-2-carboxylic acids 13 and 3-isopropylamino-2-(piperazyn-1-yl)-pyridine (14) in the presence of carbonyl diimidazole (CDI) to give corresponding amides 15 (Scheme 4). Further reactions with diethyl oxalate and basic hydrolysis of the esters 16 afforded target 2,4-diketoacids 17.…”

Section: Monocyclic Pyridinesmentioning

confidence: 99%

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Recent Developments in the Synthesis of HIV-1 Integrase Strand Transfer Inhibitors Incorporating Pyridine Moiety

Старосотников

Bastrakov

2023

IJMS

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Human immunodeficiency virus (HIV) causes one of the most dangerous diseases—acquired immunodeficiency syndrome (AIDS). An estimated about 40 million people are currently living with HIV worldwide, most of whom are already on antiretroviral therapy. This makes the development of effective drugs to combat this virus very relevant. Currently, one of the dynamically developing areas of organic and medicinal chemistry is the synthesis and identification of new compounds capable of inhibiting HIV-1 integrase—one of the HIV enzymes. A significant number of studies on this topic are published annually. Many compounds inhibiting integrase incorporate pyridine core. Therefore, this review is an analysis of the literature on the methods for the synthesis of pyridine-containing HIV-1 integrase inhibitors since 2003 to the present.

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Section: Monocyclic Pyridinesmentioning

confidence: 99%

Section: Monocyclic Pyridinesmentioning

confidence: 99%

Recent Developments in the Synthesis of HIV-1 Integrase Strand Transfer Inhibitors Incorporating Pyridine Moiety

Старосотников

Bastrakov

2023

IJMS

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“…Integrase inhibitor 1 (left) and its X-ray crystallographic structure (right) depicting its preferred tautomeric form, conformation and intramolecular hydrogen bonding (Bacsa et al, 2013; Okello et al, 2013b). …”

Section: Figmentioning

confidence: 99%

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

Nair¹,

Okello²,

Mishra³

et al. 2014

Antiviral Research

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Integration of viral DNA into human chromosomal DNA catalyzed by HIV integrase represents the “point of no return” in HIV infection. For this reason, HIV integrase is considered a crucial target in the development of new anti-HIV therapeutic agents. We have discovered a novel HIV integrase inhibitor 1, that exhibits potent antiviral activity and a favorable metabolism profile. This paper reports on the pharmacokinetics and toxicokinetics of compound 1 and the relevance of these findings with respect to further development of this integrase-targeted antiviral agent. Oral administration of compound 1 in Sprague Dawley rats revealed rapid absorption. Drug exposure increased with increasing drug concentration, indicative of appropriate dose-dependence correlation. Compound 1 exhibited suitable plasma half-life, extensive extravascular distribution and acceptable bioavailability. Toxicity studies revealed no compound-related clinical pathology findings. There were no changes in erythropoietic, white blood cell or platelet parameters in male and female rats. There was no test-article related change in other clinical chemistry parameters. In addition, there were no detectable levels of bilirubin in the urine and there were no treatment-related effects on urobilinogen or other urinalysis parameters. The preclinical studies also revealed that the no observed adverse effect level and the maximum tolerated dose were both high (> 500 mg/kg/day). The broad and significant antiviral activity and favorable metabolism profile of this integrase inhibitor, when combined with the in vivo pharmacokinetic and toxicokinetic data and their pharmacological relevance, provide compelling and critical support for its further development as an anti-HIV therapeutic agent.

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“…Synthesis of the precursor 8 from commercially available 5-bromo-2-methoxypyridine ( 3 ) involved the following steps: in situ generated aromatic nucleophile addition to aldehyde; demethylation/deoxygenation; radical bromination; benzylation; palladium-catalyzed cross-coupling; Claisen condensation; and acid or base-catalyzed hydrolysis. 24 Yields for the individual steps are indicated in brackets in Scheme 1. Compound 2 was produced in >99.8% purity.…”

mentioning

confidence: 99%

A novel molecule with notable activity against multi-drug resistant tuberculosis

Nair¹,

Okello²,

Mangu³

et al. 2015

Bioorganic & Medicinal Chemistry Letters

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Multi-drug resistant tuberculosis (MDR-TB) is emerging as a serious global health problem, which has been elevated through co-infection involving HIV and MDR-Mtb. The discovery of new compounds with anti-MDR TB efficacy and favorable metabolism profiles is an important scientific challenge. Using computational biology and ligand docking data, we have conceived a multifunctional molecule, 2, as a potential anti-MDR TB agent. This compound was produced through a multi-step synthesis. It exhibited significant in vitro activity against MDR-TB (MIC 1.56 μg/mL) and its half-life (t1/2) in human liver microsomes was 14.4 h. The metabolic profiles of compound 2 with respect to human cytochrome P450 (CYP) and uridine 5′-diphospho-glucuronosyltransferase (UGT) isozymes were favorable. Compound 2 also had relatively low in vitro cytotoxicity in uninfected macrophages. It displayed synergistic behavior against MDR-TB in combination with PA-824. Interestingly, compound 2 also displayed in vitro anti-HIV activity.

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

Cited by 9 publications

References 20 publications

Recent Developments in the Synthesis of HIV-1 Integrase Strand Transfer Inhibitors Incorporating Pyridine Moiety

Recent Developments in the Synthesis of HIV-1 Integrase Strand Transfer Inhibitors Incorporating Pyridine Moiety

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

A novel molecule with notable activity against multi-drug resistant tuberculosis

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