ISSN 1068-1620, Russian Journal of Bioorganic Chemistry, 2021, Vol. 47, No. 1, pp. 174–182. © Pleiades Publishing, Ltd., 2021. 174 Synthesis, Design, and Biological Evaluation of Novel Diethylphenylcarbamothioylphosphonate Ridha Ben Ali a, b, 1 , Rania Omrani c, 2 , Amal Ben Othman a, b , Anis Raddaoui d , Azaiez Ben Akacha c , and Michèle Véronique El May a, b a Experimental Medicine Unit, Faculty of Medicine, University of Tunis El Manar, 2092 Tunisia b Histology, Embryology and Cell Biology Laboratory, Research Unit 17ES13, Faculty of Medicine, University of Tunis El Manar, 2092 Tunis-Tunisia c Laboratory Selective Organic & Heterocyclic Synthesis Biological Activity Evaluation, Department of Chemistry, Faculty of Sciences, University of Tunis El Manar, 2092 Tunis-Tunisia d Microbiology of the Bone Marrow Transplant, Unit research N° 12ES02, Faculty of Medicine of Tunis, University of Tunis El Manar, 2092 Tunis-Tunisia Received July 4, 2020; revised July 14, 2020; accepted July 23, 2020 Abstract—The aim of this work was to synthesize a diethyl phenylcarbamothioyl phosphonate (EThmP) and evaluate its biological activities. ThmP has been prepared with high yields and its conformation was deter- mined. This phosphonothioamidate derivative was characterized by IR, and NMR Spectroscopy ( 1 H, 13 C, and 31 P). On the component of EThmP, the Hirshfeld surface analysis indicates that the major contributions for the crystal packing are H···H (53.3%), H···O (12.9%) H···S (14.5%), and C···H (17.6%) interactions. An anti- nociceptive test (the formaline test) showed that the EThmP modulates the pain during the early and late phases proved by rat behavior characterized by absence of licking, biting and shaking of the affected paw. The modulation of pain by the EThmP may be due to its anti-inflammatory effect. The Hot Plate test showed that the pretreatment with the EThmP did not modulate the pain nociception induced by maintaining the rat at a fixed temperature of 48°C. The treated rats’ behavior was characterized by elevating, licking the paw, jump- ing and fleeing. EThmP did not affect the memory capacity and acetylcholinesterase activity. The morbidity of rats was normal with no mortality or sign of toxicity. The in vitro study showed that the EThmP has no antibacterial, antifungal and antioxidant activities. The EThmP has an important dose dependent anti- inflammatory activity. Keywords: phosphonate thioamide, anti-inflammatory agent, formalin test, hot plate test, pain behavior DOI: 10.1134/S1068162021010192 INTRODUCTION The chemical synthesis is very important to develop drugs with important therapeutic effects while minimizing undesirable effects. Among the molecules developed were thioamide derivatives [1]; the Thio- amide is a functional group with the general structure R-CS–NR'R''. Many compounds containing thioam- ide core have diverse biological activities as antifungal, anti HIV, anti inflammatory, anti cancer [1–4]. For example, methimazole is used in humans for the treat- ment of hyperthyroidism by inhibiting a thyroid enzyme, the thyroid peroxidase [4]. Many studies described the preparation of thioam- ide derivatives [2, 5–10] and the best known methods are the addition of isothiocyanates to secondary amines [11], thionation of amides [8] and the reaction of dialkylphosphite with isothiocyanate in the pres- ence of strong base (t-BuOK) in anhydrous THF at room temperature which gave high yields of phospho- nothioamidates [2]. An experimental work has shown that Thiocyano- acetamide with safety profile has a maximum antioxi- dant capacity at low concentrations and an important analgesic activity. It activates rat memory by acting on brain receptors. It was also used in experimental model to prevent doxorubicin-induced damage to the gonads and spermatozoa [12]. The cyclisation of the thiocyanoacetamide formed the 3,5-diaminopyrazole which caused memory trouble and emotional state of anxiety “thigmotaxis” with important analgesic, and antioxidant activities [1]. Dealing with pain is one of the most important issues of medicine. All of the stud- ies aim to find a drug or combination of drugs in order to have more effective analgesia and fewer side effects [13, 14]. 1 Corresponding author: phone: +(216) 96-57-16-24; e-mail: ridhabenali9@gmail.com. 2 Corresponding author: phone: +(216) 24-89-44-36, e-mail: omrani.rania@gmail.co.