1,2,4-triazine analogs as novel class of therapeutic agents.

1,2,4-Triazine nucleus is a prominent structural core system present in numerous pharmacologically active compounds. Till date, various 1,2,4-triazine analogs, possesing a wide range of potent pharmacological activities, have been reported. This review is an attempt to compile the medicinal chemistry aspects of various synthesized 1,2,4-triazine analogs reported so far.

Design and Synthesis of Some Novel 4-(4-substituted aryl) Semicarbazones as Anticonvulsant Agents.

In the present study, a series of 4-(4-substituted aryl) semicarbazones were synthesized from substituted anilines and subsequently evaluated for their anticonvulsant activities. The anticonvulsant activities were established by the anticonvulsant drug development (ADD) programme NIH, USA using experimental animal, adult male FCM mice (20-25 g) and adult Sprague-Dawley rats (100-150 g) and screened against electroshock seizure, subcutaneous metrazole and minimal neurotoxicity tests in mice. Compound 7 was found equipotent to carbamazepine in both MES and ScPTZ tests. This study has highlighted the importance of distal alkyl chain which influences the anticonvulsant activity.

Synthesis and anticonvulsant activity of some substituted 1,2,4-thiadiazoles.

A series of new substituted 1,2,4-thiadiazoles were synthesized by appropriate route and screened for anticonvulsant, neurotoxic and sedative-hypnotic activity. The structures of the synthesized compounds were confirmed by IR spectroscopy, (13)C NMR and elemental (nitrogen and sulphur) analysis. After i.p. injection of the compounds to mice or rate at doses of 30, 100, and 300 mg/kg, body weights were examined in the maximal electroshock-induced seizures (MES) and subcutaneous pentylenetetrazole (scPTZ)-induced seizure models after 0.5 and 4 h. Rotorod method and phenobarbitone-induced hypnosis potentiation study were employed to examine neurotoxicity and sedative-hypnotic activity, respectively. All the compounds except 4g showed protection against MES screen after 0.5 h. Compounds 3a-c, 4a-c were active at 100 mg/kg dose i.p., whereas remaining compounds showed activity at 300 mg/kg. All 14 compounds except 3g showed neurotoxicity at 100 and 300 mg/kg after 0.5 h. Compounds 3b and 4b showed NT after 4 h. Two compounds 3b and 4g showed significant (p<0.05) percentage increase in sleeping time i.e. 67% and 59%, respectively. It may be concluded that the synthesized compounds were potent against MES-induced seizures than ScPTZ induced and showed low potency as sedative-hypnotic agent which is advantageous.

Combretastatin a-4 analogs as anticancer agents.

Combretastatin A-4 (CA-4) is one of the most potent antimitotic and antiangiogenic agents of natural origin. It has displayed potent antitumor effect in a wide variety of preclinical tumor models. Till date various CA-4 analogs have been synthesized and evaluated for anticancer activity. This review is an attempt to compile the medicinal chemistry of various synthesized CA-4 analogs.

4-sulphamoylphenyl semicarbazones with anticonvulsant activity.

A series of 4-sulphamoylphenyl semicarbazone derivatives were prepared starting from sulphanilamide and screened for anticonvulsant activity. The results indicated that greater protection was obtained in the maximal electroshock screen (MES) and subcutaneous strychnine (scSTY) than the subcutaneous pentylenetetrazole (scPTZ) tests. All the compounds showed low neurotoxicity when compared to the clinically used drugs. Compounds with substituted acetophenone (8-11) showed good activity in the rat oral MES screen. Seven compounds (6, 8-10, 12, 14 and 15) exhibited anticonvulsant activity greater than sodium valproate. Among the new derivatives evaluated, compound 10 emerged as the most active compound as indicated by its protection in the MES and scSTY screens and with low neurotoxicity. Seven compounds possessed sedative-hypnotic activity.

Anti-HIV activity of thiosemicarbazone and semicarbazone derivatives of (+/-)-3-menthone.

A series of thiosemicarbazones and semicarbazone derivatives of (+/-)-3-menthone have been synthesized and their anti-HIV activity evaluated against HIV-1(III(B))and HIV-2 (ROD). The studies revealed that maximum protection is offered by chloro-substituted derivatives 2 and 7 against HIV-1 (III(B)) and HIV-2 (ROD).

Synthesis and anti-HIV activity of some isatin derivatives.

Isatin/5-substituted Isatin was reacted with 2-aminothiazole, 2-aminopyridine, 4-methoxyaniline to form Schiff bases and the N-Mannich bases of the above Schiff bases were synthesized by reacting with formaldehyde and piperidine. The chemical structures of the synthesized compounds were confirmed by means of IR, 1H-NMR data and elemental analysis. Investigation of Anti-HIV activity was done against replication of HIV-1 (III B) and HIV-2 (ROD) in MT-4 cells. Azidothymidine (AZT) was used as the reference standard. The most active compound of the series was 3-(2-thiazolylimino)-5-bromo-1,3-dihydro-indol-2-one (VI) which demonstrated 28% and 10% protection against HIV-1 and HIV-2 respectively.

Synthesis and antibacterial activity of pyridyl thioureas and arylthiosemicarbazones.

[N-(2-pyridyl)-N'-(4-(un) substituted] thioureas and (substitutedaryl)thiosemicarbazones were synthesised and evaluated for their antibacterial activity. All aryl thiosemicarbazones showed good activity against Aeromonas hydrophilia and Salmonella typhimurium. But none of the pyridyl thioureas showed any prominent activity against tested bacteria.

Antituberculous activity of norfloxacin mannich bases with isatin derivatives.

Mannich bases of norfloxacin were synthesized by reacting them with formaldehyde and several isatin derivatives. The compounds were evaluated in vitro against Mycobacterium tuberculosis H37R(v) at 12.5 microg/ml in BACTEC 12B medium using the BACTEC radiometric system. Among the compounds tested, S-10 showed promising activity, with 100% inhibition at a concentration lower than 6.25 microg/ml.

Design of semicarbazones and their bio-isosteric analogues as potential anticonvulsants.

A series of semicarbazones and hydrazones were prepared and evaluated for anticonvulsant activity. Some compounds provided significant protection against maximal electroshock (MES) and subcutaneous strychnine induced seizures (ScSty). Compound 2a emerged as the most active compound at a dose of 30 mg/kg in ScSty test. The compounds 1a, 1g and 2a-e showed significant potentiation of sedative and hypnotic activity of pentobarbitone sodium. Thus compound 2a could serve as a prototype for future developments.

Anticonvulsant and neurotoxicity evaluation of 5-(un)-substituted isatinimino derivatives.

Various Schiff bases were prepared by reacting 5-(un)-substituted isatin with some heterocyclic compounds, viz., N-[4-(4'-chlorophenyl-thiazol-2-yl] semicarbazide, 3-amino-2-methylmercaptoquinazolin-4-one, 3-(4'-pyridyl)-4-amino-5-mercapto-4(H)-1,2,4-triazole and 4-(4'-chlorophenyl)-6-(4"-methylphenyl)-2-aminopyrimidine. The compounds were evaluated for anticonvulsant and neurotoxic properties. The compound 3-(3',4'-dihydro-2'-methylmercapto-4'-oxoquinazolin-3'-yl) iminoisatin (3) emerged as the most active analogue showing anti-MES and anti-PTZ activities better than valproic acid. All the compounds showed lower neurotoxicity than phenytoin and carbamazepine.

Synthesis and anticonvulsant activity of 4-bromophenyl substituted aryl semicarbazones.

A number of 4-bromophenyl semicarbazones were synthesised and evaluated for anticonvulsant and sedative -hypnotic activities. After intraperitoneal injection to mice, the semicarbazone derivatives were examined in the maximal electroshock seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY) and neurotoxicity (NT) screens. All the compounds showed anticonvulsant activity in one or more test models. Compound 12 showed greatest activity, being active in all the screens with very low neurotoxicity and no sedative-hypnotic activity. All the compounds except 7 had lower neurotoxicity compared to phenytoin. Three compounds (6, 11 and 14) showed greater protection than sodium valproate. The essential structural features responsible for interaction with receptor site are established within a suggested pharmacophore.

Synthesis, antibacterial, antifungal and anti-HIV activities of norfloxacin mannich bases.

Mannich bases of norfloxacin were synthesized by reacting them with formaldehyde and several isatin derivatives. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. Investigation of in vitro antimicrobial activity of compounds was done by the agar dilution method against 28 pathogenic bacteria, eight pathogenic fungi and anti-HIV activity against replication of HIV-1 (III B) in MT-4 cells. The in vivo antibacterial efficacy of selected derivatives was determined using a mouse infection model. All the synthesized compounds are more active than norfloxacin against the 13 bacteria tested. The compounds are also more active than the standard drug clotrimazole against Histoplasma capsulatum. Two compounds S-8 and S-9 have shown inhibition against HIV-1 (III B) with EC(50) values of 11.3 and 13.9 microgram/mL, respectively. In the mouse protection test, two compounds S-4 (ED(50): 1.25 mg/kg) and S-9 (ED(50): 1.62 mg/kg) are more active than norfloxacin (ED(50): 6mg/kg). Among the compounds tested, 1-ethyl-6-fluoro-1, 4-dihydro-4-oxo-7[[N(4)-[5'-bromo-3'-(4'-amino-5'-trimethoxybenzylpyr imidin-2'-yl]-imino-1'-isatinyl]methyl]N(1)-piperazinyl]-3-q uinoline carboxylicacid (S-9) showed promising activity in all the three tests.

Synthesis, antibacterial, antifungal and anti-HIV evaluation of Schiff and Mannich bases of isatin and its derivatives with triazole.

Isatin (indole 2,3-dione) and its 5-chloro and 5-bromo derivatives have been reacted with 3-(4'-pyridyl)-4-amino-5-mercapto-4-(H)-1,2,4-triazole to form Schiff bases and the N-Mannich bases of these compounds were synthesised by reacting them with formaldehyde and several secondary amines. Their chemical structures have been confirmed by means of their IR, 1H-NMR data and by elemental analysis. Investigation of antimicrobial activity of compounds was done by agar dilution method against 27 pathogenic bacteria, 8 pathogenic fungi and anti-HIV activity against replication of HIV-1 (III B) in MT-4 cells. Among the compounds tested 1-(piperidinomethyl) 5-bromo 3-[3'-(4"-pyridyl)-5'-mercapto-4'-(H)-1',2',4'-triazol 4'-yl]imino isatin showed the most favourable antimicrobial activity.

Anticonvulsant activity of p-chlorophenyl substituted arylsemicarbazones--the role of primary terminal amino group.

A series of p-chlorophenyl substituted arylsemicarbazones were synthesized and evaluated for anticonvulsant activity. Most of the compounds provided significant protection against maximal electroshock-induced seizures (MES) at 100 mg/kg after 0.5 h and at 300 mg/kg after 4 h in both MES and pentetrazole-induced (PTZ) seizures. In the strychnine-induced seizures (scSTY), the majority of the compounds showed protection at 30 mg/kg. The compound 2 was active in both MES and PTZ tests. The study has shown that the terminal primary amino group is not necessary for anticonvulsant activity.

Analgesic activity of thioureido derivatives of arylsemicarbazones.

The synthesis of a series of novel arylsemicarbazones derived from 4-aminoacetophenone and their evaluation for analgesic activity are described. The p-chloro-substituted derivatives (12-15) are extremely potent compounds as compared to standard drugs currently being used.

Synthesis and antimicrobial activity of Schiff and Mannich bases of isatin and its derivatives with pyrimidine.

Isatin and its derivatives have been reacted with 4-(4'-chlorophenyl)-6-(4"-methyl phenyl)-2-aminopyrimidine to form Schiff bases and the N-Mannich bases of these compounds were synthesized by reacting them with formaldehyde and several secondary amines. Investigation of antimicrobial activity of the compounds was made by the agar dilution method against 28 pathogenic bacteria, eight pathogenic fungi and anti-HIV activity against replication of HIV-1 (III B) in MT-4 cells. The compounds are significantly active against bacteria and fungi.

Synthesis, antibacterial, antifungal and anti-HIV activities of Schiff and Mannich bases derived from isatin derivatives and N-[4-(4'-chlorophenyl)thiazol-2-yl] thiosemicarbazide.

Isatin, its 5-chloro and 5-bromo derivatives have been reacted with N-[4-(4'-chlorophenyl)thiazol-2-yl] thiosemicarbazide to form Schiff bases and the N-Mannich bases of these compounds were synthesized by reacting them with formaldehyde and three secondary amines. Their chemical structures have been confirmed by means of IR, 1H-NMR data and by elemental analysis. Investigation of antimicrobial activity of compounds was done by agar dilution method against 28 pathogenic bacteria, 8 pathogenic fungi and anti-HIV activity against replication of HIV-1 (IIIB) in MT-4 cells. Among the compounds tested 1-[N,N-dimethylaminomethyl]-5-bromo isatin-3-{1'-[4"-(p-chlorophenyl) thiazol-2"-yl] thio semicarbazone} 10 showed the most favourable antimicrobial activity.

Evaluation of semicarbazones for anticonvulsant and sedative-hypnotic properties.

A series of semicarbazones and thiosemicarbazones were synthesized and evaluated for anti-convulsant activity. Some compounds provided significant protection against Maximal Electroshock (MES) and subcutaneous strychnine induced seizures. Compound 1 was the most active in the series with activity in a dose of 30 mg/kg in the strychnine seizure pattern test and an ED50 of 10 mg/kg in the MES test. Hence it could serve as a prototype molecule for future development. Also compounds with a p-nitrophenyl substitution in place of the amino hydrogen of semicarbazone moiety showed activity in a dose of 30 mg/kg and an ED50 of 83 mg/kg in the MES test.