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COVID-19 is a multisystemic disease caused by the SARS-CoV-2 airborne virus, a member of the Coronaviridae family. It has a positive sense single-stranded RNA genome and encodes two non-structural proteins through viral cysteine-proteases processing. Blocking this step is crucial to control virus replication. In this work, we reported the synthesis of 23 statine-based peptidomimetics to determine their ability to inhibit the main protease (Mpro) activity of SARS-CoV-2. Among the 23 peptidomimetics, 15 compounds effectively inhibited Mpro activity by 50% or more, while three compounds (7d, 8e, and 9g) exhibited maximum inhibition above 70% and IC50 < 1 µM. Compounds 7d, 8e, and 9g inhibited roughly 80% of SARS-CoV-2 replication and proved no cytotoxicity. Molecular docking simulations show putative hydrogen bond and hydrophobic interactions between specific amino acids and these inhibitors. Molecular dynamics simulations further confirmed the stability and persisting interactions in Mpro's subsites, exhibiting favorable free energy binding (ΔGbind) values. These findings suggest the statine-based peptidomimetics as potential therapeutic agents against SARS-CoV-2 by targeting Mpro. [ABSTRACT FROM AUTHOR]

In an ongoing research program for the development of new anti-tuberculosis drugs, we synthesized three series (A, B, and C) of 7-chloro-4-aminoquinolines, which were evaluated in vitro against Mycobacterium tuberculosis (MTB). Now, we report the anti-MTB and cytotoxicity evaluations of a new series, D (D01-D21). Considering the active compounds of series A (A01-A13), B (B01-B13), C (C01-C07), and D (D01-D09), we compose a data set of 42 compounds and carried out hologram quantitative structure-activity relationship (HQSAR) analysis. The amino-imino tautomerism of the 4-aminoquinoline moiety was considered using both amino (I) and imino (II) forms as independent datasets. The best HQSAR model from each dataset was internally validated and both models showed significant statistical indexes. Tautomer I model: leave-one-out (LOO) cross-validated correlation coefficient (q²) = 0.80, squared correlation coefficient (r²) = 0.97, standard error (SE) = 0.12, cross-validated standard error (SEcv) = 0.32. Tautomer II model: q² = 0.77, r² = 0.98, SE = 0.10, SEcv = 0.35. Both models were externally validated by predicting the activity values of the corresponding test set, and the tautomer II model, which showed the best external prediction performance, was used to predict the biological activity responses of the compounds that were not evaluated in the anti-MTB trials due to poor solubility, pointing out D21 for further solubility studies to attempt to determine its actual biological activity. [ABSTRACT FROM AUTHOR]

In this work, we designed and synthesized 35 new triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors (3D7 strain). Thirty compounds exhibited anti- P. falciparum activity, with IC 50 values ranging from 0.030 to 9.1 μM. The [1,2,4]triazolo[1,5- a pyrimidine derivatives were more potent than the pyrazolo[1,5- a pyrimidine and quinoline analogues. Compounds 20 , 21 , 23 and 24 were the most potent inhibitors, with IC 50 values in the range of 0.030–0.086 μM and were equipotent to chloroquine. In addition, the compounds were selective, showing no cytotoxic activity against the human hepatoma cell line HepG2. All [1,2,4]triazolo[1,5- a pyrimidine derivatives inhibited Pf DHODH activity in the low micromolar to low nanomolar range (IC 50 values of 0.08–1.3 μM) and did not show significant inhibition against the Hs DHODH homologue (0–30% at 50 μM). Molecular docking studies indicated the binding mode of [1,2,4]triazolo[1,5- a pyrimidine derivatives to Pf DHODH, and the highest interaction affinities for the Pf DHODH enzyme were in agreement with the in vitro experimental evaluation. Thus, the most active compounds against P. falciparum parasites 20 (R = CF 3 , R 1 = F; IC 50 = 0.086 μM), 21 (R = CF 3 ; R 1 = CH 3 ; IC 50 = 0.032 μM), 23 , (R = CF 3 , R 1 = CF 3 ; IC 50 = 0.030 μM) and 24 (R = CF 3 , 2-naphthyl; IC 50 = 0.050 μM) and the most active inhibitor against Pf DHODH 19 (R = CF 3 , R 1 = Cl; IC 50 = 0.08 μM - Pf DHODH) stood out as new lead compounds for antimalarial drug discovery. Their potent in vitro activity against P. falciparum and the selective inhibition of the Pf DHODH enzyme strongly suggest that this is the mechanism of action underlying this series of new [1,2,4]triazolo[1,5- a pyrimidine derivatives. Image 1 • New triazolopyrimidine, pyrazolopyrimidine and quinoline derivatives as P. falciparum inhibitors, showing no cytotoxic activity against the human hepatoma cell line HepG2. • The [1,2,4]triazolo[1,5- a pyrimidine derivatives were more potente series and were equipotent to chloroquine. • All compounds inhibited the activity of Pf DHODH and did not show significant inhibition against the Hs DHODH homologue. • Molecular docking studies indicated the binding mode of compounds to Pf DHODH. • Their combined activity against P. falciparum and inhibition of Pf DHODH enzyme suggest the mechanism of action. [ABSTRACT FROM AUTHOR]