V. Raja Solomon

3‐(3‐Ethylphenyl)‐2‐substituted hydrazino‐3H‐quinazolin‐4‐one Derivatives: New Class of Analgesic and Anti‐Inflammatory Agents

A new series of 3‐(3‐ethylphenyl)‐2‐substituted hydrazino‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 2‐hydrazino‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one with a variety of aldehydes and ketones. The title compounds were investigated for analgesic, anti‐inflammatory and ulcerogenic index behavior. The compound 2‐(N′‐3‐pentylidene‐hydrazino)‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one (AS2) emerged as the most active compound in exhibiting analgesic activity and the compound 2‐(N′‐2‐pentylidene‐hydrazino)‐3‐(3‐ethylphenyl)‐3H‐quinazolin‐4‐one (AS3) emerged as the most active compound in exhibiting anti‐inflammatory activity; and these compounds are moderately potent when compared with the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared with aspirin.

Topological descriptors in modelling antimalarial activity: N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl)piperazine as prototype

The QSAR of antimalarial activity of two distinct series of N1-(7-chloro-4-quinolyl)-1,4-bis(3-aminopropyl) piperazine analogues are investigated with DRAGON descriptors in order to rationalize their activity. Of these two series of compounds, one has amide characteristics and the other has amine characteristics. Both the analogues have shared radial centric information (ICR) as common modelling descriptor with increased centricity in the molecules as preferred feature for antimalarial activity. Apart from this, the models of amide analogues suggested in favor of distantly placed nitrogen(s) and unfavorable nature of carbonyl moieties adjacent to nitrogen in the varying portion of the molecule for the activity. Moreover, for these analogues, the regression models have preferred the lone pair electrons on heteroatoms (N and O) for purposes other than H-bonds for better activity. In case of amine analogues, the models suggested in favor of compact structural moieties in the varying parts of the molecule for improved activity. Also, for these analogues, hydrophobicity of the compound is an important factor for influencing activity. The variations in the models of amide and amine analogues are attributed to the characteristic functional differences of these analogues.

Design and synthesis of 3-(4-Ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones as a novel class of analgesic and anti-inflammatory agents

A new series of 3-(4-ethylphenyl)-2-substituted amino-3H-quinazolin-4-ones were synthesized by reacting the amino group of 2-hydrazino-3-(4-ethylphenyl)-3H-quinazolin-4-one from 4-ethyl aniline with a variety of aldehydes and ketones. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic index activities. The compound 2-(N′-3-pentylidene-hydrazino)-3-(4-ethylphenyl)-3H-quinazolin-4-one (AS2) emerged as the most active compound of the series and was moderately more potent than the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic potential when compared to aspirin.

Design and Synthesis of 2-Methylthio-3-substituted-5,6-dimethylthieno [2,3-d] pyrimidin-4(3H)-ones as Analgesic, Anti-Inflammatory and Antibacterial Agents

Pain and inflammation are simultaneous responses in bacterial infections. In current clinical practice, two groups of agents like antibacterial and non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed simultaneously. Regrettably, none of the drug possesses these activities in a single component. Exploiting the bioisosterism concept, we have documented that 2-phenyl-3-substituted quinazolines, 2,3-disubstituted quinazolines, 2-methyl-3-substituted quinazolin-4-(3H)-ones and 2-methylthio-3-substituted quinazolin-4-(3H)-ones exhibited good analgesic and anti-inflammatory activities. The present work is an extension of our ongoing efforts towards the development and identification of lead molecules by bioisostere concept, for which we designed some of 2-methylthio-3-substituted-5,6-dimethylthieno[2,3-d] pyrimidin-4(3H)-ones. The title compounds were investigated for analgesic, anti-inflammatory and antibacterial activities. While the test compounds exhibited significant activity, the compounds (6-9) showed more potent analgesic activity, and the compounds (8, 9) showed anti-inflammatory activity comparable to the reference standard diclofenac.

Synthesis and Antimalarial Activity of Novel Side Chain Modified Antimalarial Agents Derived from 4-Aminoquinoline

Malaria is one of the foremost public health problems in developing countries affecting nearly 40% of the global population. Apart from this, the past two decades emergence of drug resistance has severely limited the choice of available antimalarial drugs. Furthermore, the general trend emerging from the SAR-studies is that chloroquine resistance does not involve any change to the target of this class of drugs but involves compound specific efflux mechanism. Based on this premise a number of groups have developed short chain analogues of 4-aminoquinoline, which are active against CQ-resistant strains of P. falciparum in in vitro studies. However, these derivatives undergo biotransformation (de-alklyation) significantly affecting lipid solubility of the drug. In view of this background information, we thought that it would be interesting to study the effect of additional lipophilicity and cationic charge at the lateral side chain of 4-aminoquinoline. This prompted us to explore the cationic amino acid conjugates namely, lysine and ornithine of 4-aminoquinoline with a view to achieve improved antimalarial activity and to the best of our knowledge such amino acid conjugates have not been hitherto reported in the literature in the case of 4-aminoquinolines. In the present study, a new series of side-chain modified 4-aminoquinolines have been synthesized and found active against both susceptible and multidrug resistant strains of P. falciparum in vitro and P. yoelli in vivo. The seminal finding of the present study is that a new series of compounds having significantly more activity against CQ resistant parasites has been identified.

Synthesis of novel 3-butyl-2-substituted amino-3H-quinazolin-4-ones as analgesic and anti-inflammatory agents.

A variety of novel 3‐butyl‐2‐substituted amino‐3H‐quinazolin‐4‐ones were synthesized by reacting the amino group of 3‐butyl‐2‐hydrazino‐3H‐quinazolin‐4‐one with various aldehydes and ketones. The title compounds were investigated for analgesic, anti‐inflammatory and ulcerogenic index activities. The compound 3‐butyl‐2‐(1‐methylbutylidene‐hydrazino)‐3H‐quinazolin‐4‐one (AS3) emerged as the most active analgesic agent. Compound 3‐butyl‐2‐(1‐ethylpropylidene‐hydrazino)‐3H‐quinazolin‐4‐one (AS2) emerged as the most active anti‐inflammatory agent and is moderately more potent when compared to the reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic potential when compared to aspirin.

Design, synthesis of 4-aminoquinoline-derived thiazolidines and their antimalarial activity and heme polymerization inhibition studies.

The present study describes the synthesis of a series of new 4-aminoquinoline-derived thiazolidines and evaluation of their antimalarial activity against a NF-54 strain of Plasmodium falciparum in vitro and N-67 strain of Plasmodium yoelii in vivo. Among the series, two compounds, 2-(4-chloro-phenyl)-thiazolidine-4-carboxylic acid [2-(7-chloro-quinolin-4-ylamino)-ethyl]-amide hydrochloride (14) and 2-(2,6-dichloro-phenyl)-thiazolidine-4-carboxylic acid [2-(7-chloro-quinolin-4-ylamino)-ethyl]-amide hydrochloride (22) exhibited significant suppression of parasitaemia in the in vivo assay. All the analogues were found to form strong complex with haematin and inhibited the β-haematin formation in vitro. These results suggest that these compounds act on heme polymerization target.

4‐Cyclohexyl‐1‐substituted‐4H‐[1,2,4]triazolo [4,3‐a] quinazolin‐5‐ones: Novel Class of H1‐antihistaminic Agents

A series of novel 1‐substituted‐4‐cyclohexyl‐4H‐[1,2,4]triazolo [4,3‐a] quinazolin‐5‐ones were synthesized by the cyclization of 3‐cyclohexyl‐2‐hydrazino‐3H‐quinazolin‐4‐one with various one carbon donors. When tested for their in vivo H1‐antihistaminic activity on guinea‐pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly. The compound 4‐cyclohexyl‐1‐methyl‐4H‐[1,2,4]triazolo[4,3‐a] quinazolin‐5‐one (II) emerged as the most active compound of the series and it is more potent (72.96% protection) when compared to the reference standard chlorpheniramine maleate (71.00% protection). The compound II shows negligible sedation (9%) when compared to chlorpheniramine maleate (30%). Hence, it could serve as prototype molecule for further development as a new class of H1‐antihistamines.

Design and synthesis of 3-[(7-chloro-1-oxidoquinolin-4-ylamino)alkyl]-1,3-thiazolidin-4-ones as antimalarial agents

A new series of quinoline analogs have been synthesized and found active against P. falciparum in vitro and P. yoelli in vivo. Compounds 8, 10 and 11 exhibited superior in vitro activity compared to chloroquine. Selected compounds 8, 10 and 11 exhibited significant suppression of parasitaemia in vivo assay. These analogs form a complex with hematin and inhibit the β-hematin formation, suggesting that this class of compounds act on a heme polymerization target. Further this study confirms that quinoline ring nitrogen is essential for both transportation of the molecule across the membrane as well as for tight binding to hematin.

Synthesis and Pharmacological Investigation of 5-Substituted-3-methylsulfanyl-1H-pyrazole-4-carboxylic Acid Ethyl Esters as New Analgesic and Anti-inflammatory Agents

PURPOSE To synthesize a new series of 5-substituted-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl esters for their analgesic and anti-inflammatory activity. METHODS The title compound synthesized by reacting the amino group of 5-amino-3-methylsulfanyl-1H-pyrazole-4-carboxylic acid ethyl ester with acid anhydrides, acid chlorides and phenyl dithiocarbamates. The synthesized compounds were characterized by IR, 1H-NMR and mass spectral data; the purity of the compounds was determined by elemental analysis. The title compounds were investigated for analgesic, anti-inflammatory and ulcerogenic behaviour. RESULTS The compound 5-benzoylamino-3-methylsulfanyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester (4c) emerged as the most active compound and exhibiting imperative analgesic and anti-inflammatory activities. Interestingly the test compounds showed only mild ulcerogenic potential when compared to indomethacin. CONCLUSION The compound (4c) could serve as a lead molecule for further modification to obtain a clinically useful novel class of analgesic and anti-inflammatory agents.