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Lung cancer is one of the leading causes of cancer-associated mortality, worldwide. The overall survival rate remains low, but progress has been made in improving the diagnosis and treatment of lung cancer over the past decades. Niclosamide, a salicylanilide derivative used for the treatment of tapeworm infections, is safe, well tolerated, inexpensive and readily available. Previous studies have identified niclosamide as a potential anticancer agent. The present study demonstrated that niclosamide enhanced the effect of irradiation by inhibiting the hypoxia-inducible factor-1α/vascular endothelial growth factor signaling pathway. These findings suggest that niclosamide may be a promising candidate for clinical evaluation as part of a combined regimen for the treatment of non-small cell lung cancer.

Tuberculosis is caused by Mycobacterium tuberculosis, an intracellular pathogen that can survive in host cells, mainly in macrophages. An increase of multidrug-resistant tuberculosis qualifies this infectious disease as a major public health problem worldwide. The cellular uptake of the antimycobacterial agents by infected host cells is limited. Our approach is to enhance the cellular uptake of the antituberculars by target cell-directed delivery using drug-peptide conjugates to achieve an increased intracellular efficacy. In this study, salicylanilide derivatives (2-hydroxy-N-phenylbenzamides) with remarkable antimycobacterial activity were conjugated to macrophage receptor specific tuftsin based peptide carriers through oxime bond directly or by insertion of a GFLG tetrapeptide spacer. We have found that the in vitro antimycobacterial activity of the salicylanilides against M. tuberculosis H37Rv is preserved in the conjugates. While the free drug was ineffective on infected macrophage model, the conjugates were active against the intracellular bacteria. The fluorescently labelled peptide carriers that were modified with different fatty acid side chains showed outstanding cellular uptake rate to the macrophage model cells. The conjugation of the salicylanilides to tuftsin based carriers reduced or abolished the in vitro cytostatic activity of the free drugs with the exception of the palmitoylated conjugates. The conjugates degraded in the presence of rat liver lysosomal homogenate leading to the formation of an oxime bond-linked salicylanilide-amino acid fragment as the smallest active metabolite.

Repurposing existing drugs is one approach to address the growing concerns of multi-drug resistant bacterial pathogens in veterinary medicine. Oxyclozanide is in the anthelmintic drug class salicylanilide, which has been used primarily as a treatment and preventative for Fasciola hepatica in ruminants. The antimicrobial activity of oxyclozanide has been studied in human medicine; its activity against common small animal bacterial pathogens such as Staphylococcus pseudintermedius has yet to be determined.The aim of this study was to measure and establish the minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) of oxyclozanide against S. pseudintermedius and other common small animal bacterial pathogens.The MIC and MPC of oxyclozanide were determined from eighteen meticillin sensitive S. pseudintermedius (MSSP) isolates and eleven meticillin-resistant S. pseudintermedius (MRSP), as well as single isolates of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Enterococcus faecalis.The MIC of the eighteen meticillin-sensitive S. pseudintermedius isolates was 0.5-1 μg/mL and the MPC ranged between 16 and 32 μg/mL. The MIC of the eleven meticillin-resistant strains of S. pseudintermedius ranged from 0.5 to 2 μg/mL with a MPC ranging between 16 and 32 μg/mL. A single isolate of meticillin-resistant S. aureus (MRSA) had an MIC of 1 μg/mL and MPC 16 μg/mL. No inhibition of growth was seen at the concentrations tested for bacterial isolate strains E. coli, P. aeruginosa and E. faecalis.Oxyclozanide demonstrated in-vitro antibacterial activity against meticillin-resistant S. pseudintermedius. Further studies are needed to evaluate the potential use of oxyclozanide as a topical bactericidal agent.La réaffectation des médicaments existants est une option de gestion des préoccupations croissantes que sont les multirésistances bactériennes des pathogènes en médecine vétérinaire. L'oxyclozanide est un antihelmintique de la classe des salicylanilides, utilisé initialement comme traitement et prévention de Fasciola hepatica chez les ruminants. L'activité antimicrobienne de l'oxyclozanide a été étudiée en médecine humaine; son activité contre les pathogènes bactériens fréquents des petits animaux, tel que Staphylococcus pseudintermedius, doit encore être déterminée.Le but de cette étude était de mesurer et de déterminer la concentration minimale inhibitrice (MIC) et la concentration de prévention des mutants (MPC) de l'oxyclozanide contre S. pseudintermedius et d'autres bactéries pathogènes fréquentes chez les petits animaux. MATÉRIEL ET MÉTHODE: Les MIC et MPC de l'oxyclozanide ont été déterminés pour dix huit souches de S. pseudintermedius sensible à la méticiline (MSSP) et onze S. pseudintermedius résistant à la méticiline (MRSP), ainsi que les souches uniques de Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa et Enterococcus faecalis. RÉSULTATS: La MIC de dix huit souches de S. pseudintermedius sensible à la méticiline était de 0.5-1 μg/mL et les MPC variaient de 16 à 32 μg/mL. La MIC de onze souches de S. pseudintermedius résistantes à la méticiline variait de 0.5 à 2 μg/mL avec une MPC variant de 16 à 32 μg/mL. Une souche isolée de S. aureus résistante à la méticiline (MRSA) avait une MIC de 1 μg/mL et un MPC de 16 μg/mL. Aucune inhibition de croissance n'a été vue aux concentrations testées pour les souches bactériennes E. coli, P. aeruginosa et E. faecalis.L'oxyclozanide a démontré une activité antibactérienne in vitro contre S. pseudintermedius résistant à la méticiline. Des études supplémentaires sont nécessaires pour évaluer l'utilisation potentielle en tant qu'agent bactérien topique.INTRODUCCIÓN: el reenfoque en el uso de los medicamentos existentes es una posibilidad para abordar la creciente preocupación por la aparción de patógenos bacterianos resistentes a múltiples medicamentos en la medicina veterinaria. La oxiclozanida se encuentra en la clase de medicamentos antihelmínticos salicilanilida, que se ha utilizado principalmente como tratamiento y preventivo frente a Fasciola hepatica en rumiantes. La actividad antimicrobiana de la oxiclozanida ha sido estudiada en medicina humana; su actividad frente a patógenos bacterianos de animales pequeños comunes como Staphylococcus pseudintermedius aún no se ha determinado. OBJETIVO: el objetivo de este estudio fue medir y establecer la concentración inhibitoria mínima (MIC) y la concentración de prevención de mutaciones (MPC) de oxiclozanida frente a S. pseudintermedius y otros patógenos bacterianos comunes de animales pequeños. MÉTODOS Y MATERIALES: la MIC y la MPC de la oxiclozanida se determinaron a partir de dieciocho aislamientos de S. pseudintermedius (MSSP) sensibles a la meticilina y once aislamientos de S. pseudintermedius (MRSP) resistentes a la meticilina, así como aislamientos aislados de Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa y Enterococcus faecalis. RESULTADOS: la MIC de los dieciocho aislamientos de S. pseudintermedius sensibles a la meticilina fue de 0.5 a 1 μg/ml y la MPC osciló entre 16 y 32 μg/ml. La MIC de las once cepas de S. pseudintermedius resistentes a la meticilina osciló entre 0.5 y 2 μg/ml, con una MPC que osciló entre 16 y 32 μg/ml. Un único aislado de S. aureus resistente a meticilina (MRSA) tuvo una MIC de 1 μg/mL y MPC de 16 μg/mL. No se observó inhibición del crecimiento en las concentraciones analizadas para cepas aisladas de bacterias E. coli, P. aeruginosa y E. faecalis. CONCLUSIÓN E IMPORTANCIA CLÍNICA: la oxiclozanida demostró actividad antibacteriana in vitro frente a S. pseudintermedius resistente a la meticilina. Se necesitan estudios adicionales para evaluar el uso potencial de la oxiclozanida como agente bactericida tópico.Kratzverhalten in Zusammenhang mit einer intradermalen (i.d.) Injektion von Pruritogenen wie Histaminen und Compound 48/80 in die Haut von Mäusen und Menschen ist ein häufig verwendetes Modell, um die Forschung über den Juckreiz und die Entwicklung von Medikamenten voranzubringen. Die prädiktive Validität dieses Modells ist bei Hunden noch wenig beschrieben.Eine Evaluierung der Dosis-abhängigen Wirkungsweisen von pruritogenen Substanzen, mit einer jeweils anderen Wirkungsweise, bei gesunden Hunden.Zehn gesunde Beagles aus dem Versuchslabor.Alle Hunde wurden für 30 Minuten nach i.d. Injektion von Ziegen Anti-canine IgE (4 und 25 µg/Hautstelle), Histamin und Compound 48/80 (50, 100, 200, 400 µg/Hautstelle) über Video aufgenommen; zwei Injektionen mit gepufferter Kochsalzlösung dienten als Kontrollen. Zwei geblindete UntersucherInnen sahen das Juckreizverhalten auf allen Videoaufnahmen durch. Es wurde ein Global Wheal Score nach 30 mpi durch einen geblindeten Untersucher erfasst.Alle Hunde zeigten eine Quaddelbildung und Erythem an der Injektionsstelle des Pruritogens; der Global Wheal Score einer jeden Substanz nahm 30 mpi in allen Konzentrationen im Vergleich zu den Kontrollen signifikant zu (P ≤ 0.05). Eine geblindete Evaluierung zeigte, dass alle Pruritogene ein mildes akut juckendes Verhalten an der Injektionsstelle auslösten. Bei keinem der Hunde konnte an der Injektionsstelle ein Schmerz festgestellt werden. Im Vergleich zu den Kontrollen beeinflussten die Injektionen der pruritogenen Substanzen für keine derselben die Anzahl der Juckreizsekunden oder das Auftreten von Juckreizepisoden.Diese vorläufigen Ergebnisse zeigen, dass i.d. Injektionen der untersuchten Pruritogene kutane Quaddeln und Schübe bei gesunden Hunden auslösen können; allerdings treten Uneinheitlichkeiten bei der Auslösung des Juckreizes selbst mit den unterschiedlichen Konzentrationen der Pruritogene auf.背景: 既存の薬物を再利用することは、獣医学における多剤耐性細菌性病原体の高まる懸念に対処するための1つのアプローチである。オキシクロザニドは、反芻動物における肝蛭治療および予防剤として主に使用されてきた駆虫薬クラスのサリチルアニリドである。オキシクロザニドの抗菌活性は人医学で研究されている。 しかし、Staphylococcus pseudintermediusのような一般的な小動物の細菌性病原体に対する活性はいまだ決定されていない。 目的: 本研究の目的は、S. pseudintermediusおよび他の一般的な小動物細菌性病原体に対するオキシクロザニドの最小発育阻止濃度(MIC)および耐性菌出現阻止濃度(MPC)を測定し確立することであった。 材料および方法: オキシクロザニドのMICおよびMPCを、メチシリン感受性S. pseudintermedius(MSSP)18株およびメチシリン耐性S. pseudintermedius(MRSP)11株、ならびにStaphylococcus aureus、Escherichia coli、Pseudomonas aeruginosaおよびEnterococcus faecalisの単一株によって決定した。 結果: メチシリン感受性S. pseudintermedius 18株のMICは0.5〜1μg/ mLであり、MPCは16〜32μg/ mLの範囲であった。メチシリン耐性S. pseudintermedius11株のMICは0.5〜2μg/ mLであり、MPCは16〜32μg/ mLの範囲であった。メチシリン耐性S. aureus(MRSA)の単一株は、1 μg/mLのMICおよび16 μg/mLのMPCを有した。細菌分離株E.coli、P. aeruginosaおよびE. faecalisについて、試験した濃度では増殖阻害は見られなかった。 結論と臨床的重要性: オキシクロザニドはメチシリン耐性S. pseudintermediusに対してin vitro抗菌活性を示した。外用殺菌剤としてのオキシクロザニドの潜在的使用を評価するためにはさらなる研究が必要である。.背景: 兽医领域中致病的多重耐药菌日益增长,重新利用现有药物是解决这一问题的方法。羟氯柳苯胺属于水杨酰苯胺类驱虫药,主要用于反刍动物中肝片吸虫的治疗和预防。人类医学中已经研究了羟氯柳苯胺的抗菌活性;其对抗常见的小动物致病菌如假中间型葡萄球菌(S. pseudintermedius)的活性尚未确定。 目的: 本研究的目的是测量和建立羟氯柳苯胺对假中间型葡萄球菌和其他常见小动物致病菌的最小抑菌浓度(MIC)和突变预防浓度(MPC)。 方法和材料: 测定羟氯柳苯胺对十八株甲氧西林敏感假中间型葡萄球菌(MSSP)和十一株耐甲氧西林假中间型葡萄球菌(MRSP),以及单株金黄色葡萄球菌、大肠杆菌、铜绿假单胞菌和粪肠球菌的MIC和MPC。 结果: 羟氯柳苯胺对18株甲氧西林敏感假中间型葡萄球菌的MIC为0.5-1μg/ mL,MPC为16至32μg/ mL;对11株耐甲氧西林假中间型葡萄球菌的MIC范围为0.5至2μg/ mL,MPC范围为16至32μg/ mL;对单株耐甲氧西林金黄色葡萄球菌(MRSA)的MIC为1μg/ mL,MPC为16μg/ mL;对特定浓度的大肠杆菌、铜绿假单胞菌和粪肠球菌测试中,未观察到生长抑制。 结论和临床意义: 羟氯柳苯胺显示出对抗耐甲氧西林假中间型葡萄球菌具有体外抗菌活性,需要进一步的研究来评估羟氯柳苯胺作为外部杀菌剂的潜在用途。.O reaproveitamento de fármacos existentes em diferentes funções é uma alternativa adequada para abordar a preocupação crescente com a multirresistência em patógenos bacterianos. A oxiclozanida é um fármaco anti-helmíntico da classe das salicilanilida, que tem sido usada primariamente no tratamento e prevenção da Faciola hepatica em ruminantes. A atividade antimicrobiana da oxiclozanida tem sido estudada em medicina humana; a sua atividade antimicrobiana contra patógenos bacterianos comuns como o Staphylococcus pseudintermedius ainda não foi determinada.O objetivo deste estudo foi mensurar e estabelecer a concentração inibitória mínima (MIC) e a concentração de prevenção de mutantes (MPC) da oxiclozanida contra S. pseudintermedius e outros patógenos comuns em pequenos animais. MÉTODOS E MATERIAIS: O MIC e MPC da oxiclozanida foram determinados para dezoito isolados Staphylococcus pseudintermedius sensível à meticilina (MSSP) e onze Staphylococcus pseudintermedius resistente à meticilina (MRSP), bem como isolados únicos de Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa e Enterococcus faecalis.O MIC dos dezoito S. pseudintermedius sensíveis à meticilina foi 0.5-1 μg/mL e o MPC foi entre 16 e 32 μg/mL. O MIC das onze cepas de S. pseudintermedius resistentes à meticilina variou de 0.5 a 2 μg/mL com o MPC variando entre 16 e 32 μg/mL. Um único isolado de S. aureus multirresistente (MRSA) apresentou um MIC de 1 μg/mL e MPC de 16 μg/mL. Não foi observada inibição do crescimento nas concentrações testadas para os isolados bacterianos E. coli, P. aeruginosa e E. faecalis. CONCLUSÃO E IMPORTÂNCIA CLÍNICA: A oxiclozanida apresentou atividade antibacteriana in vitro contra S. pseudintermedius resistente à meticilina. Mais estudos são necessários para avaliar o uso potencial da oxiclozanida como um agente bactericida tópico.

The repositioning of drugs already approved by regulatory agencies for other indications is an emerging alternative for the development of new antimicrobial therapies. The repositioning process involves lower risks and costs than the de novo development of novel antimicrobial drugs. Currently, infections by adenovirus show a steady increment with a high clinical impact in immunosuppressed and immunocompetent patients. The lack of a safe and efficacious drug to treat these infections supports the search for new antiviral drugs. Here we evaluated the anti-adenovirus activity of niclosanide, oxyclozanide, and rafoxanide, three salicylanilide anthelmintic drugs. Also, we carried out the cytotoxicity evaluation and partial characterization of the mechanism of action of these drugs. The salicylanilide anthelmintic drugs showed significant anti-adenovirus activity at low micromolar concentrations with little cytotoxicity. Moreover, our mechanistic assays suggest differences in the way the drugs exert anti-adenovirus activity. Niclosamide and rafoxanide target transport of the HAdV particle from the endosome to the nuclear envelope, whilst oxyclozanide specifically targets adenovirus immediately early gene E1A transcription. Data suggests that the studied salicylanilide anthelmintic drugs could be suitable for further clinical evaluation for the development of new antiviral drugs to treat infections by adenovirus in immunosuppressed patients and in immunocompetent individuals with community-acquired pneumonia., Supported by Plan Nacional de I + D + i 2013–2016 and Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009) – co-financed by “A way to achieve Europe” ERDF, the Instituto de Salud Carlos III, Proyectos de Investigación en Salud (PI15/00489) and Proyectos de Desarrollo Tecnológico en Salud (DTS17/00130), and the Spanish Adenovirus Network (AdenoNet, BIO2015/68990-REDT). J.S.C. is supported by the “Contract to Access to the Spanish System of Research and Innovation of the Program of R + D + i of the University of Seville” (USE-13901-D) grant.

Graphical abstract, Zika virus has emerged as a potential threat to human health globally. A previous drug repurposing screen identified the approved anthelminthic drug niclosamide as a small molecule inhibitor of Zika virus infection. However, as antihelminthic drugs are generally designed to have low absorption when dosed orally, the very limited bioavailability of niclosamide will likely hinder its potential direct repurposing as an antiviral medication. Here, we conducted SAR studies focusing on the anilide and salicylic acid regions of niclosamide to improve physicochemical properties such as microsomal metabolic stability, permeability and solubility. We found that the 5-bromo substitution in the salicylic acid region retains potency while providing better drug-like properties. Other modifications in the anilide region with 2’-OMe and 2’-H substitutions were also advantageous. We found that the 4’-NO2 substituent can be replaced with a 4’-CN or 4’-CF3 substituents. Together, these modifications provide a basis for optimizing the structure of niclosamide to improve systemic exposure for application of niclosamide analogs as drug lead candidates for treating Zika and other viral infections. Indeed, key analogs were also able to rescue cells from the cytopathic effect of SARS-CoV-2 infection, indicating relevance for therapeutic strategies targeting the COVID-19 pandemic.

Two series of novel salicylanilide analogues (4a-4 g) and (4h-4t) were designed, synthesized, and characterized, especially the structure of compound 4q was further confirmed by single X-ray diffraction. The inhibitory activity on polyphenoloxidase (PPO) from the cephalothorax of Chinese white shrimp (Fenneropenaeus chinensis) was evaluated. The result indicated that all the synthesized derivatives (except 4 g and 4t) exhibited moderate PPO inhibitory properties having IC50 values in the range of 0.21 ± 0.19 to 4.32 ± 0.53 mM, whereas reference inhibitor salicylic acid and 3a have IC50 values 3.93 ± 0.43 mM and 12.83 ± 0.51 mM, respectively. Specifically, 4-nitro-benzoic acid 3-(2‑hydroxy‑benzoylamino)- propyl ester (4q) exhibited the most potent PPO inhibitory activity with an IC50 value of 0.21 ± 0.19 mM. The kinetic studies of the compound (4q) demonstrated that the inhibitory effects of the compound on the PPO were belonging to competitive inhibitors. Meanwhile, the structure-activity relationship was discussed. Therefore, compound 4q could act as a PPO inhibitor with anti-browning and antimicrobial properties to be applied in the food industry.

Inhibiting osteoclastogenesis is a promising therapeutic target for treating osteoclast-related diseases. Herein, we synthesized a series of modified salicylanilides and their corresponding 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione and 10-phenyldibenzo[b,f][1,4]oxazepin-11(10H)-one derivatives, and investigated the effects of such compounds on RANKL-induced osteoclast formation. Among them, a salicylanilide derivative (A04) and its 3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione derivative (B04) markedly suppressed RANKL-induced osteoclast differentiation and showed no significant cytotoxic effects at doses higher than that required to inhibit osteoclast formation. Both compounds reduced osteoclast formation and bone resorptive activity of osteoclasts in a dose-dependent manner. Further, the anti-osteoclastogenic effects of A04 and B04 may operate through reducing the RANKL-induced nuclear translocation of NFATc1. Accordingly, we present the potent anti-osteoclastogenic compounds A04 and B04 as promising candidates for further optimization as anti-resorptive agents.

Preclinical Research Epidermal growth factor receptor (EGFR), a validated target for anticancer drugs, plays a critical role in tumorigenesis and tumor development. A series of p-O-alkyl salicylanilide derivatives were designed and synthesized as novel EGFR inhibitors using a salicylic acid scaffold. A simulated six-membered ring strategy formed through intramolecular hydrogen bonds was employed to mimic the planar quinazoline of the EGFR antagonist, gefitinib. The derived compounds with hydroxyl at the ortho position were more potent than ones with methoxyl group. In particular, compounds 5d and 5b displayed significant EGFR inhibitory (IC50 values = 0.30 and 0.45 μM, respectively) activity as well as potent antiproliferative activity in A431 and HCT-116 tumor cells. These salicylanilides could be considered as promising lead compounds for developing novel EGFR inhibitors.

A series of novel salicylanilide ester derivatives were synthesized, characterized, and evaluated for cercaricidal potential against Schistosoma japonicum and molluscicidal potential against Oncomelania hupensis . Four derivatives exhibited remarkable cercaricidal activity superior to that of niclosamide. Among them, the most active compound, 4-chloro-2-((2-methoxy-4-nitrophenyl)carbamoyl)phenyl 4-methoxybenzoate (compound 4c), showed a marked minimum effective cercaricidal concentration as low as 0.43 μM and significant molluscicidal activity, with a 50% lethal concentration (LC 50 ) of 0.206 g/m 2 . Particularly, compound 4c displayed 88-fold decreased fish toxicity on Danio rerio and 44-fold reduced cytotoxicity on human kidney HEK293 cells in comparison with the toxicity of niclosamide. The results indicated that 4c could serve as a promising drug candidate, with environmental safety properties, against Schistosoma japonicum at transmission stages. The preliminary molecular mechanism of target compounds in Schistosoma japonicum cercariae was also investigated. Salicylanilide ester derivatives exhibited an inhibitory effect on nitric oxide synthase (NOS) but no effect on lactate dehydrogenase (LDH) and acetylcholinesterase (AChE), and a strong and significant correlation between NOS inhibitory efficacy and cercaricidal activity was observed. In addition, 4c could downregulate the expression of NOS in a dose-dependent manner. These results suggested that NOS was probably one of the drug targets of salicylanilide esters.

A simultaneous analytical method was established for the determination of seven halogenated salicylanilides, namely 5-bromo-4′-chlorosalicylanilide, dibromsalan, tribromsalan, metabromsalon, 3,3′,4′,5-tetrachlorosalicylanilide, 4′-bromosalicylanilide, and 5-chlorosalicylanilide, in cosmetics by a high performance liquid chromatography-fluorescence detector (HPLC-FLD) in this work. The seven analytes were extracted by acetonitrile and separated on a T3 column by a gradient elution program, with the mobile phase consisting of 0.1% formic water (50% at the beginning) and acetonitrile. The mobile phase, chromatographic column types, wavelength, and column temperature were optimized. The calibration curves were linear in the ranges of 100–5000 μg kg−1 for tribromsalan, metabromsalon, and 3,3′,4′,5-tetrachlorosalicylanilide and 200–5000 μg kg−1 for the remaining four analytes, with correlation coefficients greater than 0.9996. The limits of detection (LODs) and the limits of qualification (LOQs) of the method were 13.8–42.9 μg kg−1 and 46.0–143 μg kg−1, respectively. Recoveries of the seven analytes ranged from 70% to 110%, with relative standard deviations (RSDs) of less than 13%. This method exhibits uncomplicated operation, excellent linearity, high sensitivity, and superior reproducibility for the determination of halogenated salicylanilide residues in cosmetics.

The signal transducer and activator of transcription 3 (STAT3) is constitutively activated in certain cancer cells. Therefore, blocking the aberrant activity of STAT3 in tumor cells is a validated therapeutic strategy. To discover novel inhibitors of STAT3 activity, we report the salicylanilide derivatives as a new small molecule inhibitor of the STAT3 signaling pathway. The N-(3-chloro-4-fluorophenyl)-2-hydroxy-4-(3-(piperidin-1-yl)propoxy) benzamide potently inhibited the activation and transcriptional function of STAT3. These studies further validate STAT3 as a drug discovery target and provide evidence that pharmacological agents that can selectively reduce the phospho-STAT3 levels in human cancer cells result in tumor apoptosis and growth inhibition.

A poorly exploited paradigm in the antimicrobial therapy field is to target virulence traits for drug development. In contrast to target-focused approaches, antivirulence phenotypic screens enable identification of bioactive molecules that induce a desirable biological readout without making a priori assumption about the cellular target. Here, we screened a chemical library of 678 small molecules against the invasive hyphal growth of the human opportunistic yeast Candida albicans. We found that a halogenated salicylanilide (N1-(3,5-dichlorophenyl)-5-chloro-2-hydroxybenzamide) and one of its analogs, Niclosamide, an FDA-approved anthelmintic in humans, exhibited both antifilamentation and antibiofilm activities against C. albicans and the multi-resistant yeast C. auris. The antivirulence activity of halogenated salicylanilides were also expanded to C. albicans resistant strains with different resistance mechanisms. We also found that Niclosamide protected the intestinal epithelial cells against invasion by C. albicans. Transcriptional profiling of C. albicans challenged with Niclosamide exhibited a signature that is characteristic of the mitochondria-to-nucleus retrograde response. Our chemogenomic analysis showed that halogenated salicylanilides compromise the potential-dependant mitochondrial protein translocon machinery. Given the fact that the safety of Niclosamide is well established in humans, this molecule could represent the first clinically approved antivirulence agent against a pathogenic fungus.

Cationic monofunctional platinum(II)-based anticancer agents with a general formula of cis -[Pt(NH 3 ) 2 (N-donor)Cl] + have recently drawn significant attention due to their unique mode of action, distinctive anticancer spectrum, and promising antitumor activity both in vitro and in vivo . Understanding the mechanism of action of novel monofunctional platinum compounds through rational drug design will aid in the further development of active agents. In this study, we synthesized and evaluated a monofunctional platinum-based anticancer agent SA–Pt containing a bulky salicylanilide moiety. The antiproliferative activity of SA–Pt was close to that of cisplatin. Mechanism studies revealed that SA–Pt entered HeLa cells more efficiently than cisplatin, blocked the cell cycle at the S-phase, and induced apoptosis. The compound bound to DNA as effectively as cisplatin, but did not block RNA polymerase II-mediated transcription as strongly as cisplatin, indicating that once the compound formed Pt-DNA lesions, the salicylanilide group was more easily recognized and removed. This study not only enriches the family of monofunctional platinum-based anticancer agents but also guides the design of more potent monofunctional platinum complexes.

Information on the susceptibility status of Fasciola hepatica isolates is lacking in the literature, even for those isolates considered to be laboratory reference strains. Four controlled efficacy studies were conducted on two Fasciola hepatica isolates from Australia, viz. 'Oberon' and 'Sunny Corner' with treatment at either 2, 6 or 10 weeks post-infection (wpi) as defined in each study. Fluke burdens and examination of livers occurred at necropsy in weeks 12 (Study 1) or 13 (Studies 2, 3 and 4) post-infection. The triclabendazole (TCBZ) resistance status of the Oberon isolate was confirmed in 6 and 10-week old F. hepatica, utilizing the drug alone (Fasinex; 71.5% and 31.1%, respectively) and in combination with oxfendazole (Flukazole C; 79.9% and 0%, respectively). The susceptibility of this isolate to albendazole, as well as salicylanilide and sulphonamide drugs was confirmed. The Sunny Corner isolate was confirmed as susceptible to TCBZ (>99% all stages) and closantel (>90% at ≥6 wpi).

A new series of 27 diethyl 2-(phenylcarbamoyl)phenyl phosphorothioates (thiophosphates) was synthesized, characterized by NMR, IR and CHN analyses and evaluated against Mycobacterium tuberculosis H37Rv, Mycobacterium avium and two strains of Mycobacterium kansasii. The best activity against M. tuberculosis was found for O-{4-bromo-2-[(3,4-dichlorophenyl)carbamoyl]phenyl} O,O-diethyl phosphorothioate (minimum inhibitory concentration of 4 µM). The highest activity against nontuberculous mycobacteria was exhibited by O-(5-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}-phenyl) O,O-diethyl phosphorothioate with MIC values from 16 µM. Prepared thiophosphates were also evaluated against acetylcholinesterase from electric eel and butyrylcholinesterase from equine serum. Their inhibitory activity was compared to that of the known cholinesterases inhibitors galanthamine and rivastigmine. All tested compounds showed a higher (for AChE inhibition) and comparable (for BChE inhibition) activity to that of rivastigmine, with IC50s within the 8.04 to 20.2 µM range.

A series of 27 salicylanilide diethyl phosphates was prepared as a part of our on-going search for new antimicrobial active drugs. All compounds exhibited in vitro activity against Mycobacterium tuberculosis, Mycobacterium kansasii and Mycobacterium avium strains, with minimum inhibitory concentration (MIC) values of 0.5-62.5μmol/L. Selected salicylanilide diethyl phosphates also inhibit multidrug-resistant tuberculous strains at the concentration of 1μmol/L. Salicylanilide diethyl phosphates also exhibited mostly the activity against Gram-positive bacteria (MICs ≥1.95μmol/L), whereas their antifungal activity is significantly lower. The IC50 values for Hep G2 cells were within the range of 1.56-33.82μmol/L, but there is no direct correlation with MICs for mycobacteria.

Antimycobacterially active salicylanilide diethyl phosphates were evaluated to identify their potential drug target(s) for the inhibition of several mycobacterial enzymes, including isocitrate lyase, L-alanine dehydrogenase (MtAlaDH), lysineε-aminotransferase, chorismate mutase, and pantothenate synthetase. The enzymes are related to the nongrowing state ofMycobacterium tuberculosis. Salicylanilide diethyl phosphates represent new candidates with significant inhibitory activity especially against L-alanine dehydrogenase. The most activeMtAlaDH inhibitor, 5-chloro-2-[(3-chlorophenyl)carbamoyl]phenyl diethyl phosphate, has an IC50of 4.96 µM and the best docking results. Other mycobacterial enzymes were mostly inhibited by some derivatives but at higher concentrations; isocitrate lyase showed the highest resistance to salicylanilide diethyl phosphates.

The research of novel antimycobacterial drugs represents a cutting-edge topic. Thirty phenolic N-monosubstituted carbamates, derivatives of salicylanilides and 4-chlorophenol, were investigated against Mycobacterium tuberculosis H37Ra, H37Rv including multidrug- and extensively drug-resistant strains, Mycobacterium avium, Mycobacterium kansasii, Mycobacterium aurum and Mycobacterium smegmatis as representatives of nontuberculous mycobacteria (NTM) and for their cytotoxic and cytostatic properties in HepG2 cells. Since salicylanilides are multi-targeting compounds, we determined also inhibition of mycobacterial isocitrate lyase, an enzyme involved in the maintenance of persistent tuberculous infection. The minimum inhibitory concentrations were from ≤0.5 μM for both drug-susceptible and resistant M. tuberculosis and from ≤0.79 μM for NTM with no cross-resistance to established drugs. The presence of halogenated salicylanilide scaffold results into an improved activity. We have verified that isocitrate lyase is not a key target, presented carbamates showed only moderate inhibitory activity (up to 18% at a concentration of 10 μM). Most of the compounds showed no cytotoxicity for HepG2 cells and some of them were without cytostatic activity. Cytotoxicity-based selectivity indexes of several carbamates for M. tuberculosis, including resistant strains, were higher than 125, thus favouring some derivatives as promising features for future development.

A new complex of the type [Hg(k2-Saln)2] (1) was prepared from the reaction of mercury acetate and salicylanilide (HSaln) in (1:2) molar ratio EtOH as a solvent with presence an Et3N as a base. Treatment of complex (1) with diphosphine {where diphos: dppe, dppp, dppb dppf and dppmS2} in 1:1) (complex: diphos) molar ratio afforded a complexes of the types [Hg(k1-Saln)2(diphos)] (2-6),where as a complexes of the types [Hg(k1-Saln)2(phos)2] (7,8) when treatment of complex(1) with two moles of monophosphine (PPh3 or SPPh3). The prepared complexes were fully characterization by many technical such as elemental analysis, molar conductivity, infrared spectroscopy, and nuclear magnetic resonance (1H and 31P). In complex (1) the (Saln-) was bonded as bidentate chelating ligand through the oxygen atoms of the carbonyl and deprotonated hydroxyl group, whereas bonded as monodentate ligand through the oxygen atom of deprotonated hydroxyl group in all other complexes (2-8). The geometry of the complexes (1-8) is a tetrahedral around the mercury (II) ion. http://dx.doi.org/10.25130/tjps.24.2019.086

Rafoxanide is an effective treatment for the control of fluke infections in animals, but it is currently not permitted for treating animals whose milk is intended for human consumption. In this study, the persistence of rafoxanide residues in milk, and their migration to dairy products, was investigated following the treatment of six lactating dairy cows with Curafluke 10% oral drench. The highest concentration of rafoxanide residues detected in the individual cows milk ranged from 249 to 627 μg kg(-1) and occurred at 2-3 days post-treatment. At 2 and 23 days post-treatment (representing high and low residue concentrations) the milk was pooled into two independent aliquots, each containing the full day's milk produced by three cows. Milk products were made from pasteurised and unpasteurised milk. Pasteurisation appeared to have little impact on the stability of the residues. Rafoxanide concentrated sixfold in the cheese (week 0) compared to the starting milk (2070 vs. 349 μg kg(-1)) but was four times lower in whey (75 μg kg(-1)). Rafoxanide residues were up to 14 times higher in butter (week 0) than in the starting milk (5468 vs. 376 μg kg(-1)). Residues were found to further concentrate in butter and cheese at longer storage and ripening times, respectively. Skim-milk powder was manufactured from skim milk, and residues were 10-fold higher than in the starting skim milk (5468 vs. 376 μg kg(-1)) despite the 185°C temperature required for the process. Rafoxanide residues were stable in this skim-milk powder when stored at ambient temperature for at least 1 year. Results showed that detectable rafoxanide residues were excreted in milk for 47 days, and concentrated in the fat-based products. The analytical ranges of the UHPLC-MS/MS method used were 1.0-200 μg kg(-1) (milk and whey) and 10-2000 μg kg(-1) (other dairy products).

The development of novel antimicrobial agents represents a timely research topic. Eighteen salicylanilide 4-(trifluoromethyl)benzoates were evaluated against Mycobacterium tuberculosis, M. avium and M. kansasii, eight bacterial strains including methicillin-resistant Staphylococcus aureus (MRSA) and for the inhibition of mycobacterial isocitrate lyase. Some compounds were further screened against drug-resistant M. tuberculosis and for their cytotoxicity. Minimum inhibitory concentrations (MICs) for all mycobacterial strains were within 0.5–32 μmol/L, with 4-chloro-2-[4-(trifluoromethyl)phenylcarbamoyl]phenyl 4-(trifluoromethyl)benzoate superiority. Gram-positive bacteria including MRSA were inhibited with MICs ³ 0.49 μmol/L, while Gram-negative ones were much less susceptible. Salicylanilide 4-(trifluoromethyl)benzoates showed significant antibacterial properties, for many strains being comparable to standard drugs (isoniazid, benzylpenicillin) with no cross-resistance. All esters showed mild inhibition of mycobacterial isocitrate lyase and four compounds were comparable to 3-nitropropionic acid without a direct correlation between in vitro MICs and enzyme inhibition.

On a sheep farm in Northern New South Wales (NSW) of Australia a degree of anthelmintic resistance was suspected. With noticeable clinical signs of infection and sheep not responding to treatment, a faecal egg count reduction test was conducted to ascertain the broad spectrum of anthelmintic resistance at this farm. A number of classes of anthelmintics were assessed including organophosphate, macrocyclic lactone (ML) and in combination an ML, benzimidazole, levamisole and salicylanilide. In addition, the more recently registered classes of anthelmintics, monepantel (amino-acetonitrile derivative) and derquantel/abamectin combination (spiroindole+ML) were included. Ninety merino sheep naturally infected with a field strain of Haemonchus contortus were randomly allocated to 6 treatment groups (15 animals/group). Sheep were subsequently treated based on label recommendations and individual bodyweight. Faecal samples were collected post-treatment on Days 7, 14 and 21 to conduct faecal egg counts and group bulk larval cultures. Broad spectrum anthelmintic resistance was confirmed at this site with treatment efficacies ranging from 21.3% (monepantel) to 93.8% (derquantel/abamectin combination) against the H. contortus strain. Furthermore, resistance to the multi-combination anthelmintic containing 4 active ingredients was evident (52.5%). This broad spectrum of resistance highlights the need for integration of alternative sustainable methods in parasite control in order to slow development of resistance and increase the life time effectiveness of anthelmintics.

Salicylanilides possess a wide range of biological activities. A new mechanism of action of these compounds was discovered in 1998. They act as inhibitors of the two-component regulatory system (TCS) in bacteria. Conventional anticancer treatments are nonspecific to target killing of tumor cells, may induce severe systemic toxicity and produce drug resistant phenotypic growth. The aim of our study is determining antiproliferative effect of salicylanilide which is known as anthelmintic generally. In our experiments, antiproliferative and cytotoxic effects of different concentrations (400, 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.56 and 0.78 ?g/mL) of salicylanilide investigated on A549 human non-small lung cancer cells, Caco2 human colon cancer cells and MCF-7 human breast cancer cells. 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide MTT assay was performed on mitochondrial activity levels to observe cytotoxic effects on A549, Caco2 and MCF7 cells for 24 hours. As a result the required concentration to inhibit the cell growth by 50% (IC50) on A549, Caco2 and MCF7 cells for salicylanilide was 260.93 ?g/mL, 201.64 ?g/mL and 292.66 ?g/mL after incubation for 24 h, respectively. If these results are supported further molecular investigations, it may be a new approach for the treatment of lung, colon and breast cancers.

The Wnt signaling pathway plays a key role in organ and tissue homeostasis, and when dysregulated, can become a major underlying mechanism of disease, particularly cancer. We reported previously that the anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. To define Niclosamide's mechanism of Wnt/β-catenin inhibition, and to improve its selectivity and pharmacokinetic properties as an anticancer treatment, we designed a novel class of benzimidazole inhibitors of Wnt/β-catenin signaling based on SAR studies of the Niclosamide salicylanilide chemotype. Niclosamide has multiple biological activities. To address selectivity in our design, we interrogated a protonophore SAR model and used the principle of conformational restriction to identify novel Wnt/β-catenin inhibitors with less effect on ATP cellular homeostasis. These studies led to the identification of 4-chloro-2-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl) phenol (4) and related derivatives with greater selectivity for Wnt/β-catenin signaling inhibition vs. differential effects on cellular ATP homeostasis. This is the first report that the Wnt signaling inhibitory activity of Niclosamide can be translated into a new chemical class and to show that its effects on ATP homeostasis can be separated from its inhibitory effects on Wnt signaling. These compounds could be useful tools to elucidate the mechanism of Niclosamide's inhibition of Wnt signaling, and aid the discovery of inhibitors with improved pharmacologic properties to treat cancer and diseases in which Niclosamide has important biological activity.

Based on the presence of carbamoyl moiety, twenty salicylanilide N,N-disubstituted (thio)carbamates were investigated using Ellman’s method for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). O-Aromatic (thio)carbamates exhibited weak to moderate inhibition of both cholinesterases with IC50 values within the range of 1.60 to 311.0 μM. IC50 values for BChE were mostly lower than those obtained for AChE; four derivatives showed distinct selectivity for BChE. All of the (thio)carbamates produced a stronger inhibition of AChE than rivastigmine, and five of them inhibited BChE more effectively than both established drugs rivastigmine and galantamine. In general, 5-chloro-2-hydroxy-N-[4-(trifluoromethyl)- phenyl]benzamide, 2-hydroxy-N-phenylbenzamide as well as N-methyl-N-phenyl carbamate derivatives led to the more potent inhibition. O-{4-Chloro-2-[(4-chlorophenyl)carbamoyl]phenyl} dimethylcarbamothioate was identified as the most effective AChE inhibitor (IC50 = 38.98 μM), while 2-(phenylcarbamoyl)phenyl diphenylcarbamate produced the lowest IC50 value for BChE (1.60 μM). Results from molecular docking studies suggest that carbamate compounds, especially N,Ndiphenyl substituted representatives with considerable portion of aromatic moieties may work as non-covalent inhibitors displaying many interactions at peripheral anionic sites of both enzymes. Mild cytotoxicity for HepG2 cells and consequent satisfactory calculated selectivity indexes qualify several derivatives for further optimization. Pomocí Ellmanovy metody byla sledována schopnost 20 nových salicylanilidových karbamátů a thiokarbamátů inhibovat acetylcholinesterázu a butyrylcholinesterázu.

The increasing emergence especially of drug-resistant tuberculosis has led to a strong demand for new anti-tuberculosis drugs. Eighteen salicylanilide benzoates were evaluated for their inhibition potential against Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii; minimum inhibitory concentration values ranged from 0.5 to 16 μmol/L. The most active esters underwent additional biological assays. Four benzoates inhibited effectively the growth of five multidrug-resistant strains and one extensively drug-resistant strain of M. tuberculosis at low concentrations (0.25–2 μmol/L) regardless of the resistance patterns. The highest rate of multidrug-resistant mycobacteria inhibition expressed 4-chloro-2-[4-(trifluoromethyl)-phenylcarbamoyl]phenyl benzoate (0.25–1 μmol/L). Unfortunately, the most potent esters were still considerably cytotoxic, although mostly less than their parent salicylanilides.

The synthesis and biological evaluation of two series of salicylanilide derivatives on the EGFR and ErbB-2 tyrosine kinases inhibitory activities were conducted. Of the tested compounds those having an additional aryl group substituted on the anilino ring were active on the EGFR tyrosine kinase inhibition ( 7a – c and 13a , 13c , 13d , 13f ). The inhibitory activities were all in the low micromolar or submicromolar range. In addition, compound 13a was found to have dual inhibitory activities both on EGFR and ErbB-2 tyrosine kinases (1.654 ± 1.280 and 7.134 ± 1.265 μmol/L).

A series of novel sulfonamides containing 5-chloro-2-hydroxybenzaldehyde or 5-chloro-2-hydroxybenzoic acid scaffolds were designed, synthesized and characterized by IR, 1 H NMR and 13 C NMR. All ten target synthesized derivatives and starting sulfonamides were evaluated in vitro for the activity against Gram-positive and Gram-negative bacteria, fungi, Mycobacterium tuberculosis , Mycobacterium avium and Mycobacterium kansasii . The most active compound against methicillin-sensitive and methicillin-resistant Staphyloccoccus aureus was 5-chloro- N -{4-[ N -(4,6-dimethylpyrimidin-2-yl)sulfamoyl]phenyl}-2-hydroxybenzamide with MIC 15.62–31.25 μmol/L. 4-Amino- N -(thiazol-2-yl)benzenesulfonamide and 4-(5-chloro-2-hydroxybenzylideneamino)- N -(thiazol-2-yl)benzenesulfonamide have shown the best activity against M. kansasii at the concentrations of 1–4 μmol/L. The efficacy against other strains was weaker and the studied derivatives exhibited almost none antifungal potency.

This study examined the antibacterial properties of nineteen benzoxazole, isoniazid, ethionamide and salicylanilide derivatives against Staphylococcus aureus (S. aureus). It was found that three salicylanilide-derived compounds demonstrated antistaphylococcal activity: 5-Chloro-2-hydroxy-N-(4-(trifluoromethyl)phenyl)benzamide (5-Cl-4'-CF3- SAL), 4-chloro-2-(3-chlorophenylcarbamyoyl)phenyl)-2-(benzyloxycarbonylamino)propanoate (AIM31) and 4-chloro-2- (4-(trifluoromethyl)phenylcarbamoyl)phenyl acetate (AIM33). Investigation of the chemical structures of these three compounds and comparison with a non-inhibitory salicylanilide compound (i.e. 5,3'-diCl-SAL) illustrated that different combinations of chemical groups at defined positions on the salicylanilide core structure had a marked influence on antistaphylococcal activity. The most effective compound was AIM33 which inhibited staphylococcal growth and displayed an initial MIC value of 3.12 μg ml(-1) and subsequent investigation revealed that an MIC as low as of 0.5 μg ml(-1) was achievable. In this case, the dual presence of a trifluoromethyl group and an acetylated phenolic hydroxyl to the salicylanilide core structure led to greatly enhanced activity.

A series of eighteen novel esters of salicylanilides with benzenesulfonic acid were designed, synthesized and characterized by IR, 1H-NMR and 13C-NMR. They were evaluated in vitro as potential antimycobacterial agents towards Mycobacterium tuberculosis, Mycobacterium avium and two strains of Mycobacterium kansasii. In general, the minimum inhibitory concentrations range from 1 to 500 µmol/L. The most active compound against M. tuberculosis was 4-chloro-2-(4-(trifluoromethyl)phenylcarbamoyl)-phenyl benzenesulfonate, with MIC of 1 µmol/L and towards M. kansasii its isomer 5-chloro-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl benzenesulfonate (MIC of 2–4 µmol/L). M. avium was the less susceptible strain. However, generally, salicylanilide benzenesulfonates did not surpass the activity of other salicylanilide esters with carboxylic acids.

Chemotherapy of viral infections is still challenging. Salicylanilides demonstrated a wide range of biological activities including antiviral potency and the review summarizes this field. Niclosamide was described to be able to affect coronaviruses. Some salicylanilides and salicylamides could inhibit HIV virus by targeting of HIV-1 integrase or reverse transcriptase. Hepatitis C virus is another virus, which could be potentially afflicted by salicylanilides on the level of two enzymes--NS3 protease and NS5B RNA polymerase. Nitazoxanide is a nitrothiazole derivative of salicylamide useful for the treatment of protozoal and bacterial infections with an extended range of antiviral activity and innovative mechanism of action, especially against hepatitis and influenza viruses or rotaviruses. Nitazoxanide, its metabolite tizoxanide and their derivatives are a very promising stream in the development of new antiviral compounds. In this review, we summarize the antiviral activity of structures containing salicylanilide and partly salicylamide moiety.

Salicylanilides are a well-known family of pharmacological compounds, which are under renewed investigation because of the discovery of novel interesting biological activities and mechanisms of action over the last decade. This comprehensive mini-review de-scribes the biological and pharmacological properties of salicylanilides, their activity against atypical and multi-drug resist ant mycobacte-rial strains, and synthetic routes for their preparation. In particular, this review focuses on the synthesis and biological properties of sali-cylanilides and O -substituted derivates reported between 2000 and 2010, which have displayed the highest antituberculosis or antifungal activity. Keywords: Anti-MDR tuberculotics, anti-tuberculotic agents, hydroxybenzamides, salicylan ilides, salicylanilide derivates. 1. INTRODUCTION Salicylanilides ( N -substituted hydroxy benzamides) are well-known organic pharmacological compounds with numerous bio-logical activities, which were initially investigated for their antimi-crobial [1] and antifungal activities [2], as well as their usefulness as topical antimycotics and antiplaque agents [3]. Salicylanilides have also found use as molluscicidal [4] or anthelmintic agents [5] in human and veterinary practise. The most successful of these, 5,2´-dichloro-4´-nitrosalicylanilide (Niclosamide), is a member of a group of common molluscicides [6] with anthelmintic properties, and is also effective in the treatment of diphyllobothriasis and hy-menolepiasis [7]. Closantel is another broad-spectrum anthelmintic salicylanilide, which has been used as an anti-trematode, anti-nematode and anti-arthropod, in combination with benzimidazole anthelmintics such as Mebendazole [8]. Rafoxanide is highly active against

A highly efficient protocol for the preparation of aromatic amides is described by the direct reactions between salicyclic acid and aromatic amines in the presence of phosphorous trichloride under microwave irradiation. The method has several advantages over the conventional methods, including operational simplicity, good yield, and reduced reaction time.

Eleven halogenated ( S )-2-(phenylcarbamoyl)phenyl 2-acetamido-3-phenylpropanoates ( 3a – 3k ) were designed and synthesized as potential antimicrobial agents. They were evaluated in vitro against some mycobacterial, bacterial and fungal strains. These compounds were active against drug-sensitive and atypical mycobacterial strains with general MIC values from 0.25 to 16 μmol/L. The most active compounds were ( S )-4-chloro-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl 2-acetamido-3-phenylpropanoate ( 3i ) and ( S )-4-bromo-2-(4-(trifluoromethyl)phenylcarbamoyl)phenyl 2-acetamido-3-phenylpropanoate ( 3k ) which exhibited activity against MDR and XDR-TB strains with MICs from 1 to 2 μmol/L. 3k was shown to be less cytotoxic with higher IC 50 . Some compounds exhibited low MICs on Gram-positive bacteria (MICs ≥ 0.98 μmol/L) and on fungi (MICs ≥ 3.9 μmol/L).

To identify new transglycosylase inhibitors with potent anti-methicillin-resistant Staphylococcus aureus (MRSA) activities, a high-throughput screening against Staphylococcus aureus was conducted to look for antibacterial cores in our 2M compound library that consists of natural products, proprietary collection, and synthetic molecules. About 3600 hits were identified from the primary screening and the subsequent confirmation resulted in a total of 252 compounds in 84 clusters which showed anti-MRSA activities with MIC values as low as 0.1 μg/ml. Subsequent screening targeting bacterial transglycosylase identified a salicylanilide-based core that inhibited the lipid II polymerization and the moenomycin-binding activities of transglycosylase. Among the collected analogues, potent inhibitors with the IC(50) values below 10 μM against transglycosylase were identified. The non-carbonhydrate scaffold reported in this study suggests a new direction for development of bacterial transglycosylase inhibitors.

The thiation properties of the dimer of p-methoxyphenylthionophosphine sulfide, 1, has been investigated by performing reactions with a representative series of aliphatic and aromatic primary, secondary, and tertiary carboxamides in the temperature range 80-100 °C using HMPA as solvent. This new method seems to be superior to all others as in most cases quantitative yields are found. Salicylanilide, when reacted with 1, in HMPA, yields salicylthioanilide and a new type of phosphorus heterocycle, 3, whose structure has been determined by NMR-and X-ray analyses. 13C NMR data are tabulated for a series of thioamide carbons.

The preparation of new prodrug forms of anti-tuberculosis active salicylanilide esters with amino acids led to an unexpected rearrangement. The isolation and the structure determination of 2-(5-chloro-2-hydroxyphenyl)-3-(3-chlorophenyl)-5-substituted-3,5-dihydro-4H-imidazol-4-ones unambiguously confirm one of the two proposed reaction mechanisms.