Polycyclic N‐Benzamido Imides with Potent Activity against Vaccinia Virus

Abstract

The synthesis and antiviral activity of a series of novel polycyclic analogues of the orthopoxvirus egress inhibitor tecovirimat (ST-246) is presented. Several of these compounds display sub-micromolar activity against vaccinia virus, and were more potent than cidofovir (CDV). The more active compounds were about 10-fold more active than CDV, with minimum cytotoxic concentrations above 100 μM. Chemical manipulations of the two carbon-carbon double bonds present in the compounds were carried out to further explore the structure-activity relationships of these new polycyclic imides. Hydrogenation of the two carbon-carbon double bonds decreases antiviral activity, whereas either cyclopropanation or epoxidation of the double bonds fully eliminates the antiviral activity.

Modular Synthesis of Linear Bis‐ and Tris‐monodentate Fused [6]Polynorbornane‐Based Ligands and their Assembly into Coordination Cages

“…To establish strategy B as a viable means for the construction of the ligands and also install central function (in the form of either a picolylamine or aminopyridine unit) independent to end function, the presence of the endo esters of diene 4 was exploited. Hydrolysis of diester 4 followed by treatment of the resulting diacid with acetic anhydride gave anhydride 11 in good yield (84 %; Scheme ) 24. The pyridine groups were installed by reacting 3‐picolylamine and 4‐aminopyridine with anhydride 11 .…”

Efficacy of three key antiviral drugs used to treat orthopoxvirus infections: a systematic review

“…Similarly, tecovirimat has a high level of potency that is specific to OPXV (44). The efficacy of tecovirimat exceeds CDV in CPXV, VV, CML, VARV, MPXV, ECTV (39,41,(44)(45)(46)(47)(48)(49). EC50 values are consistent even in different cell lines, and tecovirimat can also completely inhibit plaque formation, virusinduced cytopathic effect and formation of extracellular VV (15,50).…”

Синтез и противовирусная активность полициклических <I>N</I>-амидоимидов на основе 4-оксатетрацикло-[5.3.2.0^2,6.0^8,10]додец-11-ен-3,5-диона

“…Ñðåäè ïðîèçâîäíûõ N-àìèäîâ 4-àçàòåòðàöèêëî [5.3.2.0 2,6 .0 8,10 ]äîäåö-11-åí-3,5-äèîíà (I) íàéäåíû ñîåäèíåíèÿ, îáëàäàþùèå íèçêîé öèòîòîêñè÷íîñòüþ, âûñîêîé ïðîòèâîâèðóñíîé àêòèâíîñòüþ è ïðîäîëaeèòåëüíûì äåéñòâèåì â îòíîøåíèè îðòîïîêñâèðóñîâ [1 -6]. Ñðåäè ýòèõ ïðîèçâîäíûõ íàèáîëüøóþ àêòèâíîñòü ïðîÿâèëî ñîåäèíåíèå I (R = 4-CF 3 , ST-246) [1,2].…”

“…Ïðîäîëaeàþòñÿ ïîèñêè íàèáîëåå îïòèìàëüíîãî ñïîñîáà ñèíòåçà ST-246 (I, R = 4-CF 3 ) [7]. Êðîìå òîãî, ïðîâåäåíû èññëåäîâàíèÿ ïî ñèíòåçó è òåñòèðîâàíèþ áëèçêèõ àíàëîãîâ ST-246, ñîäåðaeàùèõ â ñâîåì ñîñòàâå îñòîâ ïåíòàöèêëî[6.4.0.0 2,10 .0 3,7 .0 4,9 ]äîäåö-5,11-äèåíà, è ïîêàçàíî, ÷òî ïîëó÷åííûå N-áåíçàìèäîèìèäû ìåíåå àêòèâíû, ÷åì ïðîèçâîäíûå ST-246 [8]. Ñðåäè ñîåäèíåíèé I, íàðÿäó ñ ST-246, âûñîêóþ ïðîòèâîâèðóñíóþ àêòèâíîñòü ïðîÿâèëè ñîåäèíåíèÿ, ñîäåðaeàùèå â àðîìàòè÷åñêîì êîëüöå ãèäðîêñèãðóïïó â ïîëîaeåíèè 2 [3,4] è 4 àðîìàòè÷åñêîãî êîëüöà [4,5], à òàêaeå ñîåäèíåíèÿ I, ñîäåðaeàùèå, êðîìå ãèäðîêñèãðóïïû â ïîëîaeåíèè 2 àðîìàòè÷åñêîãî êîëüöà, õëîð-, íèòðî- [6] èëè ìåòèëüíóþ ãðóïïó [4,6].…”

“…Ñðåäè ñîåäèíåíèé I, íàðÿäó ñ ST-246, âûñîêóþ ïðîòèâîâèðóñíóþ àêòèâíîñòü ïðîÿâèëè ñîåäèíåíèÿ, ñîäåðaeàùèå â àðîìàòè÷åñêîì êîëüöå ãèäðîêñèãðóïïó â ïîëîaeåíèè 2 [3,4] è 4 àðîìàòè÷åñêîãî êîëüöà [4,5], à òàêaeå ñîåäèíåíèÿ I, ñîäåðaeàùèå, êðîìå ãèäðîêñèãðóïïû â ïîëîaeåíèè 2 àðîìàòè÷åñêîãî êîëüöà, õëîð-, íèòðî- [6] èëè ìåòèëüíóþ ãðóïïó [4,6]. Ñ öåëüþ ïðîäîëaeåíèÿ ïîèñêà íîâûõ âûñîêîýôôåêòèâíûõ ïðîòèâîâèðóñíûõ âåùåñòâ [9] íàìè áûë îñóùåñòâëåí ñèíòåç ðÿäà íîâûõ ñîåäèíåíèé êàê àíàëîãîâ ST-246, òàê è ñîäåðaeàùèõ äðóãèå ãðóïïû âî ôðàãìåíòå ìîëåêóëû ìåaeäó áåíçîëüíûì êîëüöîì è àìèäíîé ôóíêöèåé, èñõîäÿ èç 4-îêñàòåòðàöèêëî [5.3.2.0 2,6 .0 8,10 ]äîäåö-11-åí-3,5-äèîíà (II) è ãèäðàçèäîâ áåíçîéíûõ êèñëîò, àðèëàìèíîóêñóñíîé è ùàâåëåâîé êèñëîòû.…”