Dharmarajan Sriram

Betulinic acid and its derivatives: A review on their biological properties

Betulinic acid is a naturally occurring pentacyclic triterpenoid and has been shown to exhibit a variety of biological activities including inhibition of human immunodeficiency virus (HIV), antibacterial, antimalarial, antiinflammatory, anthelmintic and antioxidant properties. This article reports a survey of the literature dealing with betulinic acid related biological properties that has appeared from the 1990s to the beginning of 2003. A broad range of medical and pharmaceutical disciplines are covered, including a brief introduction about discovery, phytochemical aspects, organic synthesis, anti-HIV and cytotoxic mechanisms of action. Various structural modifications carried out and their biological and pharmacokinetic profiles are also incorporated.

Design, Synthesis, and Structure–Activity Correlations of Novel Dibenzo[b,d]furan, Dibenzo[b,d]thiophene, and N-Methylcarbazole Clubbed 1,2,3-Triazoles as Potent Inhibitors of Mycobacterium tuberculosis

A molecular hybridization approach is an emerging structural modification tool to design new molecules with improved pharmacophoric properties. In this study, 1,2,3-triazole-based Mycobacterium tuberculosis inhibitors and synthetic and natural product-based tricyclic (carbazole, dibenzo[b,d]furan, and dibenzo[b,d]thiophene) antimycobacterial agents were integrated in one molecular platform to prepare various novel clubbed 1,2,3-triazole hybrids using click chemistry. Structure-activity correlations and in vitro activity against M. tuberculosis strain H37Rv of new analogues revealed the order: dibenzo[b,d]thiophene > dibenzo[b,d]furan > 9-methyl-9H-carbazole series. Two of the most potent M. tuberculosis inhibitors 13h and 13q with MIC = 0.78 μg/mL (∼1.9 μM) displayed a low cytotoxicity and high selectivity index (50-255) against four different human cancer cell lines. These results together provided the potential importance of molecular hybridization and the development of triazole clubbed dibenzo[b,d]thiophene-based lead candidates to treat mycobacterial infections.

Camptothecin and its analogues: a review on their chemotherapeutic potential

Topoisomerase I (Topo-I) is a major target for anticancer drug discovery and design. As a result, Topo-I inhibitors constitute an important class of the current anticancer drugs. To date, all of the Topo-I inhibitors that have been clinically evaluated are analogues of camptothecin (CPT), an extract of the Chinese tree Camptotheca acuminata. CPT has shown significant antitumor activity to lung, ovarian, breast, pancreas and stomach cancers. In this article the, phytochemical aspect, and various structural modifications are comprehensively reviewed as in rings A, B, C, D and E. Biological activity of camptothecin, other than anticancer, reported till the year 2003 has also been discussed.

Synthesis, structure–activity relationship of novel substituted 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates as potential anti-mycobacterial and anticancer agents

Series of 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylate derivatives 7a-7zb, 8a-8d and 9a-9d were synthesized and screened for their in vitro anti-mycobacterial activity against Mycobacterium tuberculosis H(37)Rv (MTB) and cytotoxicity against three human cancer cell lines including A549, SK-N-SH and HeLa. The results indicate that six compounds are more potent and 7za is most effective anti-mycobacterial derivative compared to the standard drugs Ethambutol and Ciprofloxacin. However, 12 compounds exhibited cytotoxicity against human neuroblastoma cell line; amongst them the compound 7v is most effective compared to the standard drug Doxorubicin. This is the first report assigning in vitro anti-mycobacterial, anticancer and structure-activity relationship for this new class of 4H-chromen-1,2,3,4-tetrahydropyrimidine-5-carboxylates.

A microwave-assisted facile regioselective Fischer indole synthesis and antitubercular evaluation of novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles

A series of novel 2-aryl-3,4-dihydro-2H-thieno[3,2-b]indoles has been synthesised regioselectively in good yields from the reaction of 5-aryldihydro-3(2H)-thiophenones and arylhydrazine hydrochloride. This reaction is found to be assisted by microwaves. The thieno[3,2-b]indoles were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv (MTB) and multi-drug resistant M. tuberculosis (MDR-TB). Among 22 compounds screened, [2-(2,4-dichlorophenyl)-7-fluoro-3,4-dihydro-2H-thieno[3,2-b]indole] (6t) was found to the most active compound with MIC of 0.4 microg/mL against MTB and MDR-TB.

Synthesis and screening for anti-HIV activity of some N-Mannich bases of isatin derivatives

The effect of about 12 new compounds of Mannich bases of isatin against HIV-1 (IIIB) and HIV-2 (ROD) strains in MT 4 cells was studied. The screening method employed was MTT. In initial studies, one compound has shown maximum protection of 16% in subtoxic concentration.

Efficient synthesis and in vitro antitubercular activity of 1,2,3-triazoles as inhibitors of Mycobacterium tuberculosis

Efficient and rapid synthesis of 1,2,3-triazole derivatives has been achieved via Huisgens 1,3-dipolar cycloaddition between alkyl/arylazides and diethyl/dimethyl acetylenedicarboxylate in excellent yields under solvent-free conditions. The environmentally friendly solvent-free protocol overcomes the limitations associated with the prevailing time-consuming solution phase protocols and affords the triazoles just in 1-3 min. In vitro antitubercular activity of these triazoles was screened against Mycobacterium tuberculosis H(37)Rv strain. Four of the compounds showed MIC in the range of 1.56-3.13 μg/mL proving their potential activity.

Design, Synthesis, and Evaluation of Thiol-Activated Sources of Sulfur Dioxide (SO2) as Antimycobacterial Agents

Here, 2,4-dinitrophenylsulfonamides with tunable cysteine-activated SO(2) release profiles with half-lives of SO(2) release varying from 2 to 63 min are reported. N-Benzyl-2,4-dinitrobenzenesulfonamide (6), which is prepared in one step from commercial sources, had a potency (MIC = 0.15 μM) of inhibiting Mycobacterium tuberculosis (Mtb) higher than the clinical agent isoniazid (MIC = 0.37 μM).

Anticonvulsant and neurotoxicity evaluation of some 6-chlorobenzothiazolyl-2-thiosemicarbazones

Ten 6-chlorobenzothiazolyl-2-thiosemicarbazones were synthesised and screened for anticonvulsant and neurotoxic properties. Most of the compounds showed anticonvulsant activity against both maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole screens. Eight compounds have shown good protection in the rat p.o. MES test at 30 mg kg(-1). Compound 1 [4-(6-chlorobenzothiazol-2-yl)-1-(3-isatinimino)thiosemicarbazone] emerged as the most promising one with an ED(50) of 17.86 and 6.07 mg kg(-1) in mice i.p. and rat p.o., respectively. Compound 1 showed a weak ability to block the expression of fully kindled seizures.

Antimycobacterial activity of spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrids obtained by a three-component regio- and stereoselective 1,3-dipolar cycloaddition

Spirooxindolo-pyrrolidine, pyrrolizine and pyrrolothiazole hybrid compounds were obtained in excellent yields from the regio- and stereoselective reaction between β-nitrostyrenes and non-stabilized azomethine ylides, generated in situ from isatin and phenylglycine/proline/thiaproline. These compounds were evaluated for their in vitro activity against Mycobacterium tuberculosisH37Rv (MTB). Eleven compounds were more active than pyrazinamide and one of them, namely 6′-(3-nitrophenyl)-7′-nitro-3′,6′,7′,7a′-tetrahydro-1′H-spiro-[indoline-3,5′-pyrrolo-[1,2-c]thiazol]-2-one, displayed a 7.6 μM MIC value, which represents a potency similar to that of the first-line anti-TB drug ethambutol and 6.7 times higher than that of pyrazinamide.