FATA’s Merger with Khyber Pakhtunkhwa: An Historical Analysis

Nation-building is an evolutionary socio-political process. It not only provides security, dignity and ownership to a community, but also ensures democratic participation of people within the state to claim rights and perform duties. It enables a state to defend its sovereignty, achieve economic goals, and protect national interests at regional and global levels. Since 9/11 incident, terrorism has become a global challenge. To counter this menace Pakistan also aligned and provided land routes to foreign forces to get access to a landlocked Afghanistan. Across the Pak-Afghan border, through the tribal belt known as FATA, terrorism has spilled over Pakistan. The exclusive status of the Federally Administered Tribal Areas (FATA), in the past seventy years of Pakistan’s history, had deprived fundamental rights to the people of FATA. These tribal areas were governed by a separate law known as Frontier Crimes Regulations (FCR) made by the British in 1901. This law has proved as the main obstacle in bringing FATA in to the mainstream of Pakistan. After examining the historical and geographical aspects of FATA, the article shows how FATA remained outside the nation-building process in Pakistan. In this connection it seeks to see the position of FATA in the constitutions of Pakistan, including state initiatives to own this western belt and obstacles faced in merging FATA with Khyber Pakhtunkhwa (KPK). It narrates the events that led to the merger of FATA with the KPK and high lights future challenges as well. It recommends that FATA’s merger would help establish a strong line of defence against terrorism. ______

Synthesis, Structural Analysis and Pharmaceutical Screening of S-Substituted Derivatives of 1, 3, 4- Oxadiazole-2-Thiol and 1, 2, 4-Triazole-3-Thiol Having 4-Methylphenyl Sulfonyl Piperidine

Heterocyclic compounds are being focused by the organic and synthetic chemists because of their wide range of biological and other desirable applications. Five membered heterocyclic moieties, oxadiazoles and triazoles are among the most considered five membered heterocyclic cores for the production of new potential synthetic drugs. The most studied isomers of these heterocyclic moieties are 1,3,4- oxadiazole and 1,2,4-triazole owing to their potent pharmaceutical activities. Keeping in view the importance of 1,3,4-oxadiazole and 1,2,4-triazole heterocycles, a number of different S-substituted derivatives of 1,3,4-oxadiazole-2- thiol and 1,2,4-triazole-3-thiol having 4-methylphenyl sulfonyl piperidine have been synthesized and screened for the evaluation of pharmaceutical potential including antibacterial and enzyme inhibition. The antibacterial potential was evaluated against certain strains of Gram positive and Gram negative bacteria. Enzyme inhibition potential was evaluated against lipoxygenase (LOX) enzyme responsible for inflammation. The list of ninety seven (97) synthesized derivatives includes fifty seven (57) derivatives of 1,3,4-oxadiazole (7a-w, 11a-v, 14a-l) and forty (40) derivatives of 1,2,4-triazole (18a-t, 19a-t). The multistep protocols for all of these compounds have been described in five (5) schemes. The compound ethyl 1-tosylpiperidine-4- carboxylate (3) was synthesized by the reaction of 4-methylphenyl sulfonyl chloride (1) and ethyl isonipecotate (2) using 10% aqueous solution of Na2CO3 as reaction medium. The compound 3 was further converted into corresponding carbohydrazide (4) by hydrated hydrazine in methanol under reflux. 5-(1-(4-Methylphenylsulfonyl) piperidin-4-yl)-1,3,4-oxadiazole-2-thiol (5) was synthesized from compound (4) by reflux in ethanol in the presence of carbon disulfide (CS2) in basic medium. Twenty three (23) alkyl/aralkyl derivatives of 1,3,4-oxadiazole-2-thiol having 4-methylphenyl sulfonyl piperidine were synthesized (7a-w, Scheme-1) by the reaction of 5 and 6a-w. N-Substituted alkyl/aralkyl amines (8a-v) were made to react with 2-bromoacetyl bromide (9) to synthesize 2-bromo-N-substituted acetamides (10a-v) as electrophiles. The synthesized 1,3,4-oxadiazole-2-thiol (5) was further derivatized by these electrophiles (10a-v) to synthesize twenty two (22) N-substituted acetamide derivatives (11a-v, Scheme-2). N-substituted alkyl/aralkyl amines (8a-g,j,m,n,p,v) were made to react with 3-bromopropionyl bromide (12) to synthesize 3-bromo-Nsubstituted propanamides (13a-l). Again the synthesized 1,3,4-oxadiazole-2-thiol (5) was derivatized with these electrophiles (13a-l) to synthesize twelve (12) Nsubstituted propanamides (14a-l, Scheme-3). Compound 4 was refluxed with isothiocyanatobenzene (15) in methanol to produce N-phenyl-2-(1-4- methylphenylsulfonylpiperidine-4-carbonyl)hydrazine carbothioamide (16). The compound 16 was cyclized to 4-phenyl-5-(1-tosylpiperidin-4-yl)-4H-1,2,4-triazole-3- thiol (17) using 10% aqueous solution of NaOH as reaction medium. The synthesized 1,2,4-triazole-3-thiol (17) was used to produce twenty (20) derivatives (18a-t, Scheme-4) on reaction with different alkyl/aralkyl halides (6a-t) in a polar aprotic medium. The synthesized electrophiles, 2-bromo-N-substituted acetamides (10a-s,u), were stirred with the synthesized 1,2,4-triazole-3-thiol (17) to yield twenty (20) different N-substituted acetamide derivatives (19a-t, Scheme-5). Structures of all the synthesized compounds were confirmed using Infra Red (IR) spectroscopy, Proton Nuclear Magnetic Resonance (1H-NMR) spectroscopy, Carbon-13 Nuclear Magnetic Resonance (13C-NMR) spectroscopy and Electron Impact Mass Spectrometry (EIMS) data. Ring formation of 1,3,4-oxadiazole and 1,2,4-triazole was confirmed through 13C-NMR. The determined physical data of all the target compounds includes physical state, color, yield, melting point, molecular formula and molecular mass which are given in results section (Chapter-4). The synthesized compounds were screened for antimicrobial potential against Gram-positive and Gram-negative bacterial strains. The results of antibacterial potential are given as % inhibition and minimum inhibitory concentration (MIC) values. Among the alkyl/aralkyl S-substituted derivatives (7a-w) of 5-(1-(4-methyl phenylsulfonyl)piperidin-4-yl)-1,3,4-oxadiazole-2-thiol (5), compounds 7a, 7c and 7m remained the most active against P. aeruginosa, S. aureus and E. coli respectively and compound 7o against both of S. typhi and B. subtilis. All of these (7a, 7c, 7m, 7o) showed antibacterial activity comparable to that of the reference standard, Ciprofloxacin. Among the acetamide derivatives (11a-v) of 5-(1-(4- methylphenylsulfonyl)piperidin-4-yl)-1,3,4-oxadiazole-2-thiol (5), compounds 11c and 11s exhibited proficient activity against S. typhi and P. aeruginosa, respectively and compound 11d against three strains including E. coli, S. aureus and B. subtilis. These three most active compounds also showed activity comparable to that of Ciprofloxacin. Among the propanamide derivatives (14a-l) of 5-(1-(4- methylphenylsulfonyl) piperidin-4-yl)-1,3,4-oxadiazole-2-thiol (5), compounds 14b showed efficient activity against B. subtilis and P. aeruginosa; compounds 14d, 14f and 14g against E. coli, S. aureus and S. typhi, respectively and also comparable to that of Ciprofloxacin. Among the alkyl/aralkyl S-substituted derivatives (18a-t) of 4- phenyl-5-(1-tosylpiperidin-4-yl)-4H-1,2,4-triazole-3-thiol (17), compound 18a executed better potential against four bacterial strains S. typhi, E. coli, B. subtilis and P. aeruginosa and 18c against S. aureus. The observed potential was also comparable to the reference. Among the acetamide derivatives (19a-t) of 4-phenyl-5-(1- tosylpiperidin-4-yl)-4H-1,2,4-triazole-3-thiol (17), the most active compounds were 19a against S. typhi, 19d against E. coli, 19o against B. subtilis and 19h against P. aeruginosa with MIC value close to that of the reference. Lipoxygenase (LOX) inhibition potential was evaluated with reference to Baicalein, the reference standard. The enzyme inhibition activity results are given as % inhibition and concentration for 50% inhibition (IC50) values. Among the alkyl/aralkyl S-substituted derivatives (7a-w) of 5-(1-(4-methyl phenylsulfonyl)piperidin-4-yl)-1,3,4-oxadiazole-2-thiol (5), three the most potent inhibitors of LOX were 7a, 7b and 7c with reference of the standard, Baicalein. Among the acetamide derivatives (11a-v) of 5-(1-(4-methylphenylsulfonyl)piperidin- 4-yl)-1,3,4-oxadiazole-2-thiol (5), three the most potent inhibitors of LOX were 11m, 11n and 11t. Among the propionamide derivatives (14a-l) of 5-(1-(4- methylphenylsulfonyl)piperidin-4-yl)-1,3,4-oxadiazole-2-thiol (5), two the most potent inhibitors of LOX were 14e and 14f. Among the alkyl/aralkyl S-substituted derivatives (18a-t) of 4-phenyl-5-(1-tosylpiperidin-4-yl)-4H-1,2,4-triazole-3-thiol (17), three the most potent inhibitors of LOX were 18a, 18b and 18c. Among the acetamide derivatives (19a-t) of 4-phenyl-5-(1-tosylpiperidin-4-yl)-4H-1,2,4-triazole- 3-thiol (17), three the most potent inhibitors of LOX were 19g, 19n and 19r. The activity of all these compounds was compared to the reference, Baicalein. Furthermore, the molecular docking studies have been discussed in Chapter-4 for LOX inhibition activity. Overall a number of compounds exhibited moderate LOX inhibition potential as compared to reference standard, Baicalein. Many compounds showed excellent antibacterial potential. The most active compounds against bacterial strains might be suitable as new drug candidates in pharmaceutical industries to develop potent drugs for the different bacterial infection. The most active LOX inhibitors might be further forwarded as new drug candidates for inflammatory diseases.