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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]

Recently, many efforts have been made to develop N-methyl- d-aspartic acid receptor antagonists for treating different pathological conditions such as thrombo-embolic stroke, traumatic head injury, Huntington's, Parkinson's, and Alzheimer's diseases). However, as side-effects limit the use of most antagonists, new drugs are still required. In this work, we performed a (quantitative) structure-activity relationship analysis of 17 phenyl-amidine derivatives ( 1a- 1q), reported as N-methyl- d-aspartic acid receptor antagonists, and used this data to rationally design the triazolyl-amidines. The best (quantitative) structure-activity relationship model constructed by multiple linear regression analysis presented high data fitting ( R = 0.914) was able to explain 83.6% of the biological data variance ( R2 = 0.836), presented a satisfactory internal predictive ability ( Q2 = 0.609) and contained the descriptors (EHOMO, Ovality and cLogP). Our assays confirmed that glutamate promotes an extensive cell death in avian neurons (77%) and 2a and 2b protected the neurons from the glutamate effect (from 77% to 27% and 45%, respectively). The results of neurotoxicity and cytotoxicity on Vero cells suggested the favorable profile of 2a and 2b. Also, the molecular modeling used to predict the activity, the interaction with the receptor and the pharmacokinetic and toxicity of the triazolyl-amidines pointed them as a promising class for further exploration as N-methyl- d-aspartic acid receptor antagonists. [ABSTRACT FROM AUTHOR]

Benzophenone derivatives (BZP), an important class oforganic UV filters, are widely used in sunscreen products due to theirability to absorb in the UVA and UVB ranges. The structural, electronic,and spectral properties of BZP derivatives have been studied by densityfunctional theory (DFT) and time-dependent DFT (TD-DFT) methods. DFT/B3LYPwith the 6-31G(d) basis set is an accurate method for optimizing thegeometry of BZPs. The absorption maxima obtained from the TD-DFT calculationsin a vacuum were in agreement with the experimental absorption bandsand showed that the main electronic transitions in the UVA/UVB rangepresent π → π* character, the major transitionbeing HOMO → LUMO. The oscillator strength seems to increasein the presence of disubstitution at the para position. For proticsubstituents, the position appears to be related to the absorptionband. Absorption in the UVB range occurs in the presence of para substitution,whereas ortho substitution leads to absorption in the UVA spectralregion. The obtained results provide some features for BZP derivativesthat can be useful for customizing absorption properties (wavelengthsand intensities) and designing new BZP derivatives as sunscreens. [ABSTRACT FROM AUTHOR]

The human β1-adrenoceptor (β1AR) is a G-protein-coupled receptor (GPCR) involved in sympathetic system regulation through agonist-induced activation. The conserved CWXP-motif in helix 6 (rotamer toggle switch) is one of the most important activation switches in Class A GPCRs. In order to investigate how the agonist binding disturbs this switch, we carried out molecular dynamics simulations of a hβ1AR model in the apo and R-noradrenaline-bound forms. The results show that the agonist binding changes the β1-angle distribution of Cys336, Trp337 and Phe341 residues and increases the helix 6 bending. Overall, we provide a functional hβ1AR model, showing how the rotamer toggle switch mechanism works at atomic level. [ABSTRACT FROM PUBLISHER]

The human β1-adrenoceptor (hβ1AR) is a transmembrane (TM) protein responsible for the signal transduction pathway via agonist interaction. Despite its importance, hβ1AR activation mechanism is still unclear. The most studied and widely accepted mechanism is the disruption of a salt bridge between TM3 arginine and TM6 glutamic acid, called ionic lock. In this work, we constructed a functional hβ1AR-model equilibrated in a membrane environment to study the influence of agonist binding on the dynamical behaviour of hβ1AR and on the opening of the ionic lock. The results indicate that the agonist (R-noradrenaline) disturbs the hβ1AR, causing a TM helices rotation, disrupting the ionic lock. This rotational motion occurs in opposite directions in the intercellular and extracellular domains of hβ1AR, opening the ionic lock. [ABSTRACT FROM AUTHOR]

Abstract: The infections caused by the Herpes Simplex Virus are one of the most common sources of diseases in adults and several natural nucleoside analogues are currently used in the treatment of these infections. In vitro tests of a series of quinolonic ribonucleosides derivatives synthesized by part of our group indicated that some of them have antiviral activity against HSV-1. The conformational analysis of bioactive compounds is extremely important in order to better understand their chemical structures and biological activity. In this work, we have carried out a nuclear relaxation NMR study of 6-Me ribonucleoside derivative in order to determine if the syn or anti conformation is preferential. The NMR analysis permits the determination of inter-atomic distances by using techniques which are based on nuclear relaxation and related phenomena. Those techniques are non-selective longitudinal or spin–lattice relaxation rates and NULL pulse sequence, which allow the determination of distances between pairs of hydrogen atoms. The results of NMR studies were compared with those obtained by molecular modeling. [Copyright &y& Elsevier]

Abstract: In this study we compared the effects of naphthoquinones (α-lapachone, β-lapachone, nor-β-lapachone and Epoxy-α-lap) on growth of Trypanosoma cruzi epimastigotes forms, and on viability of VERO cells. In addition we also experimentally analyzed the most active compounds inhibitory profile against T. cruzi serine- and cysteine-proteinases activity and theoretically evaluated them against cruzain, the major T. cruzi cysteine proteinase by using a molecular docking approach. Our results confirmed β-lapachone and Epoxy-α-lap with a high trypanocidal activity in contrast to α-lapachone and nor-β-lapachone whereas Epoxy-α-lap presented the safest toxicity profile against VERO cells. Interestingly the evaluation of the active compounds effects against T. cruzi cysteine- and serine-proteinases activities revealed different targets for these molecules. β-Lapachone is able to inhibit the cysteine-proteinase activity of T. cruzi proteic whole extract and of cruzain, similar to E-64, a classical cysteine-proteinase inhibitor. Differently, Epoxy-α-lap inhibited the T. cruzi serine-proteinase activity, similar to PMSF, a classical serine-proteinase inhibitor. In agreement to these biological profiles in the enzymatic assays, our theoretical analysis showed that E-64 and β-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-α-lap showed no important interactions. Overall, our results infer that β-lapachone and Epoxy-α-lap compounds may inhibit T. cruzi epimastigotes growth by affecting T. cruzi different proteinases. Thus the present data shows the potential of these compounds as prototype of protease inhibitors on drug design studies for developing new antichagasic compounds. [ABSTRACT FROM AUTHOR]

Current drugs for treating leishmaniasis are still associated with significant toxicity and failure rates. Thus, new effective and less toxic antileishmanial agents are still in need. Herein, we tested a series of sulfonamide 4-methoxychalcone derivatives against L. amazonensis promastigote and amastigote forms to identify its antileishmanial profile against this species compared to L. braziliensis. In addition, we used molecular modeling tools to determine stereoelectronic features that may lead to the antileishmanial profile. Interestingly, all tested compounds were able to affect L. amazonensis promastigote form in a concentration-dependent manner and with low cytotoxicity, except for derivative 3g. However, our results showed that compound 3f ( para-Cl) presents the best profile against both L. amazonensis forms (promastigote and amastigote), differently from that observed for L. braziliensis, when compound 3i was the most active. Structure–activity relationship (SAR) analysis of these derivatives pointed molecular volume, HOMO density, and conformational aspects as important characteristics for parasitic profile. Overall, sulfonamide 4-methoxychalcone derivatives may be pointed out not only as lead compounds for treating leishmaniasis (i.e., 3f) but also as experimental tools presenting parasite-selectivity (i.e., 3i). [ABSTRACT FROM AUTHOR]

Abstract: Chagas disease (American trypanosomiasis) is one of the most important parasitic diseases with serious social and economic impacts mainly on Latin America. This work reports the synthesis, in vitro trypanocidal evaluation, cytotoxicity assays, and molecular modeling and SAR/QSAR studies of a new series of N-phenylpyrazole benzylidene-carbohydrazides. The results pointed 6k (X=H, Y= p-NO2, pIC50 =4.55M) and 6l (X=F, Y= p-CN, pIC50 =4.27M) as the most potent derivatives compared to crystal violet (pIC50 =3.77M). The halogen-benzylidene-carbohydrazide presented the lowest potency whereas 6l showed the most promising profile with low toxicity (0% of cell death). The best equation from the 4D-QSAR analysis (Model 1) was able to explain 85% of the activity variability. The QSAR graphical representation revealed that bulky X-substituents decreased the potency whereas hydrophobic and hydrogen bond acceptor Y-substituents increased it. [Copyright &y& Elsevier]

Abstract: Herpes Simplex Virus (HSV) infections are among the most common human diseases. In this work, we assess the structural features and electronic properties of a series of ten 1-hydroxyacridone derivatives (1a–j) recently described as a new class of non-nucleoside inhibitors of Herpes Simplex Virus-1 (HSV-1). Based on these molecules, we applied rigid analogue and isosteric replacement approaches to design and synthesize nine new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivatives (2a–i). The biological and computational results of these new molecules were compared with 1-hydroxyacridones. An inhibitory profile was observed in 10-Cl substituted 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridine derivative (2f), which presents the same substituent at the analogous position of 1-hydroxyacridone derivative (1b). The structure–activity relationship (SAR) studies pointed out the 10-position next to nitrogen atom as important for the anti-HSV-1 profile in the pyrazolo-naphthyridine derivatives tested, which reinforced the promising profile for further experimental investigation. The most potent acridone and pyrazolo-naphthridine derivatives were also submitted to an in silico ADMET screening in order to determine their overall drug-score, which confirmed their potential antiviral profile. [Copyright &y& Elsevier]

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]