Synthesis and structure-activity relationships of new chiral spiro-β-lactams highly active against HIV-1 and Plasmodium

Alves, Nuno G.; Bártolo, Inês; Alves, Américo J. S.; Fontinha, Diana; Francisco, Denise; Lopes, Susana M. M.; Soares, Maria I. L.; Simões, Carlos J. V.; Prudêncio, Miguel; Taveira, Nuno; Melo, Teresa M. V. D. Pinho e

doi:10.1016/j.ejmech.2021.113439

Cited by 21 publications

(8 citation statements)

References 49 publications

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“…The SAMPL7 blind challenge consisted of predicting the partition coefficient between water and n -octanol (log P N ) of 22 N -acylsulfonamides synthesized by Ballatore Lab [ 19 ] (see Fig. 1 ).…”

Section: Methodsmentioning

confidence: 99%

Multiple linear regression models for predicting the n‑octanol/water partition coefficients in the SAMPL7 blind challenge

Lopez

Pinheiro

Zamora

2021

J Comput Aided Mol Des

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A multiple linear regression model called MLR-3 is used for predicting the experimental n-octanol/water partition coefficient (log P N ) of 22 N-sulfonamides proposed by the organizers of the SAMPL7 blind challenge. The MLR-3 method was trained with 82 molecules including drug-like sulfonamides and small organic molecules, which resembled the main functional groups present in the challenge dataset. Our model, submitted as "TFE-MLR", presented a root-mean-square error of 0.58 and mean absolute error of 0.41 in log P units, accomplishing the highest accuracy, among empirical methods and also in all submissions based on the ranked ones. Overall, the results support the appropriateness of multiple linear regression approach MLR-3 for computing the n-octanol/water partition coefficient in sulfonamide-bearing compounds. In this context, the outstanding performance of empirical methodologies, where 75% of the ranked submissions achieved root-mean-square errors < 1 log P units, support the suitability of these strategies for obtaining accurate and fast predictions of physicochemical properties as partition coefficients of bioorganic compounds.

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Section: Methodsmentioning

confidence: 99%

Multiple linear regression models for predicting the n‑octanol/water partition coefficients in the SAMPL7 blind challenge

Lopez

Pinheiro

Zamora

2021

J Comput Aided Mol Des

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“…antimalarial [14][15][16][17], antibacterial [18], antiviral [19], anti-HIV [14,15], antioxidant [20], anticancer and antiproliferative [20,21] activities. Moreover, spiro-β-lactams have been also used as synthons for synthesis of heterocycles and other organic compounds [22].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, in-vitro biological evaluation, and molecular docking study of novel spiro-β-lactam-isatin hybrids

et al. 2022

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In our ongoing search for bioactive compounds, a class of novel spiro-β-lactam isatin hybrids has been synthesized through a [2+2] cycloaddition reaction from 1-allyl-3-(arylimino)indolin-2-one, ketenes and various aryloxy acetic acids. The formation of all cycloadducts was confirmed by FTIR, 1 H NMR, 13 C NMR, and mass spectroscopy as well as elemental analyses. The new βlactams were subsequently evaluated for their biological activities demonstrating moderate to good activities against P. falciparum K1 strain. Among them, 4b and 4e lead to the best results with IC 50 of 5.04 and 7.18 µM, respectively. The molecular docking simulation of 4b with P. falciparum dihydrofolate reductase enzyme (PfDHFR) binding site presented several important intermolecular interactions. All the synthesized β-lactams were also evaluated for their antimicrobial activities against both Gram-positive (S. aureus ATCC 25923) and Gram-negative bacteria (E. coli ATCC 28922, P. aeruginosa ATCC 27853) but unfortunately MICs up to 200 µg/mL were encountered in all cases.

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“…Well known biologically active compounds like cephalosporin and penicillin have the β-lactam ring in their structure [26]. Among β-lactams, spiro-β-lactams have received special attention since some of their derivatives have exhibited potential pharmaceutical applications including cholesterol absorption inhibition [27], antimalarial [28][29][30][31], antibacterial [32], antiviral [33], anti-HIV [28,29], antioxidant [34], anticancer and antiproliferative [34,35] activities. Moreover, spiro-β-lactams have been also used as synthons for synthesis of heterocycles and other organic compounds [36].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, in-vitro Biological Evaluation, and Molecular Docking Study of Novel spiro-β-lactam-isatin Hybrids

Jarrahpour

Jowkar

Haghighijoo

et al. 2022

Preprint

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In our ongoing search for bioactive compounds, a class of novel spiro-β-lactam isatin hybrids have been obtained by [2+2] cycloaddition reaction from 1-allyl-3-(arylimino)indolin-2-one and ketenes from various aryloxy acetic acids. The formation of all cycloadducts were confirmed by FTIR, 1H NMR, 13C NMR, and Mass spectra as well as elemental analyses. The new β-lactams were evaluated for their biological activities. The compounds 4a-g showed moderate to good activity against P. falciparum K1 strain and showed moderate to good activity. Among them, 4b and 4e demonstrated the best results with IC50 of 5.04 and 7.18, respectively. The molecular docking simulation of 4b with P. falciparum dihydrofolate reductase enzyme (PfDHFR) binding site shown several intermolecular interactions that would be consider to design the future analogs of antimalarial agents. Moreover, all the synthesized β-lactams were evaluated against some gram positive and gram negative bacteria including E. coli ATCC 28922, P. aeruginosa ATCC 27853 and S. aureus ATCC 25923 at the MIC level of 200 µg/mL and did not possess significant activity.

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Synthesis and structure-activity relationships of new chiral spiro-β-lactams highly active against HIV-1 and Plasmodium

Cited by 21 publications

References 49 publications

Multiple linear regression models for predicting the n‑octanol/water partition coefficients in the SAMPL7 blind challenge

Multiple linear regression models for predicting the n‑octanol/water partition coefficients in the SAMPL7 blind challenge

Synthesis, in-vitro biological evaluation, and molecular docking study of novel spiro-β-lactam-isatin hybrids

Synthesis, in-vitro Biological Evaluation, and Molecular Docking Study of Novel spiro-β-lactam-isatin Hybrids

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