Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

Shirvani, Pouria; Fassihi, Afshin; Saghaie, Lotfollah

doi:10.1002/cmdc.201800577

Cited by 21 publications

(8 citation statements)

References 140 publications

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“…Polyfunctionalized organic compounds have played important roles in the drug discovery process . Appropriately substituted organic compounds and heterocycles have found diverse therapeutic applications, including anti HIV, anthelmintics, anticancers, and antimicrobials . The benzimidazole ring system is quite common amongst heterocyclic pharmacophores.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Antibacterial Evaluation of New2‐Phenylbenzimidazole Derivatives

et al. 2019

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Bacterial DNA gyrase and topoisomerase IV are well-characterized targets for both fluoroquinolones (e. g. Ciprofloxacin), which inhibit the catalytic subunits GyrA/ParC, and aminocoumarins (e. g. Novobiocin), which act as GyrB/ParE ATPase inhibitors. Due to the emergence of resistance to the first class, and the safety issues related to the latter, current research is aimed at developing novel synthetic inhibitors for GyrB/ParE in order to overcome the limitations of available drugs. A novel series of benzimidazole derivatives, carrying various functional groups or heterocyclic rings, were synthesized and evaluated for their in vitro antibacterial effect. The majority of the new benzimidazole derivatives showed Gram positive antibacterial activity . Compounds 7 d, 12 a,b and 14 a were selected for the assessment of their binding affinity and enzyme inhibitory activity against the E.coli DNA gyrase and the S. aureus topoisomerase IV. The results revealed good binding as well as dual inhibition against both enzymes. Compounds 7 d (% inhibition 87.71, IC 50 : 0.61 uM) and 14 a (% inhibition: 89.3, IC 50 : 0.58 uM) showed the best results against the E.coli DNA gyrase and the S. aureus topoisomerase IV, respectively. In silico studies revealed a potential good oral absorption of compounds due to compatibility with Lipinski's rule of five. Compound 14 a showed both good druglikeness (3.76) and drug score (0.76) values giving it potential as a promising new drug.[a] O.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Antibacterial Evaluation of New2‐Phenylbenzimidazole Derivatives

et al. 2019

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“…The US Food and Drug Administration (FDA) approved several drugs to treat HIV infection [ 3 ]. An important limitation of antiviral drugs as therapeutic agents is, in many cases, their low oral bioavailability (less than 20%) and poor transport into cells, which in the case of nucleotide-based drugs is attributed to their ionizable groups [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir

et al. 2022

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The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the conjugation or combination of the lipophilic amide bond with nucleotide-based tenofovir (TFV) (1) could improve the anti-HIV activity. During the current study, the hydroxyl group of phosphonates in TFV was conjugated with the amino group of L-alanine, L-leucine, L-valine, and glycine amino acids and other long fatty ester hydrocarbon chains to synthesize 43 derivatives. Several classes of derivatives were synthesized. The synthesized compounds were characterized by 1H NMR, IR, UV, and mass spectrometry. In addition, several of the synthesized compounds were evaluated as racemic mixtures for anti-HIV activity in vitro in a single round infection assay using TZM-bl cells at 100 ng/mL. TFV (1) was used as a positive control and inhibited HIV infection by 35%. Among all the evaluated compounds, the disubstituted heptanolyl ester alanine phosphonamidate with naphthol oleate (69), pentanolyl ester alanine phosphonamidate with phenol oleate (62), and butanolyl ester alanine phosphonamidate with naphthol oleate (87) ester conjugates of TFV were more potent than parent drug TFV with 79.0%, 76.5%, 71.5% inhibition, respectively, at 100 ng/mL. Furthermore, two fatty acyl amide conjugates of tenofovir alafenamide (TAF) were synthesized and evaluated for comparative studies with TAF and TFV conjugates. Tetradecanoyl TAF conjugate 95 inhibited HIV infection by 99.6% at 100 ng/mL and showed comparable activity to TAF (97–99% inhibition) at 10–100 ng/mL but was more potent than TAF when compared at molar concentration.

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“…However, as a portent of one of the challenges that would be faced by the program in the later stages of discovery, the inhibitory potency of 3 toward a panel of 8 HIV-1 isolates that represented both macrophage-tropic (M-tropic) and T-cell (T-tropic) tropic viruses was somewhat variable, although there was no correlation with the identity of the co-receptor, either CCR5 or CXCR4 [ 5 , 6 ]. Interest in 3 as a lead molecule was heightened considerably following mechanistic studies which ruled out allosteric inhibition of HIV-1 reverse transcriptase at the non-nucleoside binding site, well known for its promiscuity, as the source of the antiviral effect [ 14 , 15 ]. This was indicative of a unique mode of action, with time-of-addition studies revealing that the molecule was acting early in the HIV-1 life cycle since the inhibitory efficacy declined as the interval between virus inoculation and compound introduction was increased [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Innovation in the discovery of the HIV-1 attachment inhibitor temsavir and its phosphonooxymethyl prodrug fostemsavir

Wang¹,

Kadow²,

Meanwell

2021

Med Chem Res

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The discovery and development of fostemsavir (2), the tromethamine salt of the phosphonooxymethyl prodrug of temsavir (1), encountered significant challenges at many points in the preclinical and clinical development program that, in many cases, stimulated the implementation of innovative solutions in order to enable further progression. In the preclinical program, a range of novel chemistry methodologies were developed during the course of the discovery effort that enabled a thorough examination and definition of the HIV-1 attachment inhibitor (AI) pharmacophore. These discoveries helped to address the challenges associated with realizing a molecule with all of the properties necessary to successfully advance through development and this aspect of the program is the major focus of this retrospective. Although challenges and innovation are not unusual in drug discovery and development programs, the HIV-1 AI program is noteworthy not only because of the serial nature of the challenges encountered along the development path, but also because it resulted in a compound that remains the first and only example of a mechanistically novel class of HIV-1 inhibitor that is proving to be very beneficial for controlling virus levels in highly treatment-experienced HIV-1 infected patients.

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Recent Advances in the Design and Development of Non‐nucleoside Reverse Transcriptase Inhibitor Scaffolds

Cited by 21 publications

References 140 publications

Synthesis and Antibacterial Evaluation of New2‐Phenylbenzimidazole Derivatives

Synthesis and Antibacterial Evaluation of New2‐Phenylbenzimidazole Derivatives

Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir

Innovation in the discovery of the HIV-1 attachment inhibitor temsavir and its phosphonooxymethyl prodrug fostemsavir

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