Unique chlorine effect in regioselective one-pot synthesis of 1-alkyl-/allyl-3-(o-chlorobenzyl) uracils: anti-HIV activity of selected uracil derivatives (original) (raw)
Related papers
Journal of Chemical Research, 2007
A series of new uracil non-nucleosides analogues of S-DABO's was synthesised by reaction of 5-alkyl-6-(p-chlorobenzyl)-2-thiouracils with chloroethyl dialkylamine hydrochloride, N-(2-chloroethyl)-pyrrolidine hydrochloride, N-(2-chloroethyl)-piperidine hydrochloride or appropriate haloethers. Novel emivirine analogues were synthesised by silylation of 5-alkyl-6-(p-chlorobenzyl)uracils and treatment with bromomethyl methyl ether, chloromethyl ethyl ether or benzyl chloromethyl ether. Compounds 6-(p-chlorobenzyl)-5-ethyl-1-ethyloxymethyluracil (9d) and 1-benzyloxymethyl-6-(4-chlorobenzyl)-5-ethyluracil (9f) showed activity against wild-type HIV-1 strain III B in MT-4 cells.
An expeditious synthesis of 6-Amido-(1H,3H)-Pyrimidine- 2,4-Diones from Uracil-6-Carboxylic Acid
Dhaka University Journal of Pharmaceutical Sciences, 2015
2,4-Dichloro pyrimidine-6-carbonylchloride (2) was synthesized by refluxing uracil-6-carboxylic acid (orotic acid) with phosphorus oxychloride and phosphorus pentachloride. Compound (2) underwent a smooth coupling reaction with a number of substituted arylamines to yield 2, 4-dichloro-6-amidopyrimidines (8-12) which were converted to the corresponding 2, 4-dimethoxy-6-amidopyrimidines (13-17) on treatment with sodium methoxide in methanol. Compounds 13-17 afforded 6-amido-(1H, 3H)-pyrimidine-2, 4-diones (18-22) in good yield on refluxing with 6 M hydrochloric acid. These pyrimidinone derivatives may exhibit antiviral actitities. DOI: http://dx.doi.org/10.3329/dujps.v13i1.21856 Dhaka Univ. J. Pharm. Sci. 13(1): 23-29, 2014 (June)
Synthesis of new uracil non-nucleoside derivatives as potential inhibitors of HIV-1
Journal of Heterocyclic Chemistry, 2003
6-(2-Phenylethyl) and 6-cyclohexyl 5-cyanouracils (1a,b) were synthesized and reacted with chloromethyl ethyl ether, benzyl chloromethyl ether, chloromethyl methyl sulfide and (2-acetoxyethoxy)methyl bromide. New uracil analogues of (S)-DHPA were synthesized by reaction of compounds (1a,b) with ((S)-2,2-dimethyl-1,3-dioxolane-4-yl) alkyl p-toluenesulfonate.
Archiv der Pharmazie, 2009
A series of new uracil non-nucleosides analogues of S-DABO's was synthesised by reaction of 5-alkyl-6-(p-chlorobenzyl)-2-thiouracils with chloroethyl dialkylamine hydrochloride, N-(2-chloroethyl)-pyrrolidine hydrochloride, N-(2-chloroethyl)-piperidine hydrochloride or appropriate haloethers. Novel emivirine analogues were synthesised by silylation of 5-alkyl-6-(p-chlorobenzyl)uracils and treatment with bromomethyl methyl ether, chloromethyl ethyl ether or benzyl chloromethyl ether. Compounds 6-(p-chlorobenzyl)-5-ethyl-1-ethyloxymethyluracil (9d) and 1-benzyloxymethyl-6-(4-chlorobenzyl)-5-ethyluracil (9f) showed activity against wild-type HIV-1 strain III B in MT-4 cells.
ChemInform, 2010
Novel emivirine and TNK-651 analogues 5a -d were synthesized by reaction of chloromethyl ethyl ether and / or benzyl chloromethyl ether, respectively, with uracils having 5-ethyl and 6-(4methylbenzyl) or 6-(3,4-dimethoxybenzyl) substituents. A series of new uracil non-nucleosides substituted at N-1 with cyclopropylmethyloxymethyl 9a -d, 2-phenylethyloxymethyl 9e -h, and 3-phenylprop-1-yloxymethyl 9i -l were prepared on treatment of the corresponding uracils with the appropriate acetals 8a -c. Some of the tested compounds showed good activity against HIV-1 wild type. Among them, 1-cyclopropylmethyloxymethyl-5-ethyl-6-(3,5-dimethylbenzyl)uracil 9c and 5-ethyl-6-(3,5-dimethylbenzyl)-1-(2-phenylethyloxymethyl)uracil 9g showed inhibitory potency equally to emivirine against HIV-1 wild type. Furthermore, compounds 9c and 9g showed marginal better activity against NNRTI resistant mutants than emivirine.
1-[2-(2-Benzoyl- and 2-benzylphenoxy)ethyl]uracils as potent anti-HIV-1 agents
Bioorganic & Medicinal Chemistry, 2011
Non-nucleoside reverse transcriptase inhibitors (NNRTI) are key components in highly active antiretroviral therapy for treating HIV-1. Herein we present the synthesis for a series of N1-alkylated uracil derivatives bearing x-(2-benzyland 2-benzoylphenoxy)alkyl substituents as novel NNRTIs. These compounds displayed anti-HIV activity similar to that of nevirapine and several of them exhibited activity against the K103N/Y181C RT mutant HIV-1 strain. Further evaluation revealed that the inhibitors were active against most nevirapine-resistant mono-and di-substituted RTs with the exception of the V106A RT. Thus, the candidate compounds can be regarded as potential lead compounds against the wild-type virus and drug-resistant forms.
ChemInform, 2010
Nove l pyrid of2,3-dJprimidines 4 have been synthesised regioseleelively by the reaelion or 6-[(dimelhylamino)melh yleneJamino-1 ,3-dimelhyl uracil 1 wilh various a ,~un s alural e d carbonyl compounds in high yields. The importance of uracil and its annulated substrates is well recognised by synthetic l as well as biological chemists 2. With the development of clinically useful anticancer and antiviral drugs (AZT, DDI, DDC, BYDU) there has recently been remarkable interest in the synthetic manipulation of uracils. However, until the emergence of HEPT 3 as a potent and selective inhibitor of HIY-l, no attention was given to the synthetic manipulation at the 6-position of uracils. Also the synthetic exploitation of the nucleophilic double bond of uracil is an undeveloped field in view of a great variety of potential products 4 • 4-Deazatoxaflavin (l ,6-dimethyl-1 ,S,6,7-tetrahydropyrimido[4,S-c]pyridazine-S,7-dione), a member of thepyrimido[4,Sc]pyridazines, inhibits the growth of Pseudomonas 568 and also binds to herrin g sperm DNA 5. Broom et.al 6. synthesised pyrido[2,3-d]pyrimidine from the reacti on of DMAD and 6-aminouracil in protic solvent, but obtained uncycli zed co ndensed acetyl enic adduct when the reaction was carri ed out in DM F. Also Wamhoff's group reported substituted pyrido-[2 ,3-d]pyrimidines from 6-substituted uracil via [4+2] cycloaddition with electron-defi cient 0lefins7. The main di sadva nt ages in thi s meth od are the limitati on to elec tron-d eficient olefins and the low yi eld du e to side reac ti ons. Hi ro ta et .al~. sy nhes ised pyrido[2 ,3d /py rimidin es by th e pall adium-medi ated CC CO Llpiing reac ti on of elec tron-defi cient olefins with urac il 1 in reflu xin g aceti c acid , but th ey used a stoichi ometric amount of ex pensive Pd (OAc)2 as a coupling reagent. In co ntinuati on of oLir studi es on urac il analog ues 9 , now we report a new, simple, effici ent and one-pot sy nth esis of no ve l pyri do[2,3-d]pyrimidin es by ex ploiting th e nucl eophilic doubl e bond of 6-[(di meth y lami no)methy lene ]ami no-I ,3-di meth y I uraci I 1. The reaction of uracil 1 with q~-un s aturated com
Indian Journal of Chemistry Section B-organic Chemistry Including Medicinal Chemistry, 2002
Nove l pyrid of2,3-dJprimidines 4 have been synthesised regioseleelively by the reaelion or 6-[(dimelhylamino)melh yleneJamino-1 ,3-dimelhyl uracil 1 wilh various a ,~un s alural e d carbonyl compounds in high yields. The importance of uracil and its annulated substrates is well recognised by synthetic l as well as biological chemists 2. With the development of clinically useful anticancer and antiviral drugs (AZT, DDI, DDC, BYDU) there has recently been remarkable interest in the synthetic manipulation of uracils. However, until the emergence of HEPT 3 as a potent and selective inhibitor of HIY-l, no attention was given to the synthetic manipulation at the 6-position of uracils. Also the synthetic exploitation of the nucleophilic double bond of uracil is an undeveloped field in view of a great variety of potential products 4 • 4-Deazatoxaflavin (l ,6-dimethyl-1 ,S,6,7-tetrahydropyrimido[4,S-c]pyridazine-S,7-dione), a member of thepyrimido[4,Sc]pyridazines, inhibits the growth of Pseudomonas 568 and also binds to herrin g sperm DNA 5. Broom et.al 6. synthesised pyrido[2,3-d]pyrimidine from the reacti on of DMAD and 6-aminouracil in protic solvent, but obtained uncycli zed co ndensed acetyl enic adduct when the reaction was carri ed out in DM F. Also Wamhoff's group reported substituted pyrido-[2 ,3-d]pyrimidines from 6-substituted uracil via [4+2] cycloaddition with electron-defi cient 0lefins7. The main di sadva nt ages in thi s meth od are the limitati on to elec tron-d eficient olefins and the low yi eld du e to side reac ti ons. Hi ro ta et .al~. sy nhes ised pyrido[2 ,3d /py rimidin es by th e pall adium-medi ated CC CO Llpiing reac ti on of elec tron-defi cient olefins with urac il 1 in reflu xin g aceti c acid , but th ey used a stoichi ometric amount of ex pensive Pd (OAc)2 as a coupling reagent. In co ntinuati on of oLir studi es on urac il analog ues 9 , now we report a new, simple, effici ent and one-pot sy nth esis of no ve l pyri do[2,3-d]pyrimidin es by ex ploiting th e nucl eophilic doubl e bond of 6-[(di meth y lami no)methy lene ]ami no-I ,3-di meth y I uraci I 1. The reaction of uracil 1 with q~-un s aturated com
Molecules
Pyrimidine nucleoside analogues are widely used to treat infections caused by the human immunodeficiency virus (HIV) and DNA viruses from the herpes family. It has been shown that 5-substituted uracil derivatives can inhibit HIV-1, herpes family viruses, mycobacteria and other pathogens through various mechanisms. Among the 5-substituted pyrimidine nucleosides, there are not only the classical nucleoside inhibitors of the herpes family viruses, 2′-deoxy-5-iodocytidine and 5-bromovinyl-2′-deoxyuridine, but also derivatives of 1-(benzyl)-5-(phenylamino)uracil, which proved to be non-nucleoside inhibitors of HIV-1 and EBV. It made this modification of nucleoside analogues very promising in connection with the emergence of new viruses and the crisis of drug resistance when the task of creating effective antiviral agents of new types that act on other targets or exhibit activity by other mechanisms is very urgent. In this paper, we present the design, synthesis and primary screening of t...