Synthesis, Antimalarial, Antileishmanial, and Cytotoxicity Activities and Preliminary In Silico ADMET Studies of 2-(7-Chloroquinolin-4-ylamino)ethyl Benzoate Derivatives.

A series of heterocyclic chloroquine hybrids, containing a chain of two carbon atoms at position four of the quinolinic chain and acting as a link between quinoline and several benzoyl groups, is synthesized and screened in vitro as an inhibitor of ß-hematin formation and in vivo for its antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA in this study. The compounds significantly reduced haeme crystallization, with IC50 values < 10 µM. The values were comparable to chloroquine's, with an IC50 of 1.50 ± 0.01 µM. The compounds 4c and 4e prolonged the average survival time of the infected mice to 16.7 ± 2.16 and 14.4 ± 1.20 days, respectively. We also studied the effect of the compounds 4b, 4c, and 4e on another important human parasite, Leishmania mexicana, which is responsible for cutaneous leishmaniasis, demonstrating a potential leishmanicidal effect against promasigotes, with an IC50 < 10 µM. Concerning the possible mechanism of action of these compounds on Lesihmania mexicana, we performed experiments demonstrating that these three compounds could induce the collapse of the parasite mitochondrial electrochemical membrane potential (Δφ). The in vitro cytotoxicity assays against mammalian cancerous and noncancerous human cell lines showed that the studied compounds exhibit low cytotoxic effects. The ADME/Tox analysis predicted moderate lipophilicity values, low unbound fraction values, and a poor distribution for these compounds. Therefore, moderate bioavailability was expected. We calculated other molecular descriptors, such as the topological polar surface area, according to Veber's rules, and except for 2 and 4i, the rest of the compounds violated this descriptor, demonstrating the low antimalarial activity of our compounds in vivo.

Novel 7-Chloro-(4-thioalkylquinoline) Derivatives: Synthesis and Antiproliferative Activity through Inducing Apoptosis and DNA/RNA Damage.

A series of 78 synthetic 7-chloro-(4-thioalkylquinoline) derivatives were investigated for cytotoxic activity against eight human cancer as well as 4 non-tumor cell lines. The results showed, with some exceptions, that sulfanyl 5-40 and sulfinyl 41-62 derivatives exhibited lower cytotoxicity for cancer cell lines than those of well-described sulfonyl N-oxide derivatives 63-82. As for compound 81, the most pronounced selectivity (compared against BJ and MRC-5 cells) was observed for human cancer cells from HCT116 (human colorectal cancer with wild-type p53) and HCT116p53-/- (human colorectal cancer with deleted p53), as well as leukemia cell lines (CCRF-CEM, CEM-DNR, K562, and K562-TAX), lung (A549), and osteosarcoma cells (U2OS). A good selectivity was also detected for compounds 73 and 74 for leukemic and colorectal (with and without p53 deletion) cancer cells (compared to MRC-5). At higher concentrations (5 × IC50) against the CCRF-CEM cancer cell line, we observe the accumulation of the cells in the G0/G1 cell phase, inhibition of DNA and RNA synthesis, and induction of apoptosis. In addition, X-ray data for compound 15 is being reported. These results provide useful scientific data for the development of 4-thioalkylquinoline derivatives as a new class of anticancer candidates.

Synthesis, Leishmanicidal, Trypanocidal, Antiproliferative Assay and Apoptotic Induction of (2-Phenoxypyridin-3-yl)naphthalene-1(2H)-one Derivatives.

The coexistence of leishmaniasis, Chagas disease, and neoplasia in endemic areas has been extensively documented. The use of common drugs in the treatment of these pathologies invites us to search for new molecules with these characteristics. In this research, we report 16 synthetic chalcone derivatives that were investigated for leishmanicidal and trypanocidal activities as well as for antiproliferative potential on eight human cancers and two nontumor cell lines. The final compounds 8−23 were obtained using the classical base-catalyzed Claisen−Schmidt condensation. The most potent compounds as parasiticidal were found to be 22 and 23, while compounds 18 and 22 showed the best antiproliferative activity and therapeutic index against CCRF-CEM, K562, A549, and U2OS cancer cell lines and non-toxic VERO, BMDM, MRC-5, and BJ cells. In the case of K562 and the corresponding drug-resistant K562-TAX cell lines, the antiproliferative activity has shown a more significant difference for compound 19 having 10.3 times higher activity against the K562-TAX than K562 cell line. Flow cytometry analysis using K562 and A549 cell lines cultured with compounds 18 and 22 confirmed the induction of apoptosis in treated cells after 24 h. Based on the structural analysis, these chalcones represent new compounds potentially useful for Leishmania, Trypanosoma cruzi, and some cancer treatments.

Synthesis and in silico ADME/Tox profiling studies of heterocyclic hybrids based on chloroquine scaffolds with potential antimalarial activity.

A series of heterocyclic chloroquine hybrids containing either a ß-phenethylamine fragment or a 2-aminoindane moiety were synthesized and screened in vitro as inhibitors of ß-hematin formation and in vivo for their antimalarial activity against chloroquine-sensitive strains of Plasmodium berghei ANKA. Although these new compounds were not found to be more active than chloroquine in vivo, all new compounds significantly reduced heme crystallization with IC50 values < 1 µM. Compounds 12 and 13 were able to inhibit heme crystallization with IC50 values of 0.39 ± 0.09 and 0.48 ± 0.02 µM, respectively, and these values were comparable to that of chloroquine with an IC50 value of 0.18 ± 0.03. It was also determined that the physicochemical and pharmacokinetic properties were moderately favorable after in silico evaluation, derivatives 8 and 10 did not present hepatotoxicity, and the in vitro hemolytic activity against red blood cells was found to be low. Spectral (infrared, nuclear magnetic resonance, and elemental analysis) data for all final compounds were consistent with the proposed structures.

In vitro evaluation and in vivo efficacy of nitroimidazole-sulfanyl ethyl derivatives against Leishmania (V.) braziliensis and Leishmania (L.) mexicana.

The aim of this study was to synthesize several small molecules of the type 5-nitroimidazole-sulfanyl and evaluate biological properties against the main Leishmania species that cause cutaneous leishmaniasis in Venezuela. Final compounds 4-7 were generated through simple nucleophilic substitution of 1-(2-chloroethyl)-2-methyl-5-nitroimidazole 3 with 2-mercaptoethanol, 1-methyl-2-mercaptoethanol, and 2-thyolacetic acid derivative. Compound 8 was synthesized via a coupling reaction between 7 and (S)-Methyl 2-amino-4-methylpentanoate hydrochloride. The inhibitory concentrations of (3, 4, 7, 8) against Leishmania (L.) mexicana and (V.) braziliensis in promastigotes and experimentally infected macrophages were determined by in vitro activity assays. Compounds 7 and 8 shown high activity against both species of Leishmania and were selected for the in vivo evaluation. Animals were infected with promastigotes of the two species and divided into four groups of ten (10) animals and a control group. Intralesional injection way was used for the treatment. The parasitological diagnostic after treatment was obtained by PCR using species specific oligonucleotides. The two Leishmania species were susceptible to compounds 7 and 8 in vivo assays. The results indicated that both compounds reduce significantly (96%) the size of the lesion and cure 63% of the mice infected with L (L) mexicana or L (V) braziliensis as was determined by PCR. The results are indicating that both compounds may represent an alternative treatment for these two Leishmania species.

The Role of Chloroquine and Hydroxychloroquine in Immune Regulation and Diseases.

Chloroquine (CQ) and hydroxychloroquine (HCQ) are derivatives of the heterocyclic aromatic compound quinoline. These economical compounds have been used as antimalarial agents for many years. Currently, they are used as monotherapy or in conjunction with other therapies for the treatment of autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS) and antiphospholipid antibody syndrome (APS). Based on its effects on the modulation of the autophagy process, various clinical studies suggest that CQ and HCQ could be used in combination with other chemotherapeutics for the treatment of various types of cancer. Furthermore, the antiviral effects showed against Zika, Chikungunya, and HIV are due to the annulation of endosomal/lysosomal acidification. Recently, CQ and HCQ were approved for the U.S. Food and Drug Administration (FDA) for the treatment of infected patients with the coronavirus SARSCoV- 2, causing the disease originated in December 2019, namely COVID-2019. Several mechanisms have been proposed to explain the pharmacological effects of these drugs: 1) disruption of lysosomal and endosomal pH, 2) inhibition of protein secretion/expression, 3) inhibition of antigen presentation, 4) decrease of proinflammatory cytokines, 5) inhibition of autophagy, 6) induction of apoptosis and 7) inhibition of ion channels activation. Thus, evidence has shown that these structures are leading molecules that can be modified or combined with other therapeutic agents. In this review, we will discuss the most recent findings in the mechanisms of action of CQ and HCQ in the immune system, and the use of these antimalarial drugs on diseases.

Is it necessary to tie the medial row in rotator cuff repair double-row constructs when using suture tape?

PURPOSE: To evaluate the selected biomechanical differences of a double-row trans-osseous equivalent rotator cuff repair with a knotless versus knot-tying medial row using suture tape in regard to repair displacement, stiffness, and ultimate load to failure. METHODS: In 16 fresh-frozen human shoulders (8 matched pairs), double-row rotator cuff repairs were performed with medial-row mattress knots (MK) on one side, the other without (NK). Two DVRT (Differential Variable Reluctance Transducer) sensors were attached between the humerus and 3 mm above the repair site and were used to measure the displacement across the repair during cycling. The biomechanical parameters measured were repair displacement, stiffness, and ultimate load to failure. The supraspinatus was loaded in a similar fashion to previously described protocol using cyclic loading and load to failure testing.1. RESULTS: All data from paired specimens were compared using paired Student t tests. No statistically significant difference (SSD) in displacement across the repair over the 200 cycles of the test was noted between the two groups (MK = 0.591 ± 0.501 mm; NK = 0.439 ± 0.417 mm, p = 0.618). No SSD in stiffness was noted between the two groups (MK = 32.87 ± 6.31 N/mm; NK = 27.98 ± 9.69 N/mm, p = 0.120). No SSD in ultimate load to failure was noted between the two groups (MK = 501.2 ± 126.1 N; NK = 416.8 ± 120.0 N, p = 0.116). CONCLUSION: There was no statistically significant different between knotless versus knotted medial row double row rotator cuff repair constructs using suture tape in regard to displacement across the repair site, stiffness and ultimate load to failure. Despite previous evidence suggesting inferiority of knotless medial row technique using suture constructs, this evidence may support the biomechanical equivalency of knotless medial row technique using suture tape.

Effects of Flavonoids and Its Derivatives on Immune Cell Responses.

BACKGROUND: Various pieces of evidence have shown that people who consume foods rich in polyphenolic and flavonoids compounds have a lower incidence of inflammatory, autoimmune diseases and cancer. OBJECTIVE: The study aimed to review the most potent compounds that affect the immune response and diseases associated with it. METHODS: Publications in PubMed and EmBase, from 1974-2018, and patents form Free patents online, Scifinder, Espacenet and Mendeley in which flavonoids, their semi-synthetic and synthetic derivatives are involved in immunosuppressive or immunostimulatory responses in vitro and in vivo. RESULTS: In vitro, flavonoids and their derivatives inhibit various transcriptional factors, which modulate differentiation, proliferation, activation of immune cells and enhance regulatory T cell generation. Some flavonoids exert anti-inflammatory effects through: Blockade of NF-κB, and NLRP3 inflammasome, inhibition of pro-inflammatory cytokine production, IL-1ß, IL-2, IL-6, TNF-α, IL-17A, down regulation of chemokines, and reduction of reactive oxygen and nitrogen species. Nevertheless, several reports have shown that some flavonoids enhance immune response by enhancing: oxygen and nitrogen radicals, antibody production, cytotoxic activity against tumours by increasing activating receptors and down regulating inhibitory receptors. In consequence, flavonoids may be potentially useful for treatment of infectious diseases and cancer. CONCLUSION: The most potent flavonoids in inflammation that modify immune responses are apigenin, quercetin and Epigallocatechin-3-Gallate (EGCG) although, other compounds are still under study and cannot be excluded. The most relevant patents concerning the use of flavones and other polyphenols were revised. A promising future of these compounds in different therapies is discussed.

What Is the Optimal Number of Samples for Culture in Patients Undergoing Surgery for Foot and Ankle Infections?

RECOMMENDATION: The optimal number of samples for culture in patients undergoing surgery for foot and ankle infections is unknown. We recommend that multiple tissue samples be taken. LEVEL OF EVIDENCE: Consensus. DELEGATE VOTE: Agree: 100%, Disagree: 0%, Abstain: 0% (Unanimous, Strongest Consensus).

Optimization of antimalarial, and anticancer activities of (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate.

Chemically modified versions of bioactive substances, are particularly useful in overcoming barriers associated with drug formulation, drug delivery and poor pharmacokinetic properties. In this study, a series of fourteen (E)-methyl 2-(7-chloroquinolin-4-ylthio)-3-(4-hydroxyphenyl) acrylate (2-15) were prepared by using a one step synthesis from 1 previously described by us as potential antimalarial and antitumor agent. Molecules were evaluated as inhibitors of ß-hematin formation, where most of them showed a significant inhibition value (% > 70). The best inhibitors were tested in vivo as potential antimalarials in mice infected with P. berghei ANKA, chloroquine susceptible strain. Three of them (5, 6, and 15) displayed antimalarial activity comparable to that of chloroquine. Also, molecules were evaluated for their cytotoxic activity against two human cancer cell lines (Jurkat E6.1 and HL60) and primary culture of human lymphocytes. Most of the synthesized compounds, except for analogs 2-6, 8, and 10-12, displayed cytotoxicity against cancer cell lines without affecting normal cells. The potency of the compounds was 15 ≫ 1, and 14 > 7, 9, and 13. Flow cytometry analysis demonstrated an increase in apoptotic cell death after 24 h. The compounds may affect tumor cell autophagy and consequently increase cell apoptosis.

The transverse force experienced by the radial head during axial loading of the forearm: A cadaveric study.

BACKGROUND: When designing a radial head replacement, the magnitude and direction of forces applied across the proximal radio-ulnar joint (PRUJ) and the radiocapitellar joint must be included. These designs often focus on axial loads transmitted to the radial head by the capitellum; however, the radial head also bears a significant transverse force at the PRUJ. Load transmission by the central band of the interosseous ligament induces a force component in a lateral direction perpendicular to the axis of the limb, which is borne by the articular surfaces of the proximal and distal radio-ulnar joints. The objective of this study is to establish the relationship between distally applied axial forces and proximal transverse reaction forces. METHODS: Five cadaveric, human forearms with intact interosseous membranes were used to measure the magnitude of transversely-directed forces experienced by the radial head during axial loading of the forearm at the lunate fossa. A Mark-10 test stand applied a gradual and continuous axial load on the articular surface of the distal radius. A Mark-10 force gauge measured the resultant transverse force experienced by the radial head in the proximal radioulnar joint. Classical mechanics and static force analysis were applied in order to predict lateral force values that would occur when the interosseous ligament is treated as the major load transmitter between the radius and ulna. FINDINGS: Acquired data show that the radial head bears a force in the transverse direction that averages 18% (SD 3.89%) in magnitude of the axial force applied at the wrist. This figure is in close accordance with the predicted value of 22% that was calculated by way of free-body plotting. INTERPRETATION: Physiologic forearm loading results in a clinically significant transverse force component transmitted through the interosseous ligament complex. The existence of transverse forces in the human forearm may explain clinical problems seen after radial head resection and suggest that radial head implants be designed to sustain substantial transverse forces. LEVEL OF EVIDENCE: Basic science study, anatomical.

The management of elbow instability using an internal joint stabilizer: preliminary results.

BACKGROUND: Nonsurgical and surgical treatments such as immobilization, transarticular pinning, and hinged or nonhinged external fixation have been used to treat unstable elbows. These methods all have drawbacks. We thought that a bent Steinmann pin introduced through the axis of ulnohumeral rotation and attached to the ulna could provide an improved method of treatment and that this could result in the development of a proper internal joint fixator that may have widespread application. QUESTIONS/PURPOSES: Does a fully internal hinged fixator crafted intraoperatively by the surgeon from a Steinmann pin for patients undergoing surgery for severe elbow instability result in restoration of range of motion and elbow stability? Does it result in new complications? METHODS: We reviewed the first 10 patients treated with the method for elbow instability. Diagnoses included fracture-dislocations of the elbow that remain unstable after fracture repair and unstable elbows that result from release of contracture or ulnohumeral synostosis. During that time, all patients meeting these criteria who underwent surgery by this surgeon (JLO) were treated with this approach. Charts, radiographs, and therapy notes were assessed at a minimum of 14 months (mean, 32 months; range, 14-59 months); no patients were lost to followup. Data recorded included age, sex, and elbow and forearm range of motion as well as any complications and reoperations that occurred. The absence of elbow instability was determined initially by radiographically observing concentric reduction of the ulnohumeral and radiocapitellar joints and later by radiography plus the absence of clinical signs and symptoms of elbow instability. RESULTS: Mean range of motion at latest followup was flexion 134°, extension -19°, pronation 75°, and supination 64°. All elbows were clinically and radiographically stable. Complications resulting in additional procedures occurred in four patients, including one recurrent deep infection in a patient with a remote history of sepsis, one wound hematoma that resolved after a drainage procedure performed in the office, one prominent implant treated by partial removal, and one patient with heterotopic ossification treated with excision of the heterotopic bone. CONCLUSIONS: This technique restores elbow stability and permits motion without the use of transcutaneous pins. It seems promising for the treatment of patients with severe elbow instability but requires a second procedure for removal. Further investigation is needed to understand its place in the surgeon's toolbox and what drawbacks it may have. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.